|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 amastigotes
|
Leishmania donovani
|
0.12
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Limonoid orthoacetates and antiprotozoal compounds from the roots of Pseudocedrela kotschyi.
Year : 2007
Volume : 70
Issue : 1
First Page : 9
Last Page : 13
Authors : Hay AE, Ioset JR, Ahua KM, Diallo D, Brun R, Hostettmann K.
Abstract : The dicholoromethane extract of Pseudocedrela kotschyi root demonstrated marked antileishmanial properties in preliminary screening of extracts from 21 species commonly used in Malian traditional medicine. Phytochemical investigation of the active extract yielded three novel phragmalin-type limonoid orthoacetates (1-3), named kotschyins A-C, and the known compounds 7-deacetylgedunin (4) and 7-deacetyl-7-oxogedunin (5). The structures of 1-3 were elucidated by analytical methods including 1D- and 2D-NMR spectroscopy together with MS spectroscopy. The relative configurations of 1-3 were assigned on the basis of NOE correlations. The extract and the isolated compounds were tested for their antiprotozoal activities against Leishmania donovani, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Plasmodium falciparum as well as for cytotoxicity toward the L-6 cell line. The crude extract and the two gedunin derivatives exhibited good in vitro activity against all of these parasites.
|
Growth inhibition of wild type Leishmania donovani LV9 at 10 uM after 48 hrs
|
Leishmania donovani
|
66.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Miltefosine affects lipid metabolism in Leishmania donovani promastigotes.
Year : 2007
Volume : 51
Issue : 4
First Page : 1425
Last Page : 1430
Authors : Rakotomanga M, Blanc S, Gaudin K, Chaminade P, Loiseau PM.
Abstract : Miltefosine (hexadecylphosphocholine [HePC]) is the first orally active antileishmanial drug. Transient HePC treatment of Leishmania donovani promastigotes at 10 microM significantly reduced the phosphatidylcholine content and enhanced the phosphatidylethanolamine (PE) content in parasite membranes, suggesting a partial inactivation of PE-N-methyltransferase. Phospholipase D activity did not seem to be affected by HePC. In addition, the enhancement of the lysophosphatidylcholine content could be ascribed to phospholipase A2 activation. Moreover, transient HePC treatment had no effect on the fatty acid alkyl chain length or the fatty acid unsaturation rate. Concerning sterols, we found a strong reduction of the C24 alkylated sterol content, and the enhancement of the cholesterol content could be the result of the HePC condensation effect with sterols. Because some of the effects observed after transient HePC treatment were different from those previously observed in HePC-resistant parasites, it could be hypothesized that continuous in vitro drug pressure induces the mechanisms of regulation in Leishmania lipid metabolism.
|
Inhibition of Leishmania donovani cytochrome c reductase at 40 uM
|
Leishmania donovani
|
5.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes.
Year : 2007
Volume : 51
Issue : 4
First Page : 1327
Last Page : 1332
Authors : Luque-Ortega JR, Rivas L.
Abstract : Miltefosine (hexadecylphosphocholine [HePC]) is currently on trial as a first-choice, orally active drug for the treatment of visceral leishmaniasis when resistance to organic pentavalent antimonials becomes epidemic. However, data on the targets involved in its leishmanicidal mechanism have, until now, been only fragmentary. We have carried out a systematic study of the alterations induced on the bioenergetic metabolism of Leishmania donovani promastigotes by HePC. Overnight incubation with HePC caused a significant decline in the intracellular ATP levels of the parasites, together with a reduction in the oxygen consumption rate and mitochondrial depolarization, while the integrity of the plasma membrane remained undamaged. In a further step, the effects of HePC on the respiratory chain were addressed in digitonized parasites. The inhibition of the oxygen consumption rate caused by HePC was not reverted either with the uncoupling agent carbonyl cyanide p-trifluoromethoxyphenylhydrazone or with tetramethyl-p-phenylenediamine plus ascorbate, which feeds the electron transport chain at the level of cytochrome c. These results suggest that cytochrome c oxidase is a likely target in the complex leishmanicidal mechanism of HePC. This was further confirmed from the finding that this enzyme was specifically inhibited in a dose-dependent manner by HePC, but not the cytochrome c reductase, ruling out an unspecific effect of HePC on the respiratory chain.
|
Inhibition of Leishmania donovani HOM/IN/80/DD8 in hamster at 12.5 mg/kg, po after 7 days
|
Leishmania donovani
|
94.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Chemotherapy of leishmaniasis Part VI: synthesis and bioevaluation of some novel terpenyl S,N- and N,N-acetals.
Year : 2007
Volume : 42
Issue : 4
First Page : 511
Last Page : 516
Authors : Suryawanshi SN, Pandey S, Rashmirathi, Bhatt BA, Gupta S.
Abstract : Some novel terpene based oxoketene S,N-acetals 2(a-g) and N,N-acetals 3(a-c) have been synthesized from oxoketene dithioacetal 1. The compounds were screened for their in vivo antileishmanial activity. Some of the compounds showed 50-70% inhibition in the hamster model.
|
Inhibition of Leishmania donovani HOM/IN/80/DD8 in hamster at 12.5 mg/kg, po after 28 days
|
Leishmania donovani
|
69.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Chemotherapy of leishmaniasis Part VI: synthesis and bioevaluation of some novel terpenyl S,N- and N,N-acetals.
Year : 2007
Volume : 42
Issue : 4
First Page : 511
Last Page : 516
Authors : Suryawanshi SN, Pandey S, Rashmirathi, Bhatt BA, Gupta S.
Abstract : Some novel terpene based oxoketene S,N-acetals 2(a-g) and N,N-acetals 3(a-c) have been synthesized from oxoketene dithioacetal 1. The compounds were screened for their in vivo antileishmanial activity. Some of the compounds showed 50-70% inhibition in the hamster model.
|
Antiamastigote activity against Leishmania donovani MHOM IN/Dd8 in mouse J-774A.1 cells by luciferase reporter gene assay after 72 hrs
|
Leishmania donovani
|
33.9
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Chemotherapy of leishmaniasis. Part V: Synthesis and in vitro bioevaluation of novel pyridinone derivatives.
Year : 2007
Volume : 42
Issue : 5
First Page : 669
Last Page : 674
Authors : Pandey S, Suryawanshi SN, Nishi, Goyal N, Gupta S.
Abstract : Some novel 2-substituted pyridinone derivatives exemplified by 3 and 4 have been synthesized from 2-methyl-gamma-pyrone and screened towards in vitro antileishmanial activity profile. Some of the compounds such as 3a, 3b, 4i and 4j displayed good antileishmanial profile.
|
Antiparasitic activity against Leishmania donovani MHOM-ET-67/L82 in amastigotes stage
|
Leishmania donovani
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of antiparasitic activities of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives.
Year : 2007
Volume : 50
Issue : 23
First Page : 5833
Last Page : 5839
Authors : Kuettel S, Zambon A, Kaiser M, Brun R, Scapozza L, Perozzo R.
Abstract : A series of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives, prepared by two synthetic routes, were in vitro assayed against three Trypanosoma strains, Leishmania donovani, and Plasmodium falciparum K1. Seven out of 17 compounds showed moderate to very good activity against blood stage T. b. rhodesiense, with 10 and 17 exhibiting highest potency (IC50 of 1.0 and 1.1 microM, respectively). Interestingly, the beta-diketone precursors 1-3 had good antitrypanosomal activity toward the insect stage, with IC50 values of 1.0-3.4 microM. Among different compounds with moderate activity against T. cruzi, compound 17 showed the lowest IC50 value of 9.5 microM; thus, the series seemed to act selectively toward the different Trypanosoma parasites. Eight compounds were moderately active against L. donovani, with 2, 3, and 12 being the most promising ones (IC50 values of 2.3-5.2 microM), whereas compound 14 was the only derivative with good activity against P. falciparum (IC50 of 3.7 microM).
|
Antileishmanial activity against Leishmania donovani after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
0.12
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli.
Year : 2007
Volume : 15
Issue : 21
First Page : 6834
Last Page : 6845
Authors : Tasdemir D, Topaloglu B, Perozzo R, Brun R, O'Neill R, Carballeira NM, Zhang X, Tonge PJ, Linden A, Rüedi P.
Abstract : The type II fatty acid pathway (FAS-II) is a validated target for antimicrobial drug discovery. An activity-guided isolation procedure based on Plasmodium falciparum enoyl-ACP reductase (PfFabI) enzyme inhibition assay on the n-hexane-, the CHCl(3-) and the aq MeOH extracts of the Turkish marine sponge Agelas oroides yielded six pure metabolites [24-ethyl-cholest-5alpha-7-en-3-beta-ol (1), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (2), 4,5-dibromopyrrole-2-carboxylic acid (3), (E)-oroidin (4), 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (5), taurine (6)] and some minor, complex fatty acid mixtures (FAMA-FAMG). FAMA, consisting of a 1:2 mixture of (5Z,9Z)-5,9-tricosadienoic (7) and (5Z,9Z)-5,9-tetracosadienoic (8) acids, and FAMB composed of 8, (5Z,9Z)-5,9-pentacosadienoic (9) and (5Z,9Z)-5,9-hexacosadienoic (10) acids in approximately 3:3:2 ratio were the most active PfFabI inhibitory principles of the hexane extract (IC(50) values 0.35 microg/ml). (E)-Oroidin isolated as free base (4a) was identified as the active component of the CHCl(3) extract. Compound 4a was a more potent PfFabI inhibitor (IC(50) 0.30 microg/ml=0.77 microM) than the (E)-oroidin TFA salt (4b), the active and major component of the aq MeOH extract (IC(50) 5.0 microg/ml). Enzyme kinetic studies showed 4a to be an uncompetitive PfFabI inhibitor (K(i): 0.4+/-0.2 and 0.8+/-0.2 microM with respect to substrate and cofactor). In addition, FAMA and FAMD (mainly consisting of methyl-branched fatty acids) inhibited FabI of Mycobacterium tuberculosis (MtFabI, IC(50)s 9.4 and 8.2 microg/ml, respectively) and Escherichia coli (EcFabI, IC(50)s 0.5 and 0.07 microg/ml, respectively). The majority of the compounds exhibited in vitro antiplasmodial, as well as trypanocidal and leishmanicidal activities without cytotoxicity towards mammalian cells. This study represents the first marine metabolites that inhibit FabI, a clinically relevant enzyme target from the FAS-II pathway of several pathogenic microorganisms.
|
Antileishmanial activity against Leishmania donovani axenic amastigotes
|
Leishmania donovani
|
440.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antiprotozoal polyacetylenes from the Tanzanian medicinal plant Cussonia zimmermannii.
Year : 2007
Volume : 70
Issue : 10
First Page : 1565
Last Page : 1569
Authors : Senn M, Gunzenhauser S, Brun R, Séquin U.
Abstract : From the petroleum ether extract of the root bark of Cussonia zimmermannii four polyacetylenes, 1- 4, were isolated, three of which ( 1- 3) were active against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Plasmodium falciparum, and Leishmania donovani.
|
Antileishmanial activity against Leishmania donovani in mouse macrophages
|
Leishmania donovani
|
710.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antiprotozoal polyacetylenes from the Tanzanian medicinal plant Cussonia zimmermannii.
Year : 2007
Volume : 70
Issue : 10
First Page : 1565
Last Page : 1569
Authors : Senn M, Gunzenhauser S, Brun R, Séquin U.
Abstract : From the petroleum ether extract of the root bark of Cussonia zimmermannii four polyacetylenes, 1- 4, were isolated, three of which ( 1- 3) were active against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Plasmodium falciparum, and Leishmania donovani.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 amastigotes by microplate assay
|
Leishmania donovani
|
310.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity.
Year : 2008
Volume : 18
Issue : 7
First Page : 2272
Last Page : 2276
Authors : Bolognesi ML, Lizzi F, Perozzo R, Brun R, Cavalli A.
Abstract : Taking advantage of the structural features of natural products showing anti-trypanosomatid activity, we designed and synthesized a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives. The library was obtained following a parallel approach and using readily available synthons. All the derivatives showed inhibitory activity toward either Trypanosoma or Leishmania species, with 8, 10, and 16 being the most active compounds against Trypanosoma brucei rhodesiense, Leishmania donovani, and Trypanosoma cruzi cells (IC(50)=50nM, IC(50)=0.28microM, and IC(50)=1.26microM, respectively).
|
Antileishmanial activity against Leishmania donovani
|
Leishmania donovani
|
0.305
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Ancistrobenomine a, the first naphthylisoquinoline oxygenated at Me-3, and related 5,1'-coupled alkaloids, from the "new" plant species ancistrocladusbenomensis.
Year : 2004
Volume : 67
Issue : 12
First Page : 2058
Last Page : 2062
Authors : Bringmann G, Dreyer M, Rischer H, Wolf K, Hadi HA, Brun R, Meimberg H, Heubl G.
Abstract : Three new 5,1'-coupled naphthylisoquinoline alkaloids, ancistrobenomine A (1), 6-O-demethylancistrobenomine A (2), and 5'-O-demethylancistrocline (3), have been isolated from the stem bark of a botanically as yet undescribed highland liana Ancistrocladus sp., proposed to be named "A. benomensis" according to the region in Peninsular Malaysia where it has been discovered on the mountain of Gunung Benom. Two of the compounds possess an unprecedented structure with a novel hydroxymethylene group at C-3 of the fully dehydrogenated isoquinoline moiety. The structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. As typical of the so-called Ancistrocladaceae type, all of the compounds isolated bear an oxygen at C-6. Biological activities of these alkaloids against different protozoic pathogens are described.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 amastigotes by axenic assay
|
Leishmania donovani
|
0.2
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160).
Year : 2007
Volume : 51
Issue : 8
First Page : 2991
Last Page : 2993
Authors : Kaiser M, Wittlin S, Nehrbass-Stuedli A, Dong Y, Wang X, Hemphill A, Matile H, Brun R, Vennerstrom JL.
Abstract : Using nonperoxidic analogs of artemisinin and OZ277 (RBx11160), the strong in vitro antiplasmodial activities of the latter two compounds were shown to be peroxide bond dependent. In contrast, the weak activities of artemisinin and OZ277 against six other protozoan parasites were peroxide bond independent. These data support the iron-dependent artemisinin alkylation hypothesis.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82
|
Leishmania donovani
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : In pursuit of natural product leads: synthesis and biological evaluation of 2-[3-hydroxy-2-[(3-hydroxypyridine-2-carbonyl)amino]phenyl]benzoxazole-4-carboxylic acid (A-33853) and its analogues: discovery of N-(2-benzoxazol-2-ylphenyl)benzamides as novel antileishmanial chemotypes.
Year : 2008
Volume : 51
Issue : 23
First Page : 7344
Last Page : 7347
Authors : Tipparaju SK, Joyasawal S, Pieroni M, Kaiser M, Brun R, Kozikowski AP.
Abstract : The first synthesis and biological evaluation of antibiotic 31 (A-33853) and its analogues are reported. Initial screening for inhibition of L. donovani, T. b. rhodesiense, T. cruzi, and P. falciparum cultures followed by determination of IC(50) in L. donovani and cytotoxicity on L6 cells revealed 31 to be 3-fold more active than miltefosine, a known antileishmanial drug. Compounds 14, 15, and 25 selectively inhibited L. donovani at nanomolar concentrations and showed much lower cytotoxicity.
|
Antileishmanial activity against Leishmania donovani amastigote infected in mouse J774A1 cells expressing green fluorescence protein by flow cytometry
|
Leishmania donovani
|
5.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Peganine hydrochloride dihydrate an orally active antileishmanial agent.
Year : 2009
Volume : 19
Issue : 9
First Page : 2585
Last Page : 2586
Authors : Khaliq T, Misra P, Gupta S, Reddy KP, Kant R, Maulik PR, Dube A, Narender T.
Abstract : Protozoic infections caused by genus Leishmania pose an enormous public health threat in developing countries, compounded by the toxicity and resistance to current therapies. Under the aegis of our ongoing program on drug discovery and development on antileishmanial agents from plants, we carried out bioassay guided fractionation on Peganum harmala seeds which resulted in the isolation of 1 as an antileishmanial agent. 2D-NMR spectral data and single crystal X-ray crystallography data indicated 1 as peganine hydrochloride in dihydrated form. The compound 1 exhibited in-vitro activity against both extracellular promastigotes as well as intracellular amastigotes residing within murine macrophages in Leishmania donovani. Furthermore, 1 also exhibited in-vivo activity, 79.6 (+/-8.07)% against established VL in hamsters at a dose of 100mg/kgb.wt.
|
Antileishmanial activity against Leishmania donovani
|
Leishmania donovani
|
0.305
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Ancistrotanzanine A, the first 5,3'-coupled naphthylisoquinoline alkaloid, and two further, 5,8'-linked related compounds from the newly described species Ancistrocladus tanzaniensis.
Year : 2003
Volume : 66
Issue : 9
First Page : 1159
Last Page : 1165
Authors : Bringmann G, Dreyer M, Faber JH, Dalsgaard PW, Staerk D, Jaroszewski JW, Ndangalasi H, Mbago F, Brun R, Reichert M, Maksimenka K, Christensen SB.
Abstract : The first phytochemical investigation of the recently discovered East African liana Ancistrocladus tanzaniensis is described, resulting in the isolation and structural elucidation of two new naphthylisoquinoline alkaloids, ancistrotanzanines A (5) and B (6), and the known compound ancistrotectoriline A (7). Ancistrotazanine A (5) represents a hitherto unprecedented 5,3'-coupling type between the naphthalene and isoquinoline portions, while 6 and 7 are 5,8'-coupled. The structures of the compounds were determined by spectroscopic, chemical, and chiroptical methods. Compounds 5 and 6 showed good activities against the pathogens of leishmaniasis and Chagas' disease, Leishmania donovani and Trypanosoma cruzi, while 5-7 displayed moderately potent antiplasmodial activities against Plasmodium falciparum parasites.
|
Antileishmanial activity against Leishmania donovani axenic amastigotes after 72 hrs by serial dilution method
|
Leishmania donovani
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Parallel synthesis and antileishmanial activity of ether-linked phospholipids.
Year : 2008
Volume : 18
Issue : 16
First Page : 4658
Last Page : 4660
Authors : Coghi P, Vaiana N, Pezzano MG, Rizzi L, Kaiser M, Brun R, Romeo S.
Abstract : The synthesis and antileishmanial activity of 18 edelfosine analogues are described. Compounds were obtained in parallel combining solid phase and solution phase synthesis. The most active analogue is characterized by the octadecyl group in position 2 of the glycerol chain. Considering that this substitution determines the loss of antitumor activity, a different mechanism of antileishmanial action can be hypothesized.
|
Antiprotozoal activity against Leishmania donovani MHOM-ET-67/L82 in mouse peritoneal macrophages
|
Leishmania donovani
|
0.125
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antiprotozoal activities of heterocyclic-substituted xanthones from the marine-derived fungus Chaetomium sp.
Year : 2008
Volume : 71
Issue : 9
First Page : 1579
Last Page : 1584
Authors : Pontius A, Krick A, Kehraus S, Brun R, König GM.
Abstract : Investigations of the marine-derived fungus Chaetomium sp. led to the isolation of the new natural products chaetoxanthones A, B, and C (1-3). Compounds 1 and 2 are substituted with a dioxane/tetrahydropyran moiety rarely found in natural products. Compound 3 was identified as a chlorinated xanthone substituted with a tetrahydropyran ring. The configurational analysis of these compounds employed CD spectroscopy, modified Mosher's method, and selective NOE gradient measurements. Compound 2 showed selective activity against Plasmodium falciparum with an IC50 value of 0.5 microg/mL without being cytotoxic toward cultured eukaryotic cells. Compound 3 displayed a moderate activity against Trypanosoma cruzi with an IC50 value of 1.5 microg/mL.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes after 72 hrs by resazurin assay
|
Leishmania donovani
|
338.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Quinuclidine derivatives as potential antiparasitics.
Year : 2007
Volume : 51
Issue : 11
First Page : 4049
Last Page : 4061
Authors : Cammerer SB, Jimenez C, Jones S, Gros L, Lorente SO, Rodrigues C, Rodrigues JC, Caldera A, Ruiz Perez LM, da Souza W, Kaiser M, Brun R, Urbina JA, Gonzalez Pacanowska D, Gilbert IH.
Abstract : There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen C2C4 trypomastigotes infected in rat L6 cells after 4 days
|
Trypanosoma cruzi
|
0.23
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiprotozoal activities of simplified analogs of naphthylisoquinoline alkaloids.
Year : 2008
Volume : 43
Issue : 1
First Page : 32
Last Page : 42
Authors : Bringmann G, Brun R, Kaiser M, Neumann S.
Abstract : The naphthylisoquinoline alkaloids (NIQs) represent a class of natural products with manifold activities against various tropical diseases. They are isolated from rare and difficult-to-cultivate tropical plants. In order to find novel, more easily accessible analogs and to study structure-activity relationships, a variety of simplified analogs were produced, which bear the functional groups typical of the NIQs, but avoid the synthetically difficult elements of chirality, stereogenic centers and rotationally hindered axes. Their syntheses and activities against Plasmodium falciparum, Trypanosoma cruzi, and Leishmania donovani are described and compared with those of the natural NIQs. Remarkably, quite good activities were found for naphthalene-devoid halogenated isoquinolinic analogs.
|
Antileishmanial activity against Leishmania donovani
|
Leishmania donovani
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of 2-pyridyl pyrimidines with in vitro antiplasmodial and antileishmanial activity.
Year : 2009
Volume : 19
Issue : 2
First Page : 401
Last Page : 405
Authors : Musonda CC, Whitlock GA, Witty MJ, Brun R, Kaiser M.
Abstract : A series of 2-pyridyl pyrimidines, reported inhibitors of Plasmodium falciparum methionine aminopeptidase 1b were synthesized and evaluated for their antiplasmodial activities. An analysis of physicochemical properties demonstrated a link between lipophilicity and antiparasitic activity. Cross screening of the library against cultured Leishmania donovani parasites revealed this class of compounds as potent inhibitors of parasite development in vitro.
|
Antileishmanial activity against Leishmania donovani
|
Leishmania donovani
|
0.305
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Ancistrotanzanine C and related 5,1'- and 7,3'-coupled naphthylisoquinoline alkaloids from Ancistrocladus tanzaniensis.
Year : 2004
Volume : 67
Issue : 5
First Page : 743
Last Page : 748
Authors : Bringmann G, Dreyer M, Faber JH, Dalsgaard PW, Staerk D, Jaroszewski JW, Ndangalasi H, Mbago F, Brun R, Christensen SB.
Abstract : Three new naphthylisoquinoline alkaloids, the 7,3'-coupled ancistrotanzanine C (6), the 5,1'-coupled O-methylancistrocladinine (7), and the likewise 5,1'-coupled O,N-dimethylancistrocladine (8, previously known only as a partial-synthetic compound), have been isolated from the highland liana Ancistrocladus tanzaniensis, along with the two known 7,3'-coupled naphthylisoquinoline alkaloids ancistrocladidine (4) and ancistrotectorine (5). All of the compounds are S-configured at C-3 and bear an oxygen at C-6, and thus belong to the so-called Ancistrocladaceae type, similar to 1-3 previously isolated from this newly discovered plant species. The structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. The biological activities of the alkaloids against the pathogens causing malaria tropica, leishmaniasis, Chagas' disease, and African sleeping sickness were evaluated.
|
Antileishmanial activity against Leishmania donovani
|
Leishmania donovani
|
0.56
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Isoneocryptolepine, a synthetic indoloquinoline alkaloid, as an antiplasmodial lead compound.
Year : 2005
Volume : 68
Issue : 5
First Page : 674
Last Page : 677
Authors : Van Miert S, Hostyn S, Maes BU, Cimanga K, Brun R, Kaiser M, Mátyus P, Dommisse R, Lemière G, Vlietinck A, Pieters L.
Abstract : The antiprotozoal activities of three naturally occurring isomeric indoloquinoline alkaloids, i.e., cryptolepine (1), neocryptolepine (2), and isocryptolepine (3), and two dimeric indoloquinoline alkaloids, cryptoquindoline (6) and biscryptolepine (7), originally obtained from the plant Cryptolepis sanguinolenta, were compared with those of a new synthetic indoloquinoline isomer, isoneocryptolepine (4), and a quaternary derivative, N-methyl-isocryptolepinium iodide (5). The latter compounds showed a high antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain K1 (IC50 of 0.23 +/- 0.04 and 0.017 +/- 0.004 microM, respectively), while the cytotoxicity (L6 cells) was 4.32 +/- 0.04 and 12.7 +/- 2.0 microM, respectively. Isoneocryptolepine (4) was found to act as an inhibitor of beta-hematin formation and as a DNA-intercalating agent.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 axenic amastigotes
|
Leishmania donovani
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro antiprotozoal activities of water-soluble, inexpensive 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives.
Year : 2008
Volume : 51
Issue : 12
First Page : 3654
Last Page : 3658
Authors : Ge JF, Arai C, Kaiser M, Wittlin S, Brun R, Ihara M.
Abstract : 3,7-Bis(dialkylamino)phenoxazinium salts were synthesized and evaluated for in vitro activities against Plasmodium falciparum, Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania donovani. Notably, the compounds showed potent antiprotozoal activities, especially against P. falciparum and T. cruzi. The compounds with alkyl side chains less than three carbons in length possessed good activities with high selective indices.
|
Antileishmanial activity against Leishmania donovani axenic amastigotes
|
Leishmania donovani
|
340.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase.
Year : 2009
Volume : 19
Issue : 11
First Page : 3031
Last Page : 3035
Authors : Cavalli A, Lizzi F, Bongarzone S, Brun R, Luise Krauth-Siegel R, Bolognesi ML.
Abstract : Novel quinazoline-type compounds were designed as inhibitors of the parasite specific enzyme trypanothione reductase (TR), and their biological activities were evaluated. Some of our compounds inhibited TR, showed selectivity for TR over human glutathione reductase, and inhibited parasite growth in vitro. We propose that the quinazoline framework is a privileged structure that can be purposely modified to design novel TR inhibitors. Furthermore, the use of privileged motifs might emerge as an innovative approach to antiparasitic lead candidates.
|
Antimicrobial activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigote forms
|
Leishmania donovani
|
142.0
nM
|
|
Journal : J. Med. Chem.
Title : Searching for new cures for tuberculosis: design, synthesis, and biological evaluation of 2-methylbenzothiazoles.
Year : 2009
Volume : 52
Issue : 21
First Page : 6757
Last Page : 6767
Authors : Huang Q, Mao J, Wan B, Wang Y, Brun R, Franzblau SG, Kozikowski AP.
Abstract : The actual development and clinical use of new therapeutics for tuberculosis (TB) have remained stagnant for years because of the complexity of the disease process, the treatment of which at present requires the administration of drug combinations over a 6 month period. There is thus an urgent need for the discovery and development of novel, more active, and less toxic anti-TB agents. In this study, we report on the chemistry and biology of a series of potent 5-(2-methylbenzothiazol-5-yloxymethyl)isoxazole-3-carboxamide derivatives, which proved to be active against replicating Mycobacterium tuberculosis (Mtb) H(37)Rv. The most potent compounds 7j and 7s were found to inhibit Mtb growth at micromolar concentrations, with MIC values of 1.4 and 1.9 microM, respectively. Impressively, all active compounds were nontoxic toward Vero cells (IC(50) > 128 microM). Moreover, the best of these compounds were also tested against protozoan parasites, and some of these compounds were found to show activity, especially against Plasmodium falciparum. These studies thus suggest that certain 2-methylbenzothiazole based compounds may serve as promising lead scaffolds for further elaboration as anti-TB drugs and as possible antimalaria drugs.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 amastigotes infected in syrian golden hamster spleen after 72 hrs
|
Leishmania donovani
|
430.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorinated rhodacyanine (SJL-01) possessing high efficacy for visceral leishmaniasis (VL).
Year : 2010
Volume : 53
Issue : 1
First Page : 368
Last Page : 373
Authors : Yang M, Arai C, Bakar Md A, Lu J, Ge JF, Pudhom K, Takasu K, Kasai K, Kaiser M, Brun R, Yardley V, Itoh I, Ihara M.
Abstract : Anti-Leishmania in vitro and in vivo activities of various rhodacyanine derivatives have been examined. Among them, the fluorinatied variant SJL-01 (8) showed IC(50) of 0.011 microM against Leishmania donovani strain MHOM/ET/67/L82 (selective index of >15000) and 95-97% inhibition against L. donovani strain MHOM/ET/67/HU in female BALB/c mice by 1.3-12.5 mg/kg x 5 iv administrations. Negative results on chromosomal aberration test and in vitro micronucleus test suggest that compound 8 is a hopeful candidate for visceral leishmaniasis (VL).
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/HU3 infected in NMRI mouse macrophage assessed as reduction in parasite burden after 24 hrs by Giemsa staining
|
Leishmania donovani
|
811.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorinated rhodacyanine (SJL-01) possessing high efficacy for visceral leishmaniasis (VL).
Year : 2010
Volume : 53
Issue : 1
First Page : 368
Last Page : 373
Authors : Yang M, Arai C, Bakar Md A, Lu J, Ge JF, Pudhom K, Takasu K, Kasai K, Kaiser M, Brun R, Yardley V, Itoh I, Ihara M.
Abstract : Anti-Leishmania in vitro and in vivo activities of various rhodacyanine derivatives have been examined. Among them, the fluorinatied variant SJL-01 (8) showed IC(50) of 0.011 microM against Leishmania donovani strain MHOM/ET/67/L82 (selective index of >15000) and 95-97% inhibition against L. donovani strain MHOM/ET/67/HU in female BALB/c mice by 1.3-12.5 mg/kg x 5 iv administrations. Negative results on chromosomal aberration test and in vitro micronucleus test suggest that compound 8 is a hopeful candidate for visceral leishmaniasis (VL).
|
Antileishmanial activity against Leishmania donovani axenic amastigotes
|
Leishmania donovani
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues.
Year : 2009
Volume : 17
Issue : 20
First Page : 7209
Last Page : 7217
Authors : Van Baelen G, Hostyn S, Dhooghe L, Tapolcsányi P, Mátyus P, Lemière G, Dommisse R, Kaiser M, Brun R, Cos P, Maes L, Hajós G, Riedl Z, Nagy I, Maes BU, Pieters L.
Abstract : Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.
|
Antileishmanial activity against Leishmania donovani infected in rat L6 cells
|
Leishmania donovani
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, stereoelectronic characterization and antiparasitic activity of new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinolines.
Year : 2010
Volume : 18
Issue : 1
First Page : 142
Last Page : 150
Authors : Pagliero RJ, Lusvarghi S, Pierini AB, Brun R, Mazzieri MR.
Abstract : The synthesis and full 3D structural characterization of nine new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinoline derivatives are reported. These belong to a library whose rationale for the design was the previous knowledge of the biological relevant properties of both structural moieties. From protozoan antiparasitic screening, compounds 3 demonstrated interesting activity against Trypanozoma cruzi with low cytotoxicity. Besides, most compounds were moderately active against Plasmodium falciparum. Of these, 3 and 9 can be considered as lead scaffolds for further optimization. The substituent on BS did not influence the 3D structure properties and the (1)H NMR spectra revealed the existence of an intramolecular weak hydrogen bond, C-Hcdots, three dots, centeredOS. Molecular modeling and X-ray crystallography also confirmed this finding, which is relevant to compound conformational preference.
|
Antiparasitic activity against Leishmania donovani MHOM/ET/67/L82 amastigotes
|
Leishmania donovani
|
270.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi.
Year : 2010
Volume : 20
Issue : 6
First Page : 1816
Last Page : 1818
Authors : Holloway GA, Parisot JP, Novello PM, Watson KG, Armstrong T, Thompson RC, Street IP, Baell JB.
Abstract : A benzhydryl tropinone oxime that is potently toxic to Trypanosoma cruzi has been previously identified. An SAR investigation determined that no part of the original compound was superfluous and all early SAR probes led to significant drops in activity. The only alteration that could be achieved without loss of activity was replacement of the aryl chloride substituent with chloro homologues. This led to the discovery of a trifluoromethyl-containing analogue with an EC(50) against T. cruzi of 30 nM and a cytotoxicity selectivity index of over 1000 relative to rat skeletal myoblast L-6 cells.
|
Antileishmanial activity against Leishmania donovani by DNA fluorescence assay
|
Leishmania donovani
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Almiramides A-C: discovery and development of a new class of leishmaniasis lead compounds.
Year : 2010
Volume : 53
Issue : 10
First Page : 4187
Last Page : 4197
Authors : Sanchez LM, Lopez D, Vesely BA, Della Togna G, Gerwick WH, Kyle DE, Linington RG.
Abstract : Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A-C (1-3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.
|
Inhibition of rat RBL2H3 cell granulation assessed as reduction of beta hexasaminidase release at 10 uM
|
Rattus norvegicus
|
87.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Computational screening for membrane-directed inhibitors of mast cell activation.
Year : 2010
Volume : 45
Issue : 6
First Page : 2700
Last Page : 2704
Authors : Batista J, Friedrichson T, Schlechtingen G, Braxmeier T, Jennings G, Bajorath J.
Abstract : Receptor-mediated signaling events frequently depend on the integrity of their membrane environments. Only a limited number of compounds are currently available that are known or thought to modulate membrane environments and affect signaling events without disrupting membrane structure. Among these are alkylphospholipids including the drug miltefosine that is approved for the treatment of breast cancer and leishmaniasis. In addition, miltefosine has recently been shown to block immunoglobulin E receptor-dependent mast cell activation. On the basis of these findings, we have explored other alkylphospholipids as potential inhibitors of mast cell activation and confirmed the inhibitory activity of five molecules. By comparing the head groups of these alkylphospolipids common pharmacophore features were determined. Through computational screening utilizing this pharmacophore information a new lipid-like inhibitory chemotype was identified that blocked mast cell activation with potency comparable to miltefosine.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/Dd8 promastigote carrying firefly luciferase gene assessed as relative luminescence unit after 72 hrs
|
Leishmania donovani
|
0.643
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and molecular docking studies of 1-phenyl-4-glycosyl-dihydropyridines as potent antileishmanial agents.
Year : 2010
Volume : 45
Issue : 6
First Page : 2381
Last Page : 2388
Authors : Pandey VP, Bisht SS, Mishra M, Kumar A, Siddiqi MI, Verma A, Mittal M, Sane SA, Gupta S, Tripathi RP.
Abstract : A series of 1-phenyl-4-glycosyl-dihydropyridines (4-17 and 19-21) were prepared by the one pot multicomponent reaction of glcosyl aldehyde, beta-keto compounds and aniline or substituted aniline in the presence of TBAHS as catalyst. The compounds were screened in vitro and in vivo for their antileishmanial activities. Most of the compounds exhibited moderate to good activity against amastigotes and promastigotes of Leishmania donovani. The compounds 4, 11, 12, 13, and 17 exhibited potent in vivo activity with selectivity index (SI) values 7.43-18.93. Molecular docking studies with these compounds revealed L. donovani PTR1 as the possible target to show antileishmanial activities.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/Dd8 amastigote carrying firefly luciferase gene infected in mouse J774A1 cells assessed as relative luminescence unit after 72 hrs
|
Leishmania donovani
|
12.11
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and molecular docking studies of 1-phenyl-4-glycosyl-dihydropyridines as potent antileishmanial agents.
Year : 2010
Volume : 45
Issue : 6
First Page : 2381
Last Page : 2388
Authors : Pandey VP, Bisht SS, Mishra M, Kumar A, Siddiqi MI, Verma A, Mittal M, Sane SA, Gupta S, Tripathi RP.
Abstract : A series of 1-phenyl-4-glycosyl-dihydropyridines (4-17 and 19-21) were prepared by the one pot multicomponent reaction of glcosyl aldehyde, beta-keto compounds and aniline or substituted aniline in the presence of TBAHS as catalyst. The compounds were screened in vitro and in vivo for their antileishmanial activities. Most of the compounds exhibited moderate to good activity against amastigotes and promastigotes of Leishmania donovani. The compounds 4, 11, 12, 13, and 17 exhibited potent in vivo activity with selectivity index (SI) values 7.43-18.93. Molecular docking studies with these compounds revealed L. donovani PTR1 as the possible target to show antileishmanial activities.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/Dd8 amastigote infected in hamster assessed as inhibition of amastigote multiplication at 30 mg/kg, po for 5 days
|
Leishmania donovani
|
95.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and molecular docking studies of 1-phenyl-4-glycosyl-dihydropyridines as potent antileishmanial agents.
Year : 2010
Volume : 45
Issue : 6
First Page : 2381
Last Page : 2388
Authors : Pandey VP, Bisht SS, Mishra M, Kumar A, Siddiqi MI, Verma A, Mittal M, Sane SA, Gupta S, Tripathi RP.
Abstract : A series of 1-phenyl-4-glycosyl-dihydropyridines (4-17 and 19-21) were prepared by the one pot multicomponent reaction of glcosyl aldehyde, beta-keto compounds and aniline or substituted aniline in the presence of TBAHS as catalyst. The compounds were screened in vitro and in vivo for their antileishmanial activities. Most of the compounds exhibited moderate to good activity against amastigotes and promastigotes of Leishmania donovani. The compounds 4, 11, 12, 13, and 17 exhibited potent in vivo activity with selectivity index (SI) values 7.43-18.93. Molecular docking studies with these compounds revealed L. donovani PTR1 as the possible target to show antileishmanial activities.
|
Antileishmanial activity against Leishmania donovani (MHOM/ET/67/L82) amastigotes after 72 hrs
|
Leishmania donovani
|
510.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antiprotozoal steroidal saponins from the marine sponge Pandaros acanthifolium.
Year : 2010
Volume : 73
Issue : 8
First Page : 1404
Last Page : 1410
Authors : Regalado EL, Tasdemir D, Kaiser M, Cachet N, Amade P, Thomas OP.
Abstract : The chemical composition of the Caribbean sponge Pandaros acanthifolium was reinvestigated and led to the isolation of 12 new steroidal glycosides, namely, pandarosides E-J (1-6) and their methyl esters (7-12). Their structures were determined on the basis of extensive spectroscopic analyses, including two-dimensional NMR and HRESIMS data. Like the previously isolated pandarosides A-D (13-16), the new compounds 1-12 share an unusual oxidized D-ring and a cis C/D ring junction. The absolute configurations of the aglycones were assigned by interpretation of CD spectra, whereas the absolute configurations of the monosaccharide units were determined by chiral GC analyses of the acid methanolysates. The majority of the metabolites showed in vitro activity against three or four parasitic protozoa. Particularly active were the compounds 3 (pandaroside G) and its methyl ester (9), which potently inhibited the growth of Trypanosoma brucei rhodesiense (IC(50) values 0.78 and 0.038 microM, respectively) and Leishmania donovani (IC(50)'s 1.3 and 0.051 microM, respectively).
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 at 4.8 ug/m after 72 hrs by fluorimetry
|
Leishmania donovani
|
92.5
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and preliminary bioactivity assays of 3,4-dichloro-5-(omega-hydroxyalkylamino)-2(5H)-furanones.
Year : 2010
Volume : 45
Issue : 9
First Page : 3993
Last Page : 3997
Authors : Gondela E, Walczak KZ.
Abstract : 5-(Omega-hydroxyalkylamino) derivatives of mucochloric acids were synthesized through a facile substitution reaction of 3,4-dichloro-5-hydroxy-2(5H)-furanone (mucochloric acid) acetate or 5-methylcarbonate with an appropriate amino alcohol or aminodiol. The obtained products were characterized and screened for their antibacterial and antiprotozoal activities.
|
Leishmanicidal activity against axenic amastigotes of Leishmania donovani MHOM/ET/67/L82 after 72 hrs
|
Leishmania donovani
|
0.26
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : 2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.
Year : 2010
Volume : 18
Issue : 21
First Page : 7475
Last Page : 7485
Authors : Tasdemir D, Sanabria D, Lauinger IL, Tarun A, Herman R, Perozzo R, Zloh M, Kappe SH, Brun R, Carballeira NM.
Abstract : Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 μg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC(50) 20.2 μg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes.
|
Antileishmanial activity against Leishmania donovani WR378 infected in golden Syrian hamster assessed as reduction in liver parasitemia at 30 mg/kg/day, po administered for five days
|
Leishmania donovani
|
88.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel arylimidamides for treatment of visceral leishmaniasis.
Year : 2010
Volume : 54
Issue : 6
First Page : 2507
Last Page : 2516
Authors : Wang MZ, Zhu X, Srivastava A, Liu Q, Sweat JM, Pandharkar T, Stephens CE, Riccio E, Parman T, Munde M, Mandal S, Madhubala R, Tidwell RR, Wilson WD, Boykin DW, Hall JE, Kyle DE, Werbovetz KA.
Abstract : Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC(50) < or = 0.12 microM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.
|
Antileishmanial activity against Leishmania donovani WR378 infected in golden Syrian hamster assessed as reduction in spleen parasitemia at 30 mg/kg/day, po administered for five days
|
Leishmania donovani
|
79.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel arylimidamides for treatment of visceral leishmaniasis.
Year : 2010
Volume : 54
Issue : 6
First Page : 2507
Last Page : 2516
Authors : Wang MZ, Zhu X, Srivastava A, Liu Q, Sweat JM, Pandharkar T, Stephens CE, Riccio E, Parman T, Munde M, Mandal S, Madhubala R, Tidwell RR, Wilson WD, Boykin DW, Hall JE, Kyle DE, Werbovetz KA.
Abstract : Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC(50) < or = 0.12 microM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.
|
Antileishmanial activity against Leishmania donovani WR378 infected in golden Syrian hamster assessed as reduction in bone marrow parasitemia at 30 mg/kg/day, po administered for five days
|
Leishmania donovani
|
91.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel arylimidamides for treatment of visceral leishmaniasis.
Year : 2010
Volume : 54
Issue : 6
First Page : 2507
Last Page : 2516
Authors : Wang MZ, Zhu X, Srivastava A, Liu Q, Sweat JM, Pandharkar T, Stephens CE, Riccio E, Parman T, Munde M, Mandal S, Madhubala R, Tidwell RR, Wilson WD, Boykin DW, Hall JE, Kyle DE, Werbovetz KA.
Abstract : Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC(50) < or = 0.12 microM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.
|
Antileishmanial activity against axenic amastigotes of Leishmania donovani
|
Leishmania donovani
|
351.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids.
Year : 2010
Volume : 45
Issue : 11
First Page : 5370
Last Page : 5383
Authors : Bringmann G, Bischof SK, Müller S, Gulder T, Winter C, Stich A, Moll H, Kaiser M, Brun R, Dreher J, Baumann K.
Abstract : Naphthylisoquinoline alkaloids have attracted considerable interest because of their intriguing structure, their unique biosynthetic origin, and their biological activities against several pathogens causing tropical diseases. Their promising pharmacologic properties make them suitable lead structures for new agents, in particular against malaria. Since these natural products are not easy to isolate in sufficient quantities or to synthesize stereoselectively, quantitative structure-activity relationship studies were accomplished to find new antiplasmodial analogs that are structurally related to the naturally occurring naphthylisoquinoline alkaloids, but more easily accessible, more active against Plasmodium falciparum, and, last but not least, less toxic. We report on the synthesis of several simplified compounds by a Suzuki coupling between the naphthalene and the isoquinoline moieties and on their activities against different pathogens causing infectious diseases. Some structures were found to exhibit excellent--and selective--activities against P. falciparum in vitro.
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 amastigotes
|
Leishmania donovani
|
0.27
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with antiparasitic activity.
Year : 2009
Volume : 53
Issue : 7
First Page : 2824
Last Page : 2833
Authors : Holloway GA, Charman WN, Fairlamb AH, Brun R, Kaiser M, Kostewicz E, Novello PM, Parisot JP, Richardson J, Street IP, Watson KG, Baell JB.
Abstract : High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 amastigote after 72 hrs
|
Leishmania donovani
|
205.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antiprotozoal activity of 1-phenethyl-4-aminopiperidine derivatives.
Year : 2009
Volume : 53
Issue : 9
First Page : 3815
Last Page : 3821
Authors : Dardonville C, Fernández-Fernández C, Gibbons SL, Jagerovic N, Nieto L, Ryan G, Kaiser M, Brun R.
Abstract : A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC50) ranging from 0.12 to 10 microM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC50 range, 0.17 to 5 microM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC50, 1.97 microM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.
|
Antipromastigote activity against Leishmania donovani MHOM/IN/80/Dd8 promastigotes assessed as luciferase activity of viable cells at 20 uM after 72 hrs by luminometry
|
Leishmania donovani
|
99.9
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and evaluation of new furanyl and thiophenyl azoles as antileishmanial agents.
Year : 2011
Volume : 46
Issue : 5
First Page : 1694
Last Page : 1700
Authors : Marrapu VK, Mittal M, Shivahare R, Gupta S, Bhandari K.
Abstract : A series of benzyloxy furanyl and benzyloxy thiophenyl azoles were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 16 compounds have shown more than 90% inhibition against promastigotes at 20 μM while 11 compounds exhibited IC50 in the range of 3.04-9.39 μM against amastigotes. Compound 4, a 3-chlorobenzyloxy furanyl imidazole emerged as the most active compound in the series with IC50 value of 3.04 μM and SI value of 19.80, and was several folds more potent than the reference drugs miltefosine and miconazole.
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 after 72 hrs by fluorimetry
|
Leishmania donovani
|
520.0
nM
|
|
Journal : J. Nat. Prod.
Title : Didemnidines A and B, indole spermidine alkaloids from the New Zealand ascidian Didemnum sp.
Year : 2011
Volume : 74
Issue : 4
First Page : 888
Last Page : 892
Authors : Finlayson R, Pearce AN, Page MJ, Kaiser M, Bourguet-Kondracki ML, Harper JL, Webb VL, Copp BR.
Abstract : Two new indole spermidine alkaloids, didemnidines A (1) and B (2), have been isolated from the New Zealand ascidian Didemnum sp. The structures of the metabolites, determined by analysis of 2D NMR spectra and confirmed via synthesis, embody an indole-3-glyoxylamide moiety linked to the N(1) position of spermidine, the latter motif being particularly rare among marine natural products. Didemnidine B and a synthetic precursor exhibited mild in vitro growth inhibition of Plasmodium falciparum with IC(50)'s of 15 and 8.4 μM, respectively.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 axenic amastigotes
|
Leishmania donovani
|
386.0
nM
|
|
Journal : J. Nat. Prod.
Title : Marinoquinolines A-F, pyrroloquinolines from Ohtaekwangia kribbensis (Bacteroidetes).
Year : 2011
Volume : 74
Issue : 4
First Page : 603
Last Page : 608
Authors : Okanya PW, Mohr KI, Gerth K, Jansen R, Müller R.
Abstract : Marinoquinoline A (1) was isolated from the gliding bacterium Ohtaekwangia kribbensis together with the novel marinoquinolines B-F (2-6). Their structures were elucidated from NMR and HRESIMS data. The pyrroloquinolines showed weak antibacterial and antifungal activities and moderate cytotoxicity against four growing mammalian cell lines with IC(50) values ranging from 0.3 to 8.0 μg/mL. In a screening against tropical parasites marinoquinolines A-F (1-6) showed activity against Plasmodium falciparum K1 with IC(50) values between 1.7 and 15 μM.
|
Antiparasitic activity against Leishmania donovani MHOM/ET/67/L82 amastigotes/axenic stage forms incubated for 72 hrs by Alamar Blue staining based fluorometric assay
|
Leishmania donovani
|
530.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antimalarial β-carbolines from the New Zealand ascidian Pseudodistoma opacum.
Year : 2011
Volume : 74
Issue : 9
First Page : 1972
Last Page : 1979
Authors : Chan ST, Pearce AN, Page MJ, Kaiser M, Copp BR.
Abstract : One tetrahydro-β-carboline, (-)-7-bromohomotrypargine (1), and three alkylguanidine-substituted β-carbolines, opacalines A, B, and C (2-4), have been isolated from the New Zealand ascidian Pseudodistoma opacum. The structures of the metabolites were determined by analysis of mass spectrometric and 2D NMR spectroscopic data. Natural products 2 and 3, synthetic debromo analogues 8 and 9, and intermediate 16 exhibited moderate antimalarial activity toward a chloroquine-resistant strain of Plasmodium falciparum, with an IC50 range of 2.5-14 μM. The biosynthesis of 1-4 is proposed to proceed via a Pictet-Spengler condensation of 6-bromotryptamine and the α-keto acid transamination product of either arginine or homoarginine. Cell separation and 1H NMR analysis of P. opacum identified tetrahydro-β-carboline 1 to be principally located in the zooids, while fully aromatized analogues 2-4 were localized to the test.
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 at pH 7.4 by microplate assay
|
Leishmania donovani
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antiprotozoal activities of 5-phenyliminobenzo[a]phenoxazine derivatives.
Year : 2011
Volume : 21
Issue : 19
First Page : 5804
Last Page : 5807
Authors : Shi XL, Ge JF, Liu BQ, Kaiser M, Wittlin S, Brun R, Ihara M.
Abstract : A series of 5-phenyliminobenzo[a]phenoxazine derivatives were synthesized. The in vitro antiprotozoal activities were evaluated against Plasmodium falciparum K1, Trypanosoma cruzi, Leishmania donovani and Trypanosoma brucei rhodesiense. N,N-Diethyl-5-((4-methoxyphenyl)imino)-5H-benzo[a]phenoxazin-9-amine shows IC(50)=0.040 μmol L(-1) with a selective index of 1425 against Plasmodium falciparum K1.
|
Antiparasitic activity against amastigotes of Leishmania donovani MHOM/ET/67/L82 infected in rat L6 cells after 72 hrs by by Alamar blue assay
|
Leishmania donovani
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biological evaluation of glycosyl-isoindigo derivatives against the pathogenic agents of tropical diseases (malaria, Chagas disease, leishmaniasis and human African trypanosomiasis).
Year : 2011
Volume : 21
Issue : 21
First Page : 6319
Last Page : 6321
Authors : Bouchikhi F, Anizon F, Brun R, Moreau P.
Abstract : The biological activities of diversely substituted glycosyl-isoindigo derivatives against the causative agents of tropical diseases (malaria, Chagas disease, leishmaniasis and human African trypanosomiasis) are reported. Some of the compounds tested showed interesting activities with good selectivity indices, particularly against Trypanosoma brucei rhodesiense. These results suggested, for the first time, that glycosyl-isoindigo derivatives could be of interest for the discovery of new lead compounds to treat tropical diseases.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 amastigotes infected in rat L6 cells after 72 hrs by alamar blue assay
|
Leishmania donovani
|
440.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based aliphatic and aromatic amines as anti-chagasic agents.
Year : 2011
Volume : 54
Issue : 23
First Page : 8214
Last Page : 8223
Authors : Papadopoulou MV, Trunz BB, Bloomer WD, McKenzie C, Wilkinson SR, Prasittichai C, Brun R, Kaiser M, Torreele E.
Abstract : A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF) T. b. rhodesiense trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.
|
Inhibition of Akt phosphorylation in insulin-stimulated human A549 cells at 10 uM treated 2 hrs before insulin stimulation measured after 30 mins by ELISA
|
Homo sapiens
|
56.31
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of cyclopentane-linked alkyl phosphocholines as potential anticancer agents that act by inhibiting Akt phosphorylation.
Year : 2012
Volume : 47
First Page : 485
Last Page : 492
Authors : Alam MM, Joh EH, Kim Y, Oh YI, Hong J, Kim B, Kim DH, Lee YS.
Abstract : Three new series of novel alkylphosphocholine (APC) derivatives containing a cyclopentane ring near the phosphocholine head group were synthesized. In the first set of analogues, the phosphocholine head group was attached to the secondary alcohol of trans-2-(hydroxymethyl)cyclopentanol, whereas in the second and third sets of analogues, the phosphocholine head group was linked to the primary alcohol of trans- and cis-2-(hydroxymethyl)cyclopentanol, respectively. Of the compounds synthesized, compound 6d most potently inhibited Akt phosphorylation with an IC(50) value of 3.6 μM, its potency was greater than the reference compounds miltefosine, perifosine, and erufosine. Compounds 6b and 6d exhibited the most potent growth-inhibitory effects on A549, MCF-7, and KATO-III human cancer cell lines. These compounds also showed more active anti-proliferative effects than the reference compounds. Importantly, the cytotoxic effects of these compounds on A549 cell line were proportional to their abilities to inhibit Akt phosphorylation, which supports that these synthesized APC compounds are novel inhibitors of the Akt cell survival pathway.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 after 72 hrs by resazurin-based spectrophotometric assay
|
Leishmania donovani
|
445.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Bis(oxyphenylene)benzimidazoles: a novel class of anti-Plasmodium falciparum agents.
Year : 2011
Volume : 19
Issue : 24
First Page : 7493
Last Page : 7500
Authors : Mayence A, Vanden Eynde JJ, Kaiser M, Brun R, Yarlett N, Huang TL.
Abstract : A small library of 26 2,2'-[alkane-α,ω-diylbis(oxyphenylene)]bis-1H-benzimidazoles has been prepared and evaluated against Giardia intestinalis, Entamoeba histolytica, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. Among the tested compounds, eight derivatives (17, 19, 20, 24, 27, 30, 32 and 35) exhibited an anti-Plasmodium falciparum activity characterized by IC(50) values in the range of 180-410 nM (0.11-0.21 μg/mL) and selectivity indexes (IC(50) rat skeletal myoblasts L6 cells vs IC(50)P. falciparum K1 strain) varying between 92 and more than 450. Two of the eight novel drug leads, namely compounds 19 and 32, were also active against G. intestinalis and L. donovani with selectivity indexes of 122 and >164 respectively.
|
Leishmanicidal activity against Leishmania donovani MHOM/ET/67/L82 amastigote forms after 72 hrs by resazurin assay
|
Leishmania donovani
|
0.171
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and anti-protozoal activity of novel dihydropyrrolo[3,4-d][1,2,3]triazoles.
Year : 2012
Volume : 48
First Page : 296
Last Page : 304
Authors : Dürüst Y, Karakuş H, Kaiser M, Tasdemir D.
Abstract : 1,2,4-Oxadiazole and 1,2,3-triazole containing heterocyclic compounds continue to gain interest in synthesis of chemical entities and exhibit various biological activities as anti-protozoal and anti-cancer agents. By using the principle of bioisosterism, a series of novel oxadiazolyl pyrrolo triazole diones; namely, (3aS,6aR)-1-((3-(4-substituted phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-phenyl-1,6a-dihydropyrrolo[3,4-d][1,2,3] triazole-4,6(3aH,5H)-diones (5a-k) was designed and synthesized by the 1,3-dipolar cycloaddition reaction of novel 5-azidomethyl 3-aryl substituted 1,2,4-oxadiazoles (4a-k) with N-phenyl maleimide. The structures of all the cycloadducts were elucidated by means of spectroscopic methods and physical characteristics. The in vitro anti-protozoal and cytotoxic activities of these novel heterocyclic compounds were investigated.
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes after 72 hrs by alamar blue assay
|
Leishmania donovani
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photo-dimers.
Year : 2012
Volume : 20
Issue : 4
First Page : 1482
Last Page : 1493
Authors : McCracken ST, Kaiser M, Boshoff HI, Boyd PD, Copp BR.
Abstract : Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of Mycobacterium tuberculosis and a range of tropical diseases including Plasmodium falciparum and Leishmania donovani. In an effort to expand the structure-activity relationship of this compound class towards infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesized. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense and Trypanosoma cruzi. Of the styryl-pyranones, natural product 3 and non-natural styrene and naphthalene substituted examples 13, 18, 21, 22 and 23 exhibited antimalarial activity (IC(50) <10 μM) with selectivity indices (SI) >10. Δ(7) Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers 5 and 34 exhibited moderate IC(50)s of 2.3 to 17 μM towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers 31 and 33 were identified as being moderately active towards P. falciparum (IC(50) 1.5 and 1.7 μM) with good selectivity (SI ~80). The 4-tert-butyl aniba-dimer A analogue 33 also exhibited activity towards L. donovani (IC(50) 4.5 μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis.
|
Antileishmanial activity against axenic amastigote stage of Leishmania donovani MHOM/ET/67/L82 infected in rat L6 cells after 72 hrs by alamar blue assay
|
Leishmania donovani
|
0.19
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and structure-activity relationships of N-benzoyl-2-hydroxybenzamides as agents active against P. falciparum (K1 strain), Trypanosomes, and Leishmania.
Year : 2012
Volume : 55
Issue : 7
First Page : 3088
Last Page : 3100
Authors : Stec J, Huang Q, Pieroni M, Kaiser M, Fomovska A, Mui E, Witola WH, Bettis S, McLeod R, Brun R, Kozikowski AP.
Abstract : In our efforts to identify novel chemical scaffolds for the development of new antiprotozoal drugs, a compound library was screened against Toxoplasma gondii tachyzoites with activity discovered for N-(4-ethylbenzoyl)-2-hydroxybenzamide 1a against T. gondii as described elsewhere. Synthesis of a compound set was guided by T. gondii SAR with 1r found to be superior for T. gondii , also active against Thai and Sierra Leone strains of Plasmodium falciparum , and with superior ADMET properties as described elsewhere. Herein, synthesis methods and details of the chemical analysis of the compounds in this series are described. Further, this series of N-benzoyl-2-hydroxybenzamides was repurposed for testing against four other protozoan parasites: Trypanosoma brucei rhodesiense , Trypanosoma cruzi , Leishmania donovani , and P. falciparum (K1 isolate). Structure-activity analyses led to the identification of compounds in this set with excellent antileishmanial activity (compound 1d). Overall, compound 1r was the best and had activity 21-fold superior to that of the standard antimalarial drug chloroquine against the K1 P. falciparum isolate.
|
Antileishmanial activity against Leishmania donovani MHOM-ET67/L82 amastigotes
|
Leishmania donovani
|
382.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents.
Year : 2012
Volume : 55
Issue : 11
First Page : 5554
Last Page : 5565
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Chatelain E, Kaiser M, Wilkinson SR, McKenzie C, Ioset JR.
Abstract : A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against Trypanosoma cruzi intracellular amastigotes (IC(50) ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≤ IC(50) < 6.0 μM) against Trypanosoma brucei rhodesiense trypomastigotes were 5-31-fold more active against bloodstream-form Trypanosoma brucei brucei trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani . Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.
|
Antiprotozoal activity against Leishmania donovani axenic amastigotes
|
Leishmania donovani
|
490.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Alkynoic fatty acids inhibit topoisomerase IB from Leishmania donovani.
Year : 2012
Volume : 22
Issue : 19
First Page : 6185
Last Page : 6189
Authors : Carballeira NM, Cartagena M, Sanabria D, Tasdemir D, Prada CF, Reguera RM, Balaña-Fouce R.
Abstract : 2-Alkynoic fatty acids display antimycobacterial, antifungal, and pesticidal activities but their antiprotozoal activity has received little attention. In this work we synthesized the 2-octadecynoic acid (2-ODA), 2-hexadecynoic acid (2-HDA), and 2-tetradecynoic acid (2-TDA) and show that 2-ODA is the best inhibitor of the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) with an EC(50)=5.3±0.7μM. The potency of LdTopIB inhibition follows the trend 2-ODA>2-HDA>2-TDA, indicating that the effectiveness of inhibition depends on the fatty acid carbon chain length. All of the studied 2-alkynoic fatty acids were less potent inhibitors of the human topoisomerase IB enzyme (hTopIB) as compared to LdTopIB. 2-ODA also displayed in vitro activity against Leishmania donovani (IC(50)=11.0μM), but it was less effective against other protozoa, Trypanosoma cruzi (IC(50)=48.1μM) and Trypanosoma brucei rhodesiense (IC(50)=64.5μM). The antiprotozoal activity of the 2-alkynoic fatty acids, in general, followed the trend 2-ODA>2-HDA>2-TDA. The experimental information gathered so far indicates that 2-ODA is a promising antileishmanial compound.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 amastigotes infected in golden hamster assessed as inhibition of parasite multiplication at 30 mg/kg, po for 5 days measured on day 7 by Giemsa staining
|
Leishmania donovani
|
95.28
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Chemotherapy of leishmaniasis. Part IX: synthesis and bioevaluation of aryl substituted ketene dithioacetals as antileishmanial agents.
Year : 2012
Volume : 22
Issue : 21
First Page : 6728
Last Page : 6730
Authors : Kumar S, Tiwari A, Suryawanshi SN, Mittal M, Vishwakarma P, Gupta S.
Abstract : A new series of aryl substituted ketene dithioacetals 6a-h was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. Two compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC(50) values 3.56 and 5.12 μM and were found promising as compared with reference drug, miltefosine. On the basis of good Selectivity Indices (S.I.), they were further tested for their in vivo response against L. donovani/hamster model and showed significant inhibition of parasite multiplication 78% and 83%, respectively. These compounds were better than the existing antileishmanials in respect to IC(50) and SI values, but were less active than miltefosine in vivo.
|
Antitrypanosomal activity against axenic amastigote form of Leishmania donovani MHOM-ET-67/L82 assessed as growth inhibition after 72 hrs by inverted microscopy
|
Leishmania donovani
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Conjugation of quinones with natural polyamines: toward an expanded antitrypanosomatid profile.
Year : 2012
Volume : 55
Issue : 23
First Page : 10490
Last Page : 10500
Authors : Lizzi F, Veronesi G, Belluti F, Bergamini C, López-Sánchez A, Kaiser M, Brun R, Krauth-Siegel RL, Hall DG, Rivas L, Bolognesi ML.
Abstract : A combinatorial library of quinone-polyamine conjugates designed to optimize the antitrypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid-phase approach. The conjugates were evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and several showed promising activity. A subset also inhibited trypanothione reductase in vitro and induced oxidase activity of the enzyme. A highly potent analogue (7) was identified with activity against T. brucei as low as 70 nM and a selectivity index of 72. Interestingly, the presence of a cadaverine tail confers to 7 the ability to target mitochondrial function in Leishmania. In fact, in L. donovani promastigotes, we verified for 7 a decrease of cytoplasmic ATP and mitochondrial potential. Therefore, the current results support the suitability of the conjugation approach for the development of novel polyamine conjugates with enhanced therapeutic potential.
|
Antileishmanial activity against amastigote form of Leishmania aethiopica MHOM/ET/82/117-82 infected in BALB/c mouse peritoneal exudate macrophages after 5 days
|
Leishmania aethiopica
|
0.121
ug.mL-1
|
|
Journal : Med Chem Res
Title : Evaluation of antileishmanial activities of triglycerides isolated from roots of Moringa stenopetala
Year : 2013
Volume : 22
Issue : 10
First Page : 4592
Last Page : 4599
Authors : Bekele B, Adane L, Tariku Y, Hailu A
|
Antileishmanial activity against promastigote form of Leishmania aethiopica MHOM/ET/82/117-82 infected in BALB/c mouse peritoneal exudate macrophages after 72 hr
|
Leishmania aethiopica
|
0.136
ug.mL-1
|
|
Journal : Med Chem Res
Title : Evaluation of antileishmanial activities of triglycerides isolated from roots of Moringa stenopetala
Year : 2013
Volume : 22
Issue : 10
First Page : 4592
Last Page : 4599
Authors : Bekele B, Adane L, Tariku Y, Hailu A
|
Anti-protozoal activity against Leishmania donovani MHOM-ET-67/L82 amastigotes after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
0.144
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Asymmetric synthesis and anti-protozoal activity of the 8,4'-oxyneolignans virolin, surinamensin and analogues.
Year : 2013
Volume : 60
First Page : 240
Last Page : 248
Authors : Rye CE, Barker D.
Abstract : The asymmetric synthesis of 8,4'-oxyneolignans (-)-virolin, (-)-surinamensin and a number of analogues has been achieved. A divergent synthesis was used, with all compounds being elaborated from a single chiral aldehyde derived from ethyl lactate. In the 15 compounds that were tested, the level of substitution on the A-ring was found to directly influence the activity against Leishmania donovani whilst the activity against Plasmodium falciparum was influenced by numerous substitution and stereochemical factors.
|
Antiprotozoal activity against amastigote/ axenic stage of Leishmania donovani MHOM-ET-67/L82 after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
530.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and preliminary structure-activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds.
Year : 2013
Volume : 23
Issue : 2
First Page : 452
Last Page : 454
Authors : Liew LP, Kaiser M, Copp BR.
Abstract : Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC(50) 0.89 μM). Preliminary structure-activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC(50) 8.6 nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics.
|
Antiparasitic activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes after 70 hrs by by Alamar blue assay
|
Leishmania donovani
|
360.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro antimalarial testing of neocryptolepines: SAR study for improved activity by introduction and modifications of side chains at C2 and C11 on indolo[2,3-b]quinolines.
Year : 2013
Volume : 56
Issue : 4
First Page : 1431
Last Page : 1442
Authors : Mei ZW, Wang L, Lu WJ, Pang CQ, Maeda T, Peng W, Kaiser M, El Sayed I, Inokuchi T.
Abstract : To obtain a high antimalarial activity with neocryptolepine derivatives, modifying and changing the side chains at the C11 position with varying the substituents of an electron-withdrawing or electron-donating nature at the C2 position for a SAR study were executed. Installation of alkylamino and ω-aminoalkylamino groups at the C11 position of the neocryptolepine core was successful. For further variation, the aminoalkylamino substituents were transformed into the corresponding acyclic or cyclic carbamides or thiocarbamides. These side chain modified neocryptolepine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro and for cytotoxicity toward mammalian L6 cells. Among the tested compounds, the compound 17f showed an IC50 of 2.2 nM for CQS (NF54) and a selectivity index of 1400, and 17i showed an IC50 of 2.2 nM for CQR (K1), a selectivity index of 1243, and a resistance index of 0.5.
|
Leishmanicidal activity against Leishmania donovani MHOM/IN/80/Dd8 infected in golden hamster at 50 mg/kg, ip for 5 consecutive days measured on day 7 of last drug administration by Giemsa staining method
|
Leishmania donovani
|
95.28
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Chemotherapy of leishmaniasis part X: synthesis and bioevaluation of novel terpenyl heterocycles.
Year : 2013
Volume : 23
Issue : 1
First Page : 248
Last Page : 251
Authors : Tiwari A, Kumar S, Suryawanshi SN, Mittal M, Vishwakarma P, Gupta S.
Abstract : Some novel α and β ionone based chalcones and their dihydropyrazolidines/pyrazolidines have been synthesized and evaluated for their in vitro and in vivo antileishmanial activities against Leishmania donovani. Amongest all, one compound (4d) exhibited significant in vitro activity against intracellular amastigotes of Leishmania donovani with IC(50) values of 7.49 μM and was found promising as compared to reference drug, miltefosine. On the basis of good Selectivity Index (S.I.), the compound was further tested for its in vivo response against Leishmania donovani/hamster model and has shown significant inhibition of parasite multiplication (81%). The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent.
|
Antileishmanial activity against Leishmania donovani LV82 infected in BALB/c mouse model of visceral leishmaniasis assessed as inhibition of liver parasitemia at 10 mg/kg/day, ip for 5 days starting 7 days post-infection
|
Leishmania donovani
|
97.0
%
|
|
Journal : J. Nat. Prod.
Title : 8,8-dialkyldihydroberberines with potent antiprotozoal activity.
Year : 2013
Volume : 76
Issue : 3
First Page : 311
Last Page : 315
Authors : Endeshaw M, Zhu X, He S, Pandharkar T, Cason E, Mahasenan KV, Agarwal H, Li C, Munde M, Wilson WD, Bahar M, Doskotch RW, Kinghorn AD, Kaiser M, Brun R, Drew ME, Werbovetz KA.
Abstract : Semisynthetic 8,8-dialkyldihydroberberines (8,8-DDBs) were found to possess mid- to low-nanomolar potency against Plasmodium falciparum blood-stage parasites, Leishmania donovani intracellular amastigotes, and Trypanosoma brucei brucei bloodstream forms. For example, 8,8-diethyldihydroberberine chloride (5b) exhibited in vitro IC50 values of 77, 100, and 5.3 nM against these three parasites, respectively. In turn, two 8,8-dialkylcanadines, obtained by reduction of the corresponding 8,8-DDBs, were much less potent against these parasites in vitro. While the natural product berberine is a weak DNA binder, the 8,8-DDBs displayed no affinity for DNA, as assessed by changes in the melting temperature of poly(dA·dT) DNA. Selected 8,8-DDBs showed efficacy in mouse models of visceral leishmaniasis and African trypanosomiasis, with 8,8-dimethyldihydroberberine chloride (5a) reducing liver parasitemia by 46% in L. donovani-infected BALB/c mice when given at an intraperitoneal dose of 10 mg/kg/day for five days. The 8,8-DDBs may thus serve as leads for discovering new antimalarial, antileishmanial, and antitrypanosomal drug candidates.
|
Antileishmanial activity against amastigotes of Leishmania donovani MHOM/IN/60/Dd8 infected in golden hamster assessed as amastigote count at 30 mg/kg/day, po administered for 5 days measured on day 7 of post last dose by Giemsa staining
|
Leishmania donovani
|
98.1
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a new class of natural product-inspired quinazolinone hybrid as potent antileishmanial agents.
Year : 2013
Volume : 56
Issue : 11
First Page : 4374
Last Page : 4392
Authors : Sharma M, Chauhan K, Shivahare R, Vishwakarma P, Suthar MK, Sharma A, Gupta S, Saxena JK, Lal J, Chandra P, Kumar B, Chauhan PM.
Abstract : The high potential of quinazolinone containing natural products and their derivatives in medicinal chemistry led us to discover four novel series of 53 compounds of quinazolinone based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal activity against intracellular amastigotes (IC50 from 0.65 ± 0.2 to 7.76 ± 2.1 μM) as compared to miltefosine (IC50 = 8.4 ± 2.1 μM) and nontoxic toward the J-774A.1 cell line and Vero cells. Moreover, activation of Th1 type and suppression of Th2 type immune responses and induction in nitric oxide generation proved that 8a and 8g induce murine macrophages to prevent survival of parasites. Compounds 8a and 8g exhibited significant in vivo inhibition of parasite 73.15 ± 12.69% and 80.93 ± 10.50% against Leishmania donovani /hamster model. Our results indicate that compounds 8a, 8g, and 9f represent a new structural lead for this serious and neglected disease.
|
Antileishmanial activity against amastigotes of Leishmania donovani assessed as inhibition of parasite growth at 40 uM after 72 hrs by luciferase reporter assay
|
Leishmania donovani
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Chemotherapy of leishmaniasis. Part XII: design, synthesis and bioevaluation of novel triazole integrated phenyl heteroterpenoids as antileishmanial agents.
Year : 2013
Volume : 23
Issue : 10
First Page : 2925
Last Page : 2928
Authors : Suryawanshi SN, Tiwari A, Kumar S, Shivahare R, Mittal M, Kant P, Gupta S.
Abstract : A novel series of triazole integrated phenyl heteroterpenoids have been synthesized and screened for their in vitro activity against intracellular amastigote form of Leishmania donovani. Among all tested compounds, compound 3a was found to be the most active with IC50 6.4μM and better selectivity index (SI) 18 as compared to reference drugs, miltefosine and miconazole. When evaluated in vivo in L. donovani/hamster model, 3a has exhibited 79±11% inhibition of parasite multiplication at 50mgkg(-1)×5days on day 7 post treatment.
|
Antitrypanosomal activity against Leishmania donovani MHOM-ET-67/L82 amastigotes after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
366.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : New Promising Compounds with in Vitro Nanomolar Activity against Trypanosoma cruzi.
Year : 2013
Volume : 4
Issue : 6
First Page : 538
Last Page : 541
Authors : Friggeri L, Scipione L, Costi R, Kaiser M, Moraca F, Zamperini C, Botta B, Di Santo R, De Vita D, Brun R, Tortorella S.
Abstract : The antiparasitic activity of azole and new 4-aminopyridine derivatives has been investigated. The imidazoles 1 and 3-5 showed a potent in vitro antichagasic activity with IC50 values in the low nanomolar concentration range. The (S)-1, (S)-3, and (S)-5 enantiomers showed (up to) a thousand-fold higher activity than the reference drug benznidazole and furthermore low cytotoxicity on rat myogenic L6 cells.
|
Antiprotozoal activity against Leishmania donovani promastigotes infected in BALB/c mouse assessed as inhibition of liver parasitemia at 10 mg/kg, po qd for 5 days
|
Leishmania donovani
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiprotozoal activity of dicationic m-terphenyl and 1,3-dipyridylbenzene derivatives.
Year : 2013
Volume : 56
Issue : 13
First Page : 5473
Last Page : 5494
Authors : Patrick DA, Ismail MA, Arafa RK, Wenzler T, Zhu X, Pandharkar T, Jones SK, Werbovetz KA, Brun R, Boykin DW, Tidwell RR.
Abstract : 4,4″-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of ≤ 3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of ≤ 10 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses.
|
Antimicrobial activity against Leishmania donovani MHOM/ET/67/L82 amastigote form after 70 hrs by Alamar blue assay
|
Leishmania donovani
|
490.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis.
Year : 2013
Volume : 66
First Page : 450
Last Page : 465
Authors : Ferrins L, Rahmani R, Sykes ML, Jones AJ, Avery VM, Teston E, Almohaywi B, Yin J, Smith J, Hyland C, White KL, Ryan E, Campbell M, Charman SA, Kaiser M, Baell JB.
Abstract : A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC₅₀ of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.
|
Antileishmanial activity against Leishmania donovani infected in golden hamster assessed as inhibition of parasite multiplication at 30 mg/kg, po for 5 days measured after 7 days by Giemsa staining-based assay
|
Leishmania donovani
|
98.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of aryl pyrimidine derivatives as potential leishmanicidal agents.
Year : 2013
Volume : 23
Issue : 18
First Page : 5235
Last Page : 5238
Authors : Suryawanshi SN, Kumar S, Shivahare R, Pandey S, Tiwari A, Gupta S.
Abstract : A series of substituted aryl pyrimidine derivatives was synthesized and evaluated in vitro for their antileishmanial potential against intracellular amastigotes of Leishmania donovani using reporter gene luciferase assay. Among all, 8 compounds showed promising IC50 values ranging from 0.5 to 12.9 μM. Selectivity indices (S.I.) of all these compounds are far better than reference drugs, sodium stibogluconate (SSG) and miltefosine. On the basis of good S.I., compounds were further screened for their in vivo antileishmanial activity against L. donovani/hamster model. Compounds 2d, 4a and 4b have shown significant inhibition of parasitic multiplication that is 88.4%, 78.1% and 78.2%, respectively at a daily dose of 50 mg/kg × 5 days, when administered intraperitoneally. Compound 2d is most promising one, which may provide a new lead that could be exploited as a new antileishmanial agent.
|
Cytotoxicity against human HepG2 cells after 48 hrs by neutral red
|
Homo sapiens
|
25.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antifungal activities of miltefosine analogs.
Year : 2013
Volume : 23
Issue : 17
First Page : 4828
Last Page : 4831
Authors : Ravu RR, Chen YL, Jacob MR, Pan X, Agarwal AK, Khan SI, Heitman J, Clark AM, Li XC.
Abstract : Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a-3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5-5.0 μg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5-3.3 μg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.
|
Cytotoxicity against pig LLC-PK11 cells after 48 hrs by neutral red
|
Sus scrofa
|
2.7
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antifungal activities of miltefosine analogs.
Year : 2013
Volume : 23
Issue : 17
First Page : 4828
Last Page : 4831
Authors : Ravu RR, Chen YL, Jacob MR, Pan X, Agarwal AK, Khan SI, Heitman J, Clark AM, Li XC.
Abstract : Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a-3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5-5.0 μg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5-3.3 μg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.
|
Cytotoxicity against african green monkey Vero cells after 48 hrs by neutral red
|
Chlorocebus sabaeus
|
25.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antifungal activities of miltefosine analogs.
Year : 2013
Volume : 23
Issue : 17
First Page : 4828
Last Page : 4831
Authors : Ravu RR, Chen YL, Jacob MR, Pan X, Agarwal AK, Khan SI, Heitman J, Clark AM, Li XC.
Abstract : Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a-3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5-5.0 μg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5-3.3 μg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.
|
Antiprotozoal activity against Leishmania donovani assessed as parasite growth inhibition
|
Leishmania donovani
|
361.0
nM
|
|
Journal : J. Med. Chem.
Title : Natural product derived antiprotozoal agents: synthesis, biological evaluation, and structure-activity relationships of novel chromene and chromane derivatives.
Year : 2013
Volume : 56
Issue : 18
First Page : 7442
Last Page : 7448
Authors : Harel D, Schepmann D, Prinz H, Brun R, Schmidt TJ, Wünsch B.
Abstract : Various natural products with the chromane and chromene scaffold exhibit high antiprotozoal activity. The natural product encecalin (7) served as key intermediate for the synthesis of different ethers 9, amides 11, and amines 12. The chromane analogues 14 and the phenols 15 were obtained by reductive amination of ketones 13 and 6, respectively. Angelate 3, ethers 9, and amides 11 did not show considerable antiprotozoal activity. However, the chromene and chromane derived amines 12, 14, and 15 revealed promising antiprotozoal activity and represent novel lead compounds. Whereas benzylamine 12a and α-methylbenzylamine 12g were active against P. falciparum with IC50 values in the range of chloroquine, the analogous phenols 15a and 15b were unexpectedly 10- to 25-fold more potent than chloroquine with selectivity indexes of 6760 and 1818, respectively. The phenylbutylamine 14d based on the chromane scaffold has promising activity against T. brucei rhodesiense and L. donovani.
|
Antimicrobial activity against Leishmania donovani MHOM-ET-67/L82 amastigotes after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
378.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based piperazines and 2-amino-1,3-benzothiazoles as antichagasic agents.
Year : 2013
Volume : 21
Issue : 21
First Page : 6600
Last Page : 6607
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Kaiser M, Chatelain E, Ioset JR.
Abstract : We have previously shown that 3-nitro-1H-1,2,4-triazole-based amines demonstrate significant trypanocidal activity, in particular against Trypanosoma cruzi, the causative parasite of Chagas disease. In the present work we further expanded our research by evaluating in vitro the trypanocidal activity of nitrotriazole-based piperazines and nitrotriazole-based 2-amino-1,3-benzothiazoles to establish additional SARs. All nitrotriazole-based derivatives were active or moderately active against T. cruzi; however two of them did not fulfill the selectivity criteria. Five derivatives were active or moderately active against Trypanosoma brucei rhodesiense while one derivative was moderately active against Leishmania donovani. Active compounds against T. cruzi demonstrated selectivity indexes (toxicity to host cells/toxicity to T. cruzi amastigotes) from 117 to 1725 and 12 of 13 compounds were up to 39-fold more potent than the reference compound benznidazole. Detailed SARs are discussed.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
89.28
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
93.25
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Antiparasitic activity against promastigote forms of Leishmania donovani MHOM/ET/67/HU3) infected in RAW 264.7 cells after 48 hrs by SYBR Green I assay
|
Leishmania donovani
|
700.0
nM
|
|
Journal : MedChemComm
Title : Introduction of methionine mimics on 3-arylthiophene: influence on protein farnesyltransferase inhibition and on antiparasitic activity
Year : 2013
Volume : 4
Issue : 6
First Page : 1034
Last Page : 1041
Authors : Bosc D, Mouray E, Grellier P, Cojean S, Loiseau PM, Dubois J
|
Antiprotozoal activity against Leishmania donovani MHOMET-67/L82
|
Leishmania donovani
|
280.0
nM
|
|
Journal : MedChemComm
Title : Synthesis of cyanine dyes and investigation of their in vitro antiprotozoal activities
Year : 2012
Volume : 3
Issue : 11
First Page : 1435
Last Page : 1442
Authors : Ge J, Zhang Q, Lu J, Kaiser M, Wittlin S, Brun R, Ihara M
|
Antipromastigote activity against Leishmania donovani MHOM/IN/80/Dd8 expressing luciferase firefly reporter gene at 25 uM after 72 hrs by luminescence assay
|
Leishmania donovani
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of chalcones as potential antileishmanial agents.
Year : 2014
Volume : 81
First Page : 359
Last Page : 366
Authors : Gupta S, Shivahare R, Korthikunta V, Singh R, Gupta S, Tadigoppula N.
Abstract : Antileishmanial activities of thirty-five synthetic chalcones have been examined. Among them, ten compounds (4, 6, 16, 22, 23, 24, 25, 29, 35 and 37) exhibited potent in vitro activity (IC50 range from 1.70 to 8 μM) against extracellular promastigotes and intracellular amastigotes form of Leishmania donovani. Two promising compounds 22 and 37 were tested in vivo in L. donovani/hamster model. Chalcone 37 showed 83.32% parasite inhibition at a dose of 50 mg/kg for 10 days whereas, 75.89% parasite inhibition at 100 mg/kg dose for 5 days by intraperitoneal route at day 7 post-treatment.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 infected in golden hamster assessed as inhibition of amastigotes multiplication at 30 mg/kg, po for 5 days treatment started 15 days after infection measured on day 7
|
Leishmania donovani
|
98.5
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of chalcones as potential antileishmanial agents.
Year : 2014
Volume : 81
First Page : 359
Last Page : 366
Authors : Gupta S, Shivahare R, Korthikunta V, Singh R, Gupta S, Tadigoppula N.
Abstract : Antileishmanial activities of thirty-five synthetic chalcones have been examined. Among them, ten compounds (4, 6, 16, 22, 23, 24, 25, 29, 35 and 37) exhibited potent in vitro activity (IC50 range from 1.70 to 8 μM) against extracellular promastigotes and intracellular amastigotes form of Leishmania donovani. Two promising compounds 22 and 37 were tested in vivo in L. donovani/hamster model. Chalcone 37 showed 83.32% parasite inhibition at a dose of 50 mg/kg for 10 days whereas, 75.89% parasite inhibition at 100 mg/kg dose for 5 days by intraperitoneal route at day 7 post-treatment.
|
Antileishmanial activity against extracellular promastigote form of Leishmania donovani MHOM/IN/80/Dd8 expressing firefly luciferase gene assessed as inhibition of parasitic multiplication at 25 uM after 96 hrs by luminescence analysis
|
Leishmania donovani
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and biological studies of chromenochalcones as potential antileishmanial agents.
Year : 2014
Volume : 57
Issue : 8
First Page : 3342
Last Page : 3357
Authors : Shivahare R, Korthikunta V, Chandasana H, Suthar MK, Agnihotri P, Vishwakarma P, Chaitanya TK, Kancharla P, Khaliq T, Gupta S, Bhatta RS, Pratap JV, Saxena JK, Gupta S, Tadigoppula N.
Abstract : Antileishmanial activities of a library of synthetic chalcone analogues have been examined. Among them, five compounds (11, 14, 16, 17, 22, and 24) exhibited better activity than the marketed drug miltefosine in in vitro studies against the intracellular amastigotes form of Leishmania donovani. Three promising compounds, 16, 17, and 22, were tested in a L. donovani/hamster model. Oral administration of chalcone 16, at a concentration of 100 mg/kg of body weight per day for 5 consecutive days, resulted in >84% parasite inhibition at day 7 post-treatment and it retained the activity until day 28. The molecular and immunological studies revealed that compound 16 has a dual nature to act as a direct parasite killing agent and as a host immunostimulant. Pharmacokinetics and serum albumin binding studies also suggest that compound 16 has the potential to be a candidate for the treatment of the nonhealing form of leishmaniasis.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 amastigotes infected in syrian golden hamster assessed as decrease in parasite count in spleen at 30 mg/kg/day, po for 5 days measured on day 7 after last dose administration by giemsa staining
|
Leishmania donovani
|
98.5
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and biological studies of chromenochalcones as potential antileishmanial agents.
Year : 2014
Volume : 57
Issue : 8
First Page : 3342
Last Page : 3357
Authors : Shivahare R, Korthikunta V, Chandasana H, Suthar MK, Agnihotri P, Vishwakarma P, Chaitanya TK, Kancharla P, Khaliq T, Gupta S, Bhatta RS, Pratap JV, Saxena JK, Gupta S, Tadigoppula N.
Abstract : Antileishmanial activities of a library of synthetic chalcone analogues have been examined. Among them, five compounds (11, 14, 16, 17, 22, and 24) exhibited better activity than the marketed drug miltefosine in in vitro studies against the intracellular amastigotes form of Leishmania donovani. Three promising compounds, 16, 17, and 22, were tested in a L. donovani/hamster model. Oral administration of chalcone 16, at a concentration of 100 mg/kg of body weight per day for 5 consecutive days, resulted in >84% parasite inhibition at day 7 post-treatment and it retained the activity until day 28. The molecular and immunological studies revealed that compound 16 has a dual nature to act as a direct parasite killing agent and as a host immunostimulant. Pharmacokinetics and serum albumin binding studies also suggest that compound 16 has the potential to be a candidate for the treatment of the nonhealing form of leishmaniasis.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 amastigotes infected in syrian golden hamster assessed as decrease in parasite count in spleen at 30 mg/kg/day, po for 5 days measured on day 28 after last dose administration by giemsa staining
|
Leishmania donovani
|
83.2
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and biological studies of chromenochalcones as potential antileishmanial agents.
Year : 2014
Volume : 57
Issue : 8
First Page : 3342
Last Page : 3357
Authors : Shivahare R, Korthikunta V, Chandasana H, Suthar MK, Agnihotri P, Vishwakarma P, Chaitanya TK, Kancharla P, Khaliq T, Gupta S, Bhatta RS, Pratap JV, Saxena JK, Gupta S, Tadigoppula N.
Abstract : Antileishmanial activities of a library of synthetic chalcone analogues have been examined. Among them, five compounds (11, 14, 16, 17, 22, and 24) exhibited better activity than the marketed drug miltefosine in in vitro studies against the intracellular amastigotes form of Leishmania donovani. Three promising compounds, 16, 17, and 22, were tested in a L. donovani/hamster model. Oral administration of chalcone 16, at a concentration of 100 mg/kg of body weight per day for 5 consecutive days, resulted in >84% parasite inhibition at day 7 post-treatment and it retained the activity until day 28. The molecular and immunological studies revealed that compound 16 has a dual nature to act as a direct parasite killing agent and as a host immunostimulant. Pharmacokinetics and serum albumin binding studies also suggest that compound 16 has the potential to be a candidate for the treatment of the nonhealing form of leishmaniasis.
|
Antiparasitic activity against axenic amastigote forms of Leishmania donovani MHOM/ET/67/L82 assessed as inhibition of growth after 72 hrs by resazurin assay
|
Leishmania donovani
|
390.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides as potential antitrypanosomal agents.
Year : 2014
Volume : 87
First Page : 79
Last Page : 88
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Kaiser M.
Abstract : We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.
|
Anti-leishmanial activity against Leishmania donovani MHOM/IND/80/Dd8 amastigotes infected in human THP1 cells incubated for 72 hrs at 37 degC by DAPI staining based assay
|
Leishmania donovani
|
880.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and anti-leishmanial activity of novel symmetrical bispyridinium cyclophanes.
Year : 2015
Volume : 89
First Page : 362
Last Page : 369
Authors : Gómez-Pérez V, Manzano JI, García-Hernández R, Castanys S, Gamarro F, Campos JM.
Abstract : Nine novel symmetrical bispyridinium cyclophanes have been synthesized. They are rigid derivatives with an upper spacer which joins the two exocyclic amino groups, and a lower spacer joining the two positively charged nitrogen atoms. At least one of the two spacers is an aliphatic linker, such as an alkane or oxyalkane fragment. The activity of these compounds has been evaluated against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major. All the cyclophanes are more active against L. major, with EC50 in intracellular amastigotes of between 1 and 17 μM, they exhibit very low toxicity against mammalian cells THP-1 and in some cases they present a higher selectivity index than the reference anti-leishmanial drugs amphotericin B and miltefosine. Compound 9 [2,8-Diaza-1,9(4,1)-dipyridinacyclotetradecaphan-1(1),9(1)-bis(ilium) dibromide] is the most active one among cyclophane derivatives against intracellular amastigotes of L. donovani (EC50 7.6 ± 0.2 μM) while L. major amastigotes are 6-fold more susceptible to the compound (EC50 1.26 ± 0.3 μM). Compound 9 produces depolarization of the mitochondrial membrane and a decrease in the ATP levels that leads to death of the parasites. The anti-leishmanial activity of this macrocyclic salts is independent of the Leishmania enzymes ethanolamine kinase and choline/ethanolamine kinase.
|
Antiparasitic activity against Leishmania donovani
|
Leishmania donovani
|
459.0
nM
|
|
Journal : J. Nat. Prod.
Title : Xenortide Biosynthesis by Entomopathogenic Xenorhabdus nematophila.
Year : 2014
Volume : 77
Issue : 8
First Page : 1976
Last Page : 1980
Authors : Reimer D, Nollmann FI, Schultz K, Kaiser M, Bode HB.
Abstract : The biosynthesis gene cluster of the xenortides and a new derivative, xenortide D, which is produced in only trace amounts, was identified in Xenorhabdus nematophila. The structure of xenortide D was elucidated using a combination of labeling experiments followed by MS analysis and was confirmed by synthesis. Bioactivity tests revealed a weak activity of tryptamine-carrying xenortides against Plasmodium falciparum and Trypanosoma brucei.
|
Antimicrobial activity against amastigote form of Leishmania donovani MHOM/ET/67/L82 after 70 hrs by alamar blue assay
|
Leishmania donovani
|
0.2
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei.
Year : 2014
Volume : 57
Issue : 15
First Page : 6393
Last Page : 6402
Authors : Ferrins L, Gazdik M, Rahmani R, Varghese S, Sykes ML, Jones AJ, Avery VM, White KL, Ryan E, Charman SA, Kaiser M, Bergström CA, Baell JB.
Abstract : A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
|
Antileishmanial activity against promastigote stage of Leishmania aethiopica after 24 hrs by alamar blue staining-based fluorescence assay
|
Leishmania aethiopica
|
3.192
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : New heterocyclic hybrids of pyrazole and its bioisosteres: design, synthesis and biological evaluation as dual acting antimalarial-antileishmanial agents.
Year : 2015
Volume : 94
First Page : 30
Last Page : 44
Authors : Bekhit AA, Hassan AM, Abd El Razik HA, El-Miligy MM, El-Agroudy EJ, Bekhit Ael-D.
Abstract : A new series of pyrazole derivatives were synthesized by hybridization with five-membered heterocyclic moieties such as thiazoles, thiazolidinones, 1,3,4-thiadiazoles and pyrazolines. The compounds were evaluated for their in vivo antimalarial activity against Plasmodium berghei infected mice and the most active derivatives were further examined for their in vitro antimalarial activity against chloroquine resistant (RKL9) strain of Plasmodium falciparum. Compounds 2c, 2d, 4b, 4c, 4d, 5a, 6c, 8c and 9b had more than 90% parasite suppression activity of that found with the antimalarial reference standard drug, chloroquine phosphate and had lower IC50 values than chloroquine. Compounds 4b and 9b were the most active derivatives, and their activities were 5-fold higher than chloroquine. All the newly synthesized compounds were evaluated for their in vitro antileishmanial activity against Leishmania aethiopica promastigotes and amastigote. The results showed that compounds 2c, 2d, 3d, 4b, 4c, 4d and 5a had lower or similar IC50 values than the reference standard drugs, amphotericin B and miltefosine. Compound 3d had the highest antileishmanial activity. Collectively, compounds 2c, 2d, 4b, 4c, 4d and 5a exhibited dual activity against malaria and leishmaniasis and were safe and well tolerated by the experimental animals orally up to 300 mg/kg and parenterally up to 100 mg/kg.
|
Antileishmanial activity against amastigote stage of Leishmania aethiopica after 72 hrs by resazurin staining-based fluorescence assay
|
Leishmania aethiopica
|
0.3
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : New heterocyclic hybrids of pyrazole and its bioisosteres: design, synthesis and biological evaluation as dual acting antimalarial-antileishmanial agents.
Year : 2015
Volume : 94
First Page : 30
Last Page : 44
Authors : Bekhit AA, Hassan AM, Abd El Razik HA, El-Miligy MM, El-Agroudy EJ, Bekhit Ael-D.
Abstract : A new series of pyrazole derivatives were synthesized by hybridization with five-membered heterocyclic moieties such as thiazoles, thiazolidinones, 1,3,4-thiadiazoles and pyrazolines. The compounds were evaluated for their in vivo antimalarial activity against Plasmodium berghei infected mice and the most active derivatives were further examined for their in vitro antimalarial activity against chloroquine resistant (RKL9) strain of Plasmodium falciparum. Compounds 2c, 2d, 4b, 4c, 4d, 5a, 6c, 8c and 9b had more than 90% parasite suppression activity of that found with the antimalarial reference standard drug, chloroquine phosphate and had lower IC50 values than chloroquine. Compounds 4b and 9b were the most active derivatives, and their activities were 5-fold higher than chloroquine. All the newly synthesized compounds were evaluated for their in vitro antileishmanial activity against Leishmania aethiopica promastigotes and amastigote. The results showed that compounds 2c, 2d, 3d, 4b, 4c, 4d and 5a had lower or similar IC50 values than the reference standard drugs, amphotericin B and miltefosine. Compound 3d had the highest antileishmanial activity. Collectively, compounds 2c, 2d, 4b, 4c, 4d and 5a exhibited dual activity against malaria and leishmaniasis and were safe and well tolerated by the experimental animals orally up to 300 mg/kg and parenterally up to 100 mg/kg.
|
Antiprotozoal activity against axenic amastigote stage of Leishmania donovani MHOM-ET-67/L82 by alamar-blue assay
|
Leishmania donovani
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Antiprotozoal activity and DNA binding of dicationic acridones.
Year : 2015
Volume : 58
Issue : 4
First Page : 1940
Last Page : 1949
Authors : Montalvo-Quirós S, Taladriz-Sender A, Kaiser M, Dardonville C.
Abstract : Dicationic acridone derivatives were synthesized and their antiparasitic activity was evaluated. Acridones displayed in vitro nanomolar IC50 values against Trypanosoma brucei rhodesiense STIB900 with selectivity indices >1000. Compounds 1b, 3a, and 3b were as potent as the reference drug melarsoprol in this assay. Submicromolar-range activities were observed against wild-type (NF54) and resistant (K1) strains of Plasmodium falciparum, whereas no significant activity was detected against Trypanosoma cruzi or Leishmania donovani. Compounds 1a and 1b were curative in the STIB900 mouse model for human African trypanosomiasis. UV spectrophotometric titrations and circular dichroism (CD) experiments with fish sperm (FS) DNA showed that these compounds form complexes with DNA with binding affinities in the 10(4) M(-1) range. Biological and biophysical data show that antiparasitic activity, toxicity, and DNA binding of this series of acridones are dependent on the relative position of both imidazolinium cations on the heterocyclic scaffold.
|
PubChem BioAssay. SW480 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
478.17
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. RKO viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
437.18
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. SNU-C1 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
964.87
nM
|
|
Title : PubChem BioAssay data set
|
Antileishmanial activity against Leishmania donovani infected in visceral leishmaniasis BALB/c mouse model assessed as reduction of liver parasitemia at 10 mg/kg/day, ip administered for 5 days
|
Leishmania donovani
|
93.6
%
|
|
Journal : Bioorg. Med. Chem.
Title : SAR refinement of antileishmanial N(2),N(4)-disubstituted quinazoline-2,4-diamines.
Year : 2015
Volume : 23
Issue : 16
First Page : 5182
Last Page : 5189
Authors : Zhu X, Van Horn KS, Barber MM, Yang S, Wang MZ, Manetsch R, Werbovetz KA.
Abstract : Visceral leishmaniasis is a neglected parasitic disease that has a high fatality rate in the absence of treatment. New drugs that are inexpensive, orally active, and effective could be useful tools in the fight against this disease. We previously showed that N(2),N(4)-disubstituted quinazoline-2,4-diamines displayed low- to sub-micromolar potency against intracellular Leishmania, and lead compound N(4)-(furan-2-ylmethyl)-N(2)-isopropyl-7-methylquinazoline-2,4-diamine (4) exhibited modest efficacy in an acute murine model of visceral leishmaniasis. In the present work, thirty-one N(2),N(4)-disubstituted quinazoline-2,4-diamines that had not previously been examined for their antileishmanial activity were evaluated for their potency and selectivity against Leishmania donovani, the causative parasite of visceral leishmaniasis. Quinazoline-2,4-diamines with aromatic substituents at both N(2) and N(4) exhibited potent in vitro antileishmanial activity but relatively low selectivity, while compounds substituted with small alkyl groups at either N(2) or N(4) generally showed lower antileishmanial potency but were less toxic to a murine macrophage cell line. Based on their in vitro antileishmanial potency, N(4)-benzyl-N(2)-(4-chlorobenzyl)quinazoline-2,4-diamine (15) and N(2)-benzyl-N(4)-isopropylquinazoline-2,4-diamine (40) were selected for in vivo evaluation of their pharmacokinetic and antileishmanial properties. While 15 displayed a longer plasma half-life and a greater area under the curve than 40, both compounds showed low efficacy in an acute murine visceral leishmaniasis model. Although the present study did not identify new quinazoline-2,4-diamines with promising in vivo efficacy, the reduced in vitro toxicity of derivatives bearing small alkyl groups at either N(2) or N(4) may provide clues for the design of safe and effective antileishmanial quinazolines.
|
Antitrypanosomal activity against amastigotes of Leishmania donovani MHOM/ET/67/L82 after 72 hrs by inverted microscope analysis
|
Leishmania donovani
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile.
Year : 2015
Volume : 58
Issue : 16
First Page : 6422
Last Page : 6434
Authors : Prati F, Bergamini C, Molina MT, Falchi F, Cavalli A, Kaiser M, Brun R, Fato R, Bolognesi ML.
Abstract : A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases.
|
Leishmanicidal activity against Leishmania braziliensis MHOM/BR/01/BA788 after 48 hrs
|
Leishmania braziliensis
|
700.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel dialkylphosphorylhydrazones: Synthesis, leishmanicidal evaluation and theoretical investigation of the proposed mechanism of action.
Year : 2015
Volume : 101
First Page : 1
Last Page : 12
Authors : da Matta CB, de Queiroz AC, Santos MS, Alexandre-Moreira MS, Gonçalves VT, Del Cistia Cde N, Sant'Anna CM, DaCosta JB.
Abstract : As part of a program to develop new drugs for the treatment of neglected diseases, new dialkylphosphorylhydrazones were synthesized and evaluated against the trypanosomatid parasites Leishmania braziliensis and Leishmania amazonensis. The synthesis of these compounds proved satisfactory with yields ranging from moderate to good. The most active compounds against L. braziliensis presented IC50 values in the 10(-2) μM range, similar to that of the reference drug pentamidine. Two compounds, 4m and 4n, showed a significant dose dependent decrease in the infection index of L. amazonensis infected macrophages and caused a complete healing of nodules and ulcers when tested in vivo against L. amazonensis-infected mice, but the control of parasite burden at the inoculation site was statistically significant only in the case of treatment with 4n. A target fishing (reverse docking) approach using molecular docking with 15 enzymes of L. braziliensis indicated that the probable target of the active compounds was hexokinase, the first enzyme of the glycolytic pathway.
|
Antiamastigote activity against Leishmania amazonensis MHOM/BR/87/BA125 infected in BALB/c mouse peritoneal macrophages assessed as inhibition of infection index at 100 uM after 48 hrs by Giemsa staining
|
Leishmania amazonensis
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel dialkylphosphorylhydrazones: Synthesis, leishmanicidal evaluation and theoretical investigation of the proposed mechanism of action.
Year : 2015
Volume : 101
First Page : 1
Last Page : 12
Authors : da Matta CB, de Queiroz AC, Santos MS, Alexandre-Moreira MS, Gonçalves VT, Del Cistia Cde N, Sant'Anna CM, DaCosta JB.
Abstract : As part of a program to develop new drugs for the treatment of neglected diseases, new dialkylphosphorylhydrazones were synthesized and evaluated against the trypanosomatid parasites Leishmania braziliensis and Leishmania amazonensis. The synthesis of these compounds proved satisfactory with yields ranging from moderate to good. The most active compounds against L. braziliensis presented IC50 values in the 10(-2) μM range, similar to that of the reference drug pentamidine. Two compounds, 4m and 4n, showed a significant dose dependent decrease in the infection index of L. amazonensis infected macrophages and caused a complete healing of nodules and ulcers when tested in vivo against L. amazonensis-infected mice, but the control of parasite burden at the inoculation site was statistically significant only in the case of treatment with 4n. A target fishing (reverse docking) approach using molecular docking with 15 enzymes of L. braziliensis indicated that the probable target of the active compounds was hexokinase, the first enzyme of the glycolytic pathway.
|
Antiparasitic activity against axenic amastigote stage of Leishmania donovani MHOM-ET-67/L82 assessed as parasite growth inhibition after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
162.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation.
Year : 2015
Volume : 23
Issue : 19
First Page : 6467
Last Page : 6476
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, O'Shea IP, Wilkinson SR, Kaiser M, Chatelain E, Ioset JR.
Abstract : 3-Nitro-1H-1,2,4-triazole- and 2-nitro-1H-imidazole-based amides with an aryloxy-phenyl core were synthesized and evaluated as antitrypanosomal agents. All 3-nitrotriazole-based derivatives were extremely potent anti-Trypanosoma cruzi agents at sub nM concentrations and exhibited a high degree of selectivity for the parasite. The 2-nitroimidazole analogs were only moderately active against T. cruzi amastigotes and exhibited low selectivity. Both types of compound were active against Leishmania donovani axenic amastigotes with excellent selectivity for the parasite, whereas three 2-nitroimidazole-based analogs were also moderately active against infected macrophages. However, no compound demonstrated selective activity against Trypanosoma brucei rhodesiense. The most potent in vitro anti-T. cruzi compounds were tested in an acute murine model and reduced the parasites to an undetectable level after five days of treatment at 13 mg/kg/day. Such compounds are potential inhibitors of T. cruzi CYP51 and, being excellent substrates for the type I nitroreductase (NTR) which is specific to trypanosomatids, work as prodrugs and constitute a new generation of effective and more affordable antitrypanosomal agents.
|
Antiparasitic activity against amastigote form of Leishmania donovani MHOM/ET/67/L82 assessed as growth inhibition after 70 hrs by resazurin dye-based fluorometric analysis
|
Leishmania donovani
|
572.0
nM
|
|
Journal : MedChemComm
Title : Synthesis and evaluation of phenoxymethylbenzamide analogues as anti-trypanosomal agents
Year : 2015
Volume : 6
Issue : 3
First Page : 403
Last Page : 406
Authors : Manos-Turvey A, Watson EE, Sykes ML, Jones AJ, Baell JB, Kaiser M, Avery VM, Payne RJ
|
Antileishmanial activity against axenic amastigote forms of Leishmania donovani MHOM/ET/67/L82 assessed as inhibition of growth
|
Leishmania donovani
|
162.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents.
Year : 2015
Volume : 103
First Page : 325
Last Page : 334
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, O'Shea IP, Wilkinson SR, Kaiser M.
Abstract : Novel linear 3-nitro-1H-1,2,4-triazole-based piperazides were synthesized and evaluated as antitrypanosomal agents. In addition, some bisarylpiperazine-ethanones which were formed as by-products were also screened for antiparasitic activity. Most 3-nitrotriazole-based derivatives were potent and selective against Trypanosoma cruzi parasites, but only one displayed these desired properties against Trypanosoma brucei rhodesiense. Moreover, two 3-nitrotriazole-based chlorophenylpiperazides were moderately and selectively active against Leishmania donovani. Although the bisarylpiperazine-ethanones were active or moderately active against T. cruzi, none of them demonstrated an acceptable selectivity. In general, 3-nitrotriazole-based piperazides were less toxic to host L6 cells than the previously evaluated 3-nitrotriazole-based piperazines and seven of 13 were 1.54- to 31.2-fold more potent antichagasic agents than the reference drug benznidazole. Selected compounds showed good ADMET characteristics. One potent in vitro antichagasic compound (3) was tested in an acute murine model and demonstrated antichagasic activity after a 10-day treatment of 15 mg/kg/day. However, neither compound 3 nor benznidazole showed a statistically significant P value compared to control due to high variability in parasite burden among the untreated animals. Working as prodrugs, 3-nitrotriazole-based piperazides were excellent substrates of trypanosomal type I nitroreductases and constitute a novel class of potentially effective and more affordable antitrypanosomal agents.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/HU3 amastigotes infected in mouse RAW264.7 cells assessed as growth inhibition after 48 hrs by SYBR green 1 staining based fluorescence assay
|
Leishmania donovani
|
730.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Highly improved antiparasitic activity after introduction of an N-benzylimidazole moiety on protein farnesyltransferase inhibitors.
Year : 2016
Volume : 109
First Page : 173
Last Page : 186
Authors : Bosc D, Mouray E, Cojean S, Franco CH, Loiseau PM, Freitas-Junior LH, Moraes CB, Grellier P, Dubois J.
Abstract : In our search for new protein farnesyltransferase inhibitors with improved antiparasitic activities, we modified our previously developed 3-arylthiophene series of inhibitors by replacing the thioisopropyl group by different substituted imidazolylmethanamino moieties. Twenty four new derivatives were synthesized and evaluated against human and parasite farnesyltransferases, and their anti-parasitic activity was determined against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani. Introduction of a N-p-substituted-benzylimidazole led to significantly increase the inhibition of parasite proliferation in the submicromolar range. The structure of the best inhibitors was parasite dependent. Three compounds possess IC50 values at the same range as the reference miltefosine against L. donovani proliferation and other new derivatives display high level of anti-trypanosomal activity against T. cruzi, higher or in the same order of magnitude as the reference compounds benznidazole and nifurtimox.
|
Antileishmanial activity against amastigote stage of Leishmania donovani MHOM/IN/80/Dd8 infected in golden hamster at 30 mg/kg, po administered for 5 days measured on day 7 of last dose by Geimsa staining method
|
Leishmania donovani
|
98.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of a diverse indole-2-carboxamides as a potent antileishmanial chemotypes.
Year : 2016
Volume : 110
First Page : 237
Last Page : 245
Authors : Pandey S, Chauhan SS, Shivahare R, Sharma A, Jaiswal S, Gupta S, Lal J, Chauhan PM.
Abstract : A novel series of highly diverse indole-2-carboxamides was synthesized utilizing the isocyanide based multicomponent reaction (IMCR)-post modification approach and were identified as potential antileishmanial chemotype. Among the synthesized 18 analogues, 12 analogues exhibited better antileishmanial activity against intracellular amastigotes form of Leishmania donovani (IC50 values of 0.6-7.5 μM) as compared to standard drugs miltefosine and sodium stibogluconate. The compounds were also non-toxic towards Vero cells. Compounds 2b, 2m and 2p with significant in vitro activity were then evaluated for their in vivo efficacy following intraperitoneal route. These three compounds at a concentration of 50 mg/kg/day for 5 consecutive days showed 70.0, 63.5 and 63.4% inhibition of Leishmania amastigotes, respectively at day 7 post treatment in hamster model of visceral leishmaniasis.
|
Antileishmanial activity against amastigote stage of Leishmania infantum in early curative golden hamster chronic visceral leishmaniasis model assessed as reduction in parasite load in liver at 20 mg/kg, po qd administered for 5 days by Giemsa staining-based microscopic analysis
|
Leishmania infantum
|
81.8
%
|
|
Journal : J. Med. Chem.
Title : Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.
Year : 2016
Volume : 59
Issue : 6
First Page : 2530
Last Page : 2550
Authors : Thompson AM, O'Connor PD, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Martin D, Franzblau SG, Wan B, Wang Y, Ma Z, Denny WA.
Abstract : 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.
|
Antileishmanial activity against amastigote stage of Leishmania infantum in early curative golden hamster chronic visceral leishmaniasis model assessed as reduction in parasite load in spleen at 20 mg/kg, po qd administered for 5 days by Giemsa staining-based microscopic analysis
|
Leishmania infantum
|
92.0
%
|
|
Journal : J. Med. Chem.
Title : Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.
Year : 2016
Volume : 59
Issue : 6
First Page : 2530
Last Page : 2550
Authors : Thompson AM, O'Connor PD, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Martin D, Franzblau SG, Wan B, Wang Y, Ma Z, Denny WA.
Abstract : 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.
|
Antileishmanial activity against amastigote stage of Leishmania infantum in early curative golden hamster chronic visceral leishmaniasis model assessed as reduction in parasite load in bone marrow at 20 mg/kg, po qd administered for 5 days by Giemsa staining-based microscopic analysis
|
Leishmania infantum
|
84.7
%
|
|
Journal : J. Med. Chem.
Title : Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.
Year : 2016
Volume : 59
Issue : 6
First Page : 2530
Last Page : 2550
Authors : Thompson AM, O'Connor PD, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Martin D, Franzblau SG, Wan B, Wang Y, Ma Z, Denny WA.
Abstract : 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.
|
Antileishmanial activity against Leishmania donovani LV82 promastigotes infected in BALB/c mouse model of visceral leishmaniasis assessed as suppression of liver parasitemia at 10 mg/kg/day, ip QD administered 1 week post infection for 5 consecutive days and measured 2 weeks post infection
|
Leishmania donovani
|
98.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents.
Year : 2016
Volume : 26
Issue : 10
First Page : 2551
Last Page : 2556
Authors : Zhu X, Farahat AA, Mattamana M, Joice A, Pandharkar T, Holt E, Banerjee M, Gragg JL, Hu L, Kumar A, Yang S, Wang MZ, Boykin DW, Werbovetz KA.
Abstract : Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis models when given orally. Eighteen compounds containing a single pyridylimidamide terminal group (mono-AIAs) were synthesized and evaluated for their antileishmanial potential. Six of these compounds exhibited sub-micromolar potency against both intracellular Leishmania donovani and Leishmania amazonensis amastigotes, and three of these compounds also displayed selectivity indexes of 25 or greater for the parasites compared to a J774 macrophage cell line. When given orally at a dose of 100mg/kg/day for five days, compound 1b (N-(3-isopropoxy-4-(5-phenylfuran-2-yl)phenyl)picolinimidamide methanesulfonate) reduced liver parasitemia by 46% in L. donovani-infected mice. Mono-AIAs are thus a new class of candidate molecules for antileishmanial drug development.
|
Antileishmanial activity against Leishmania donovani LV82 promastigotes infected in BALB/c mouse model of visceral leishmaniasis assessed as suppression of liver parasitemia at 10 mg/kg/day, po QD administered 1 week post infection for 5 consecutive days and measured 2 weeks post infection
|
Leishmania donovani
|
96.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents.
Year : 2016
Volume : 26
Issue : 10
First Page : 2551
Last Page : 2556
Authors : Zhu X, Farahat AA, Mattamana M, Joice A, Pandharkar T, Holt E, Banerjee M, Gragg JL, Hu L, Kumar A, Yang S, Wang MZ, Boykin DW, Werbovetz KA.
Abstract : Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis models when given orally. Eighteen compounds containing a single pyridylimidamide terminal group (mono-AIAs) were synthesized and evaluated for their antileishmanial potential. Six of these compounds exhibited sub-micromolar potency against both intracellular Leishmania donovani and Leishmania amazonensis amastigotes, and three of these compounds also displayed selectivity indexes of 25 or greater for the parasites compared to a J774 macrophage cell line. When given orally at a dose of 100mg/kg/day for five days, compound 1b (N-(3-isopropoxy-4-(5-phenylfuran-2-yl)phenyl)picolinimidamide methanesulfonate) reduced liver parasitemia by 46% in L. donovani-infected mice. Mono-AIAs are thus a new class of candidate molecules for antileishmanial drug development.
|
Antileishmanial activity against axenic amastigote stage of Leishmania donovani MHOM/ET/67/L82 assessed as inhibition of parasite growth after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
156.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds.
Year : 2016
Volume : 117
First Page : 179
Last Page : 186
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Szular J, Kaiser M.
Abstract : A small series of 5-nitro-2-aminothiazole-based amides containing arylpiperazine-, biphenyl- or aryloxyphenyl groups in their core were synthesized and evaluated as antitrypanosomatid agents. All tested compounds were active or moderately active against Trypanosoma cruzi amastigotes in infected L6 cells and Trypanosoma brucei brucei, four of eleven compounds were moderately active against Leishmania donovani axenic parasites while none were deemed active against T. brucei rhodesiense. For the most active/moderately active compounds a moderate selectivity against each parasite was observed. There was good correlation between lipophilicity (clogP value) and antileishmanial activity or toxicity against L6 cells. Similarly, good correlation existed between clogP values and IC50 values against T. cruzi in structurally related subgroups of compounds. Three compounds were more potent as antichagasic agents than benznidazole but were not activated by the type I nitrorectusase (NTR).
|
Leishmanicidal activity against promastigote form of Leishmania donovani MHOM/IN/80/DD8 after 48 hrs by resazurin dye-based fluorometric method
|
Leishmania donovani
|
150.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and antileishmanial activity of C7- and C12-functionalized dehydroabietylamine derivatives.
Year : 2016
Volume : 121
First Page : 445
Last Page : 450
Authors : Dea-Ayuela MA, Bilbao-Ramos P, Bolás-Fernández F, González-Cardenete MA.
Abstract : Abietane-type diterpenoids, either naturally occurring or synthetic, have shown a wide range of pharmacological actions, including antiprotozoal properties. In this study, we report on the antileishmanial evaluation of a series of (+)-dehydroabietylamine derivatives functionalized at C7 and/or C12. Thus, the activity in vitro against Leishmania infantum, Leishmania donovani, Leishmania amazonensis and Leishmania guyanensis, was studied. Most of the benzamide derivatives showed activities at low micromolar concentration against cultured promastigotes of Leishmania spp. (IC50 = 2.2-46.8 μM), without cytotoxicity on J774 macrophage cells. Compound 15, an acetamide, was found to be the most active leishmanicidal agent, though it presented some cytotoxicity on J774 cells. Among the benzamide derivatives, compounds 8 and 10, were also active against L. infantum intracellular amastigotes, being 18- and 23-fold more potent than the reference compound miltefosine, respectively. Some structure-activity relationships have been identified for the antileishmanial activity in these dehydroabietylamine derivatives.
|
Antileishmanial activity against Leishmania donovani amastigote forms infected in Balb/c mouse assessed as inhibition of parasitic burden in liver at 5 mg/kg, po administered for 5 consecutive days measured on day 7 post last treatment by Giemsa staining based assay relative to control
|
Leishmania donovani
|
75.0
%
|
|
Journal : J Med Chem
Title : Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.
Year : 2017
Volume : 60
Issue : 3
First Page : 1041
Last Page : 1059
Authors : Anand D, Yadav PK, Patel OP, Parmar N, Maurya RK, Vishwakarma P, Raju KS, Taneja I, Wahajuddin M, Kar S, Yadav PP.
Abstract : A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
|
Antileishmanial activity against Leishmania donovani amastigote forms infected in Balb/c mouse assessed as inhibition of parasitic burden in spleen at 5 mg/kg, po administered for 5 consecutive days measured on day 7 post last treatment by Giemsa staining based assay relative to control
|
Leishmania donovani
|
61.0
%
|
|
Journal : J Med Chem
Title : Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.
Year : 2017
Volume : 60
Issue : 3
First Page : 1041
Last Page : 1059
Authors : Anand D, Yadav PK, Patel OP, Parmar N, Maurya RK, Vishwakarma P, Raju KS, Taneja I, Wahajuddin M, Kar S, Yadav PP.
Abstract : A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
|
Decrease in TGFbeta level in Balb/c mouse splenocytes infected with Leishmania donovani amastigote forms at 25 mg/kg, po administered for 5 consecutive days measured on day 4 post last treatment by sandwich ELISA relative to control
|
Mus musculus
|
87.5
%
|
|
Journal : J Med Chem
Title : Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.
Year : 2017
Volume : 60
Issue : 3
First Page : 1041
Last Page : 1059
Authors : Anand D, Yadav PK, Patel OP, Parmar N, Maurya RK, Vishwakarma P, Raju KS, Taneja I, Wahajuddin M, Kar S, Yadav PP.
Abstract : A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
|
Decrease in IL-10 level in Balb/c mouse splenocytes infected with Leishmania donovani amastigote forms at 25 mg/kg, po administered for 5 consecutive days measured on day 4 post last treatment by sandwich ELISA relative to control
|
Mus musculus
|
88.7
%
|
|
Journal : J Med Chem
Title : Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.
Year : 2017
Volume : 60
Issue : 3
First Page : 1041
Last Page : 1059
Authors : Anand D, Yadav PK, Patel OP, Parmar N, Maurya RK, Vishwakarma P, Raju KS, Taneja I, Wahajuddin M, Kar S, Yadav PP.
Abstract : A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
|
Decrease in TGFbeta level in Balb/c mouse splenocytes infected with Leishmania donovani amastigote forms at 25 mg/kg, po administered for 5 consecutive days measured on day 7 post last treatment by sandwich ELISA relative to control
|
Mus musculus
|
94.6
%
|
|
Journal : J Med Chem
Title : Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.
Year : 2017
Volume : 60
Issue : 3
First Page : 1041
Last Page : 1059
Authors : Anand D, Yadav PK, Patel OP, Parmar N, Maurya RK, Vishwakarma P, Raju KS, Taneja I, Wahajuddin M, Kar S, Yadav PP.
Abstract : A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
|
Decrease in IL-10 level in Balb/c mouse splenocytes infected with Leishmania donovani amastigote forms at 25 mg/kg, po administered for 5 consecutive days measured on day 7 post last treatment by sandwich ELISA relative to control
|
Mus musculus
|
92.9
%
|
|
Journal : J Med Chem
Title : Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.
Year : 2017
Volume : 60
Issue : 3
First Page : 1041
Last Page : 1059
Authors : Anand D, Yadav PK, Patel OP, Parmar N, Maurya RK, Vishwakarma P, Raju KS, Taneja I, Wahajuddin M, Kar S, Yadav PP.
Abstract : A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
|
Antileishmanial activity against Leishmania donovani MHOM/SD/62/ISCL2D axenic amastigotes after 72 hrs by alamar blue assay
|
Leishmania donovani
|
300.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and activity of nucleoside-based antiprotozoan compounds.
Year : 2017
Volume : 25
Issue : 7
First Page : 2091
Last Page : 2104
Authors : Tran HA, Zheng Z, Wen X, Manivannan S, Pastor A, Kaiser M, Brun R, Snyder FF, Back TG.
Abstract : Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas' disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50=110nM and SI=1010, while a modified guanosine displayed potent activities against L. donovani (IC50=60nM, SI=2720) and T. brucei (IC50=130nM, SI=1250), as well as moderate activity against T. cruzi (IC50=3.4µM, SI=48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.
|
Inhibition of biofilm formation of fluconazole-resistant Candida albicans at 2 to 4 ug/ml after 24 hrs by XTT assay
|
Candida albicans
|
90.0
%
|
|
Journal : J Med Chem
Title : Tackling Fungal Resistance by Biofilm Inhibitors.
Year : 2017
Volume : 60
Issue : 6
First Page : 2193
Last Page : 2211
Authors : Wu S, Wang Y, Liu N, Dong G, Sheng C.
Abstract : The high incidence and mortality of invasive fungal infections and serious drug resistance have become a global public health issue. The ability of fungal cells to form biofilms is an important reason for the emergence of severe resistance to most clinically available antifungal agents. Targeting fungal biofilm formation by small molecules represents a promising new strategy for the development of novel antifungal agents. This perspective will provide a comprehensive review of fungal biofilm inhibitors. In particular, discovery strategies, chemical structures, antibiofilm/antifungal activities, and structure-activity relationship studies will be discussed. Development of inhibitors to treat biofilm-related resistant fungal infections is a new yet clinically unexploited paradigm, and there is still a long way to go to clinical application. Better understanding of fungal biofilms in combination with systematic drug discovery efforts will pave the way for potential clinical applications.
|
Disruption of biofilm of fluconazole-resistant Candida albicans at 8 to 32 ug/ml after 24 hrs by XTT assay
|
Candida albicans
|
90.0
%
|
|
Journal : J Med Chem
Title : Tackling Fungal Resistance by Biofilm Inhibitors.
Year : 2017
Volume : 60
Issue : 6
First Page : 2193
Last Page : 2211
Authors : Wu S, Wang Y, Liu N, Dong G, Sheng C.
Abstract : The high incidence and mortality of invasive fungal infections and serious drug resistance have become a global public health issue. The ability of fungal cells to form biofilms is an important reason for the emergence of severe resistance to most clinically available antifungal agents. Targeting fungal biofilm formation by small molecules represents a promising new strategy for the development of novel antifungal agents. This perspective will provide a comprehensive review of fungal biofilm inhibitors. In particular, discovery strategies, chemical structures, antibiofilm/antifungal activities, and structure-activity relationship studies will be discussed. Development of inhibitors to treat biofilm-related resistant fungal infections is a new yet clinically unexploited paradigm, and there is still a long way to go to clinical application. Better understanding of fungal biofilms in combination with systematic drug discovery efforts will pave the way for potential clinical applications.
|
Antileishmanial activity against Leishmania infantum amastigotes infected in golden hamster assessed as inhibition of parasite burden in liver at 40 mg/kg, po once daily for 5 consecutive days by Giemsa staining based microscopic method relative to control
|
Leishmania infantum
|
99.0
%
|
|
Journal : J Med Chem
Title : Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.
Year : 2018
Volume : 61
Issue : 6
First Page : 2329
Last Page : 2352
Authors : Thompson AM, O'Connor PD, Marshall AJ, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, Denny WA.
Abstract : Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
|
Antileishmanial activity against Leishmania infantum amastigotes infected in golden hamster assessed as inhibition of parasite burden in spleen at 40 mg/kg, po once daily for 5 consecutive days by Giemsa staining based microscopic method relative to control
|
Leishmania infantum
|
99.5
%
|
|
Journal : J Med Chem
Title : Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.
Year : 2018
Volume : 61
Issue : 6
First Page : 2329
Last Page : 2352
Authors : Thompson AM, O'Connor PD, Marshall AJ, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, Denny WA.
Abstract : Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
|
Antileishmanial activity against Leishmania infantum amastigotes infected in golden hamster assessed as inhibition of parasite burden in bone marrow at 40 mg/kg, po once daily for 5 consecutive days by Giemsa staining based microscopic method relative to control
|
Leishmania infantum
|
96.8
%
|
|
Journal : J Med Chem
Title : Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.
Year : 2018
Volume : 61
Issue : 6
First Page : 2329
Last Page : 2352
Authors : Thompson AM, O'Connor PD, Marshall AJ, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, Denny WA.
Abstract : Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
|
Antileishmanial activity against Leishmania infantum isolate LEM3323 after 3 to 5 days
|
Leishmania infantum
|
740.0
nM
|
|
Journal : J Med Chem
Title : Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.
Year : 2018
Volume : 61
Issue : 6
First Page : 2329
Last Page : 2352
Authors : Thompson AM, O'Connor PD, Marshall AJ, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, Denny WA.
Abstract : Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
|
Antiprotozoal activity against amastigote form of Leishmania donovani MHOM/ET/67/L82 after 72 hrs by Alamar Blue assay
|
Leishmania donovani
|
130.0
nM
|
|
Journal : J Nat Prod
Title : Antiprotozoal Activity-Based Profiling of a Dichloromethane Extract from Anthemis nobilis Flowers.
Year : 2017
Volume : 80
Issue : 2
First Page : 459
Last Page : 470
Authors : De Mieri M, Monteleone G, Ismajili I, Kaiser M, Hamburger M.
Abstract : A dichlomethane extract of Anthemis nobilis flower cones showed promising in vitro antiprotozoal activity against Trypanosoma brucei rhodesiense and Leishmania donovani, with IC50 values of 1.43 ± 0.50 and 1.40 ± 0.07 μg/mL, respectively. A comprehensive profiling of the most active fractions afforded 19 sesquiterpene lactones, including 15 germacranolides, two seco-sesquiterpenes, one guaianolide sesquiterpene lactone, and one cadinane acid. Of these, 13 compounds were found to be new natural products. The compounds were characterized by extensive spectroscopic data analysis (1D and 2D NMR, HRMS, circular dichroism) and computational methods, and their in vitro antiprotozoal activity was evaluated. The furanoheliangolide derivative 15 showed high potency and selectivity in vitro against T. b. rhodesiense bloodstream forms (IC50 0.08 ± 0.01 μM; SI 63). In silico calculations were consistent with the drug-like properties of 15.
|
Antiparasitic activity against Leishmania donovani MHOM-ET-67/L82 axenic amastigotes after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
250.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Lead selection of antiparasitic compounds from a focused library of benzenesulfonyl derivatives of heterocycles.
Year : 2017
Volume : 27
Issue : 17
First Page : 3945
Last Page : 3949
Authors : Pagliero RJ, Kaiser M, Brun R, Nieto MJ, Mazzieri MR.
Abstract : A library of 89 synthetic benzenesulfonyl derivatives of heterocycles with drug-like properties was assayed for in vitro antiparasitic activity and the results were added to our previously reported derivatives for a comprehensive SAR evaluation. Four compounds showed an IC50 between 0.25 and 3μM against Leishmania donovani and low cytotoxicity. Compound G{16} (1-(2,3,5,6-tetramethylphenylsulfonyl)-2-methylindoline), was particularly interesting with an IC50 similar to the reference drug miltefosine. Seven compounds showed an IC50 below 6µM against Trypanosoma cruzi, and three of them (E{3}, E{9} and G{3}) were identified as lead scaffolds for further optimization based on their activity-toxicity profile. Two promising structures (B{15} and G{15}) showed moderate inhibitory activity against Plasmodium falciparum. In general, the presence of a benzenesulfonyl moiety improves the antiparasitic activity of the heterocycles included in this study (with the exception of Trypanosoma brucei rhodesiense), validating the criteria used in the selection of the privileged structures and diversification used to generate this library. SAR analysis showed that the presence of lipophilic and electron withdrawing groups were favorable for the antiparasitic activity.
|
Antileishmanial activity against Leishmania donovani amastigotes infected in golden hamster assessed as reduction of parasite burden in liver at 40 mg/kg, po once daily for 5 consecutive days
|
Leishmania donovani
|
92.6
%
|
|
Journal : J Med Chem
Title : 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.
Year : 2017
Volume : 60
Issue : 10
First Page : 4212
Last Page : 4233
Authors : Thompson AM, O'Connor PD, Marshall AJ, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Franzblau SG, Wan B, Wang Y, Ma Z, Cooper CB, Denny WA.
Abstract : Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.
|
Antileishmanial activity against Leishmania donovani amastigotes infected in golden hamster assessed as reduction of parasite burden in spleen at 40 mg/kg, po once daily for 5 consecutive days
|
Leishmania donovani
|
99.5
%
|
|
Journal : J Med Chem
Title : 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.
Year : 2017
Volume : 60
Issue : 10
First Page : 4212
Last Page : 4233
Authors : Thompson AM, O'Connor PD, Marshall AJ, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Franzblau SG, Wan B, Wang Y, Ma Z, Cooper CB, Denny WA.
Abstract : Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.
|
Antileishmanial activity against Leishmania donovani amastigotes infected in golden hamster assessed as reduction of parasite burden in bone marrow at 40 mg/kg, po once daily for 5 consecutive days
|
Leishmania donovani
|
89.0
%
|
|
Journal : J Med Chem
Title : 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.
Year : 2017
Volume : 60
Issue : 10
First Page : 4212
Last Page : 4233
Authors : Thompson AM, O'Connor PD, Marshall AJ, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Franzblau SG, Wan B, Wang Y, Ma Z, Cooper CB, Denny WA.
Abstract : Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.
|
Antiprotozoal activity against amastigote form of Leishmania donovani MHOM/ET/67/L82 after 72 hrs by Alamar Blue assay
|
Leishmania donovani
|
432.0
nM
|
|
Journal : J Nat Prod
Title : Dioncophyllines C2, D2, and F and Related Naphthylisoquinoline Alkaloids from the Congolese Liana Ancistrocladus ileboensis with Potent Activities against Plasmodium falciparum and against Multiple Myeloma and Leukemia Cell Lines.
Year : 2017
Volume : 80
Issue : 2
First Page : 443
Last Page : 458
Authors : Li J, Seupel R, Feineis D, Mudogo V, Kaiser M, Brun R, Brünnert D, Chatterjee M, Seo EJ, Efferth T, Bringmann G.
Abstract : Dioncophylline F (1), the first 5,8'-coupled dioncophyllaceous alkaloid (i.e., lacking an oxygen function at C-6 and possessing an R-configuration at C-3), was isolated from the recently described Congolese liana Ancistrocladus ileboensis. Two further, likewise Dioncophyllaceae-type, alkaloids, the dioncophyllines C2 (2) and D2 (3), were identified, along with the Ancistrocladaceae-type compound ancistrocladisine B (4), which is oxygenated at C-6 and S-configured at C-3. The structures of the new compounds were determined by spectroscopic, chemical, and chiroptical methods. The stereostructure of 1 was further confirmed by total synthesis. As a consequence of the lack of a methyl group ortho to their biaryl axes, both dioncophylline F (1) and the 7,8'-coupled dioncophylline D2 (3) occur as pairs of configurationally semistable and, thus, slowly interconverting atropo-diastereomers, whereas dioncophylline C2 (2), with its 5,1'-linkage, is configurationally stable at the axis. Eight further known naphthylisoquinolines were isolated from A. ileboensis, among them dioncophylline A (P-10), its 4'-O-demethyl analogue P-11, and 5'-O-methyldioncophylline D (7), which were found to display strong cytotoxic activities against multiple myeloma INA-6 cells (P-10 even stronger than the standard drug melphalan) and against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant subline, CEM/ADR5000. Moreover, the dioncophyllines 1, 3, and 7 showed high-and specific-activities against the malaria parasite Plasmodium falciparum.
|
Antiprotozoal activity against amastigote form of Leishmania donovani MHOM/ET/67/L82 after 72 hrs by alamar blue assay
|
Leishmania donovani
|
510.0
nM
|
|
Journal : J Nat Prod
Title : Antiprotozoal Linear Furanosesterterpenoids from the Marine Sponge Ircinia oros.
Year : 2017
Volume : 80
Issue : 9
First Page : 2566
Last Page : 2571
Authors : Chianese G, Silber J, Luciano P, Merten C, Erpenbeck D, Topaloglu B, Kaiser M, Tasdemir D.
Abstract : Chemical investigation of the marine sponge Ircinia oros yielded four linear furanosesterterpenoids, including the known metabolites ircinin-1 (1) and ircinin-2 (2) and two new compounds, ircinialactam E (3) and ircinialactam F (4). Their chemical structures were elucidated by using a combination of [α]D, NMR, HRMS, and FT-IR spectroscopy. The absolute configuration of C-18 in compounds 1-3 was identified as R by electronic circular dichroism (ECD) spectroscopy coupled with time-dependent density functional theory calculations. Compounds 1-4 showed moderate leishmanicidal, trypanocidal, and antiplasmodial activities (IC50 values 28-130 μM). This is the second report of rare glycinyl lactam derivatives 3 and 4 from the genus Ircinia.
|
Antileishmanial activity against Leishmania donovani amastigote forms after 72 hrs by alamar blue staining based fluorescence assay
|
Leishmania donovani
|
432.0
nM
|
|
Journal : J Nat Prod
Title : Jozilebomines A and B, Naphthylisoquinoline Dimers from the Congolese Liana Ancistrocladus ileboensis, with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line.
Year : 2017
Volume : 80
Issue : 10
First Page : 2807
Last Page : 2817
Authors : Li J, Seupel R, Bruhn T, Feineis D, Kaiser M, Brun R, Mudogo V, Awale S, Bringmann G.
Abstract : Two new naphthylisoquinoline dimers, jozilebomines A (1a) and B (1b), were isolated from the roots of the Congolese plant Ancistrocladus ileboensis, along with the known dimer jozimine A2 (2). These compounds are Dioncophyllaceae-type metabolites, i.e., lacking oxygen functions at C-6 and with an R-configuration at C-3 in their tetrahydroisoquinoline moieties. The dimers 1a and 1b consist of two 7,1'-coupled naphthylisoquinoline monomers linked through an unprecedented 3',6″-coupling in the binaphthalene core and not, as in 2, via the C-3-positions of the two naphthalene units. Thus, different from the C2-symmetric jozimine A2 (2), the new jozilebomines are constitutionally unsymmetric. The central biaryl axis of each of the three dimers is rotationally hindered, so that 1a, 1b, and 2 possess three consecutive chiral axes. The two jozilebomines have identical constitutions and the same absolute configurations at all four stereogenic centers, but differ from each other in their axial chirality. Their structural elucidation was achieved by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and calculated ECD data. They exhibited distinct and specific antiplasmodial activities. All dimers showed potent cytotoxicity against HeLa human cervical cancer cells and preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions. Furthermore, these dimers significantly inhibited the colony formation of PANC-1 cells, even when exposed to noncytotoxic concentration for a short time. Jozilebomines A (1a) and B (1b) and jozimine A2 (2) represent novel potential candidates for future drug development against pancreatic cancer.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes after 70 hrs by alamar blue staining based fluorescence assay
|
Leishmania donovani
|
120.0
nM
|
|
Journal : J Nat Prod
Title : Phytochemical Study of Salvia leriifolia Roots: Rearranged Abietane Diterpenoids with Antiprotozoal Activity.
Year : 2018
Volume : 81
Issue : 6
First Page : 1384
Last Page : 1390
Authors : Farimani MM, Khodaei B, Moradi H, Aliabadi A, Ebrahimi SN, De Mieri M, Kaiser M, Hamburger M.
Abstract : Phytochemical investigation of the lipophilic extract of the roots of Salvia leriifolia resulted in the isolation of the new rearranged abietane diterpenoids leriifoliol (1) and leriifolione (2), together with 10 known diterpenoids. Structure elucidations were performed via extensive NMR and HRESIMS data, and the absolute configurations of compounds 1 and 3-5 were established by evaluation of experimental and calculated ECD spectra. The antiplasmodial activity of the new isolates was assayed against Trypanosoma brucei rhodesiense, T. cruzi, Plasmodium falciparum, and Leishmania donovani and also toxicity against rat myoblast (L6) cells. Compound 1 displayed antimalarial and low cytotoxic activity with IC50 values of 0.4 and 33.6 μM, respectively, and a selectivity index of 84. Compound 2 displayed activity against T. brucei, T. cruzi, and L. donovani, with IC50 values of 1.0, 4.6, and 1.0 μM, respectively. Putative biosynthetic pathways toward the formation of 1, 2, and 3 are proposed. Leriifoliol (1) is the first 20- nor-9,10- seco-abietane, while 2 exhibits an uncommon 6-6-5 fused-ring system.
|
Antileishmanial activity against axenic amastigote stage of Leishmania infantum MHOM/MA/67/ITMAP-263 assessed as inhibition of parasite metabolic activity after 48 hrs by luciferase reporter assay
|
Leishmania infantum
|
800.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study.
Year : 2018
Volume : 155
First Page : 135
Last Page : 152
Authors : Pedron J, Boudot C, Hutter S, Bourgeade-Delmas S, Stigliani JL, Sournia-Saquet A, Moreau A, Boutet-Robinet E, Paloque L, Mothes E, Laget M, Vendier L, Pratviel G, Wyllie S, Fairlamb A, Azas N, Courtioux B, Valentin A, Verhaeghe P.
Abstract : To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.
|
Antibiofilm activity against Candida albicans SC5314 assessed as inhibition of biofilm formation at 2 to 4 ug/ml after 24 hrs by XTT reduction assay
|
Candida albicans SC5314
|
90.0
%
|
|
Journal : J Med Chem
Title : Emerging New Targets for the Treatment of Resistant Fungal Infections.
Year : 2018
Volume : 61
Issue : 13
First Page : 5484
Last Page : 5511
Authors : Liu N, Tu J, Dong G, Wang Y, Sheng C.
Abstract : With the increasing morbidity and mortality of invasive fungal infections and the emergence of severe antifungal drug resistance, new drug targets and novel antifungal agents are urgently needed. Recently, better understanding of fungal pathogenesis has contributed to the rapid emergence of potential antifungal drug targets. This perspective aims to provide a comprehensive review of new antifungal targets and of medicinal chemistry efforts toward inhibitor discovery. Particular focus will be placed on the druggability of the targets and their potential to treat resistant fungal infections. Innovative strategies for the next generation of antifungal therapy, such as virulence factors, protein-protein interactions, and immune response-based proteins, will also be highlighted.
|
Antibiofilm activity against Candida albicans SC5314 assessed as inhibition of mature biofilm formation at 8 to 32 ug/ml after 24 hrs by XTT reduction assay
|
Candida albicans SC5314
|
90.0
%
|
|
Journal : J Med Chem
Title : Emerging New Targets for the Treatment of Resistant Fungal Infections.
Year : 2018
Volume : 61
Issue : 13
First Page : 5484
Last Page : 5511
Authors : Liu N, Tu J, Dong G, Wang Y, Sheng C.
Abstract : With the increasing morbidity and mortality of invasive fungal infections and the emergence of severe antifungal drug resistance, new drug targets and novel antifungal agents are urgently needed. Recently, better understanding of fungal pathogenesis has contributed to the rapid emergence of potential antifungal drug targets. This perspective aims to provide a comprehensive review of new antifungal targets and of medicinal chemistry efforts toward inhibitor discovery. Particular focus will be placed on the druggability of the targets and their potential to treat resistant fungal infections. Innovative strategies for the next generation of antifungal therapy, such as virulence factors, protein-protein interactions, and immune response-based proteins, will also be highlighted.
|
Antileishmanial activity against stationary-phase Leishmania amazonensis MHOM/BR/75/LTB0016 promastigotes infected in human THP1-derived macrophages by serial dilution based light microscopic method
|
Leishmania amazonensis
|
750.0
nM
|
|
Journal : J Nat Prod
Title : Efficacy of Apigenin and Miltefosine Combination Therapy against Experimental Cutaneous Leishmaniasis.
Year : 2018
Volume : 81
Issue : 8
First Page : 1910
Last Page : 1913
Authors : Emiliano YSS, Almeida-Amaral EE.
Abstract : Leishmaniasis is a neglected tropical disease caused by several different species of Leishmania. Treatment of leishmaniasis involves a limited drug arsenal that is associated with severe side effects, high costs, and drug resistance. Therefore, combination therapy has emerged as a strategy to improve leishmaniasis treatment. Here, we report the interaction of miltefosine and apigenin in vitro and in vivo. Combination therapy using low doses of these two drugs results in good clinical and parasitological responses.
|
Antileishmanial activity against stationary-phase Leishmania amazonensis MHOM/BR/75/LTB0016 promastigotes infected in human THP1-derived macrophages at apigenin to test compound ratio of 4:1 by serial dilution based light microscopic method
|
Leishmania amazonensis
|
440.0
nM
|
|
Journal : J Nat Prod
Title : Efficacy of Apigenin and Miltefosine Combination Therapy against Experimental Cutaneous Leishmaniasis.
Year : 2018
Volume : 81
Issue : 8
First Page : 1910
Last Page : 1913
Authors : Emiliano YSS, Almeida-Amaral EE.
Abstract : Leishmaniasis is a neglected tropical disease caused by several different species of Leishmania. Treatment of leishmaniasis involves a limited drug arsenal that is associated with severe side effects, high costs, and drug resistance. Therefore, combination therapy has emerged as a strategy to improve leishmaniasis treatment. Here, we report the interaction of miltefosine and apigenin in vitro and in vivo. Combination therapy using low doses of these two drugs results in good clinical and parasitological responses.
|
Antileishmanial activity against stationary-phase Leishmania amazonensis MHOM/BR/75/LTB0016 promastigotes infected in human THP1-derived macrophages at apigenin to test compound ratio of 3:2 by serial dilution based light microscopic method
|
Leishmania amazonensis
|
730.0
nM
|
|
Journal : J Nat Prod
Title : Efficacy of Apigenin and Miltefosine Combination Therapy against Experimental Cutaneous Leishmaniasis.
Year : 2018
Volume : 81
Issue : 8
First Page : 1910
Last Page : 1913
Authors : Emiliano YSS, Almeida-Amaral EE.
Abstract : Leishmaniasis is a neglected tropical disease caused by several different species of Leishmania. Treatment of leishmaniasis involves a limited drug arsenal that is associated with severe side effects, high costs, and drug resistance. Therefore, combination therapy has emerged as a strategy to improve leishmaniasis treatment. Here, we report the interaction of miltefosine and apigenin in vitro and in vivo. Combination therapy using low doses of these two drugs results in good clinical and parasitological responses.
|
Antiplasmodial activity against Leishmania donovani MHOM-ET-67/L82 axenic amastigotes after 72 hrs by Alamar blue assay
|
Leishmania donovani
|
432.0
nM
|
|
Journal : J Nat Prod
Title : Mbandakamine-Type Naphthylisoquinoline Dimers and Related Alkaloids from the Central African Liana Ancistrocladus ealaensis with Antiparasitic and Antileukemic Activities.
Year : 2018
Volume : 81
Issue : 4
First Page : 918
Last Page : 933
Authors : Tshitenge DT, Feineis D, Mudogo V, Kaiser M, Brun R, Seo EJ, Efferth T, Bringmann G.
Abstract : Four new dimeric naphthylisoquinoline alkaloids, michellamine A5 (2) and mbandakamines C-E (4-6), were isolated from the Congolese plant Ancistrocladus ealaensis, along with the known dimer mbandakamine A (3). They represent constitutionally unsymmetric dimers, each consisting of two 5,8'-coupled naphthylisoquinoline monomers. While the molecular halves of michellamine A5 (2) are linked via C-6' of both of the naphthalene moieties, i.e., via the least-hindered positions, so that the central biaryl axis is configurationally unstable and not an additional element of chirality, the mbandakamines 3-6 possess three consecutive stereogenic axes. Their monomeric units are linked through an unprecedented 6',1″-coupling in the binaphthalene core, leading to a high steric load, since the central axis is located in one of the peri-positions, neighboring one of the outer axes. In addition, four new 5,8'-coupled monomeric naphthylisoquinolines, viz., ancistroealaines C-F (7-10), were identified, along with four "naphthalene-devoid" tetra- and dihydroisoquinolines, named ealaines A-D (11-14). The new mbandakamines C (4) and D (5) showed pronounced activities against the malaria parasite Plasmodium falciparum, and they were likewise found to display strong cytotoxic activities against human leukemia (CCRF-CEM) and multi-drug-resistant tumor cells (CEM/ADR5000).
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 amastigotes infected in golden hamsters assessed as inhibition of splenic parasite burden at 30 mg/kg, po for 5 consecutive days initiated after 2 days of biopsy and measured on day 7 post last dose by Giemsa staining-based assay relative to control
|
Leishmania donovani
|
98.1
%
|
|
Journal : MedChemComm
Title : An insight into tetrahydro-β-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.
Year : 2017
Volume : 8
Issue : 9
First Page : 1824
Last Page : 1834
Authors : Purohit P, Pandey AK, Singh D, Chouhan PS, Ramalingam K, Shukla M, Goyal N, Lal J, Chauhan PMS.
Abstract : A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives (<b>14a-u</b>) have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant <i>in vitro</i> activity against the promastigote (IC<sub>50</sub> from 0.59 ± 0.35 to 31 ± 1.27 μM) and intracellular amastigote forms (IC<sub>50</sub> from 1.57 ± 0.12 to 17.6 ± 0.2 μM) of <i>L. donovani</i>, and their activity is comparable with standard drugs miltefosine and sodium stibogluconate. The most active compound <b>14t</b> was further studied <i>in vivo</i> against the <i>L. donovani</i>/golden hamster model at a dose of 50 mg kg<sup>-1</sup> through the intraperitoneal route for 5 consecutive days, which displayed 75.04 ± 7.28% inhibition of splenic parasite burden. Pharmacokinetics of compound <b>14t</b> was studied in the golden Syrian hamster, and following a 50 mg kg<sup>-1</sup> oral dose, the compound was detected in hamster serum for up to 24 h. It exhibited a large volume of distribution (651.8 L kg<sup>-1</sup>), high clearance (43.2 L h<sup>-1</sup> kg<sup>-1</sup>) and long mean residence time (10 h).
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes after 72 hrs by alamar blue staining based fluorescence assay
|
Leishmania donovani
|
560.0
nM
|
|
Journal : Eur J Med Chem
Title : Biological evaluation and structure-activity relationships of imidazole-based compounds as antiprotozoal agents.
Year : 2018
Volume : 156
First Page : 53
Last Page : 60
Authors : Saccoliti F, Madia VN, Tudino V, De Leo A, Pescatori L, Messore A, De Vita D, Scipione L, Brun R, Kaiser M, Mäser P, Calvet CM, Jennings GK, Podust LM, Costi R, Di Santo R.
Abstract : We discovered a series of azole antifungal compounds as effective antiprotozoal agents. They displayed promising inhibitory activities within the micromolar-submicromolar range against P. falciparum, L. donovani, and T. b. rhodesiense. Moreover, most of such compounds showed excellent nanomolar IC50 against T. cruzi, showing also very low cytotoxicity. Discussion of structure-activity relationships and biological data for these compounds are provided against the different parasites. To assess the mechanism of action against T. cruzi we proved that the most potent compounds (3b, 3j-l) inhibited the T. cruzi CYP51. Moreover, the most active derivative 3j dramatically reduced parasitemia in T. cruzi mouse model without acute toxicity.
|
Antileishmanial activity against axenic amastigote stage of Leishmania infantum assessed as inhibition of parasite metabolic activity after 48 hrs by luciferase reporter gene based luminescence assay
|
Leishmania infantum
|
800.0
nM
|
|
Journal : Eur J Med Chem
Title : 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.
Year : 2018
Volume : 157
First Page : 115
Last Page : 126
Authors : Fersing C, Boudot C, Pedron J, Hutter S, Primas N, Castera-Ducros C, Bourgeade-Delmas S, Sournia-Saquet A, Moreau A, Cohen A, Stigliani JL, Pratviel G, Crozet MD, Wyllie S, Fairlamb A, Valentin A, Rathelot P, Azas N, Courtioux B, Verhaeghe P, Vanelle P.
Abstract : Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.
|
Antileishmanial activity against Leishmania aethiopica amastigotes
|
Leishmania aethiopica
|
0.3
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Leishmania treatment and prevention: Natural and synthesized drugs.
Year : 2018
Volume : 160
First Page : 229
Last Page : 244
Authors : Bekhit AA, El-Agroudy E, Helmy A, Ibrahim TM, Shavandi A, Bekhit AEA.
Abstract : Leishmaniasis affects over 150 million people all over the world, especially in subtropical regions. Currently used antileishmanial synthesized drugs are associated with some drawbacks such as resistance and cytotoxicity, which hamper the chances of treatment. Furthermore, effective leishmanial vaccines are not well developed. Promising chemotherapy, either from natural or synthetic compounds, was or still is the most promising treatment. This review focuses on recent findings in drugs used for the treatment of leishmaniasis including; chemical and natural antileishmanial moieties, different potential targets, as well as various trials of vaccination development. Special emphasis has been paid to the mechanisms of the drugs, their safety and where possible, the structure-activity relationship to enable guided future drug discovery.
|
Antileishmanial activity against Leishmania infantum amastigotes infected in Syrian hamster assessed as reduction in parasite load in liver at 20 mg/kg/day, po for 10 days relative to control
|
Leishmania infantum
|
81.2
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Antileishmanial activity against Leishmania infantum amastigotes infected in Syrian hamster assessed as reduction in parasite load in spleen at 20 mg/kg/day, po for 10 days relative to control
|
Leishmania infantum
|
97.33
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Inhibition of human ERG at 10 uM incubated for 2 hrs by fluorescence polarization assay relative to control
|
Homo sapiens
|
-16.9
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Inhibition of human microsomal CYP1A2 expressed in baculovirus infected insect cells at 10 uM using luciferin-1A2 as substrate preincubated with enzyme/substrate mixture for 30 mins followed by further incubation with NADPH for 30 mins by CYP450 luciferase Glo assay relative to control
|
Homo sapiens
|
-20.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Inhibition of human microsomal CYP2C9 expressed in baculovirus infected insect cells at 10 uM using luciferin-H as substrate preincubated with enzyme/substrate mixture for 30 mins followed by further incubation with NADPH for 30 mins by CYP450 luciferase Glo assay relative to control
|
Homo sapiens
|
-0.8
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Inhibition of human microsomal CYP2C19 expressed in baculovirus infected insect cells at 10 uM using luciferin-H EGE as substrate preincubated with enzyme/substrate mixture for 30 mins followed by further incubation with NADPH for 30 mins by CYP450 luciferase Glo assay relative to control
|
Homo sapiens
|
7.9
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Inhibition of human microsomal CYP2D6 expressed in baculovirus infected insect cells at 10 uM using luciferin-ME as substrate preincubated with enzyme/substrate mixture for 30 mins followed by further incubation with NADPH for 30 mins by CYP450 luciferase Glo assay relative to control
|
Homo sapiens
|
30.8
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Inhibition of human microsomal CYP3A4 expressed in baculovirus infected insect cells at 10 uM using luciferin-IPA as substrate preincubated with enzyme/substrate mixture for 30 mins followed by further incubation with NADPH for 30 mins by CYP450 luciferase Glo assay relative to control
|
Homo sapiens
|
8.4
%
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.
Year : 2019
Volume : 183
First Page : 111676
Last Page : 111676
Authors : Borsari C, Jiménez-Antón MD, Eick J, Bifeld E, Torrado JJ, Olías-Molero AI, Corral MJ, Santarem N, Baptista C, Severi L, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Linciano P, Tait A, Costantino L, Luciani R, Tejera Nevado P, Zander-Dinse D, Franco CH, Ferrari S, Moraes CB, Cordeiro-da-Silva A, Ponterini G, Clos J, Alunda JM, Costi MP.
Abstract : Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC50 7.5 μM) and T. brucei (EC50 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/DD8 promastigotes after 48 hrs by resazurin dye-based fluorometric analysis
|
Leishmania donovani
|
150.0
nM
|
|
Journal : J Nat Prod
Title : Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies.
Year : 2019
Volume : 82
Issue : 4
First Page : 823
Last Page : 831
Authors : Hamulić D, Stadler M, Hering S, Padrón JM, Padrón JM, Bassett R, Rivas F, Loza-Mejía MA, Dea-Ayuela MA, González-Cardenete MA.
Abstract : The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (-)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure-activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10-16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species ( L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABAA receptors (α1β2γ2s) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes assessed as growth inhibition after 72 hrs by Alamar Blue dye-based fluorometric analysis
|
Leishmania donovani
|
800.0
nM
|
|
Journal : J Nat Prod
Title : A Near-Complete Series of Four Atropisomeric Jozimine A2-Type Naphthylisoquinoline Dimers with Antiplasmodial and Cytotoxic Activities and Related Alkaloids from Ancistrocladus abbreviatus.
Year : 2019
Volume : 82
Issue : 11
First Page : 3033
Last Page : 3046
Authors : Fayez S, Li J, Feineis D, Aké Assi L, Kaiser M, Brun R, Anany MA, Wajant H, Bringmann G.
Abstract : Three new naphthylisoquinoline dimers, jozibrevines A-C (1a-c), were isolated from the West African shrub Ancistrocladus abbreviatus, along with the known dimer jozimine A2 (1d). The two molecular moieties of 1a-d are coupled via the sterically constrained 3',3″-positions of their two naphthalene units, so that the central biaryl linkage is rotationally hindered. With the two outer axes also being chiral, 1a-d possess three consecutive stereogenic axes. The four isolated dimers all have the same constitutions and identical absolute configurations at the four stereogenic centers, but differ by their axial chirality. They belong to the extremely small class of Dioncophyllaceae-type naphthylisoquinoline dimers, i.e., being devoid of oxygen functions at C-6 and bearing the R-configuration at C-3 in their isoquinoline portions. Besides these dimers, the plant produces predominantly typical Ancistrocladaceae-type monomeric compounds, i.e., with the S-configuration at C-3 and an oxygen function at C-6, such as the new ancistrobrevines K (5) and L (6). Furthermore, a new hybrid-type (i.e., mixed Ancistrocladaceae/Dioncophyllaceae-type) alkaloid was identified, named ancistrobrevine M (7), which is 3R-configured and 6-oxygenated. Remarkable was the discovery of its "inverse hybrid-type" counterpart, dioncoline A (8). It is the as yet only known 3S-configured naphthylisoquinoline lacking an O-functionality at C-6. The new jozibrevines A-C (1a-c) exhibited pronounced antiplasmodial activities in the submicromolar range, with 1a being the most potent compound (IC50, 0.012 μM). Furthermore, jozimine A2 (1d) showed cytotoxicity against human colon carcinoma (HT-29), fibrosarcoma (HT1080), and multiple myeloma (MM.1S) cancer cells, displaying IC50 values of 12.0, 9.0, and 5.0 μM, respectively, whereas jozibrevines A (1a) and B (1b) were nontoxic in this concentration range.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/HU3 intracellular amastigotes infected in human THP1 cells after 96 hrs by prolong-gold antifade-reagent/DAPI staining based assay
|
Leishmania donovani
|
910.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Pharmacological Studies of 4-Hydroxyphenyl-Derived Phosphonium Salts Active in a Mouse Model of Visceral Leishmaniasis.
Year : 2019
Volume : 62
Issue : 23
First Page : 10664
Last Page : 10675
Authors : Manzano JI, Cueto-Díaz EJ, Olías-Molero AI, Perea A, Herraiz T, Torrado JJ, Alunda JM, Gamarro F, Dardonville C.
Abstract : We report the discovery of new 4-hydroxyphenyl phosphonium salt derivatives active in the submicromolar range (EC50 from 0.04 to 0.28 μM, SI > 10) against the protozoan parasite Leishmania donovani. The pharmacokinetics and in vivo oral efficacy of compound 1 [(16-(2,4-dihydroxyphenyl)-16-oxohexadecyl)triphenylphosphonium bromide] in a mouse model of visceral leishmaniasis were established. Compound 1 reduced the parasite load in spleen (98.9%) and liver (95.3%) of infected mice after an oral dosage of four daily doses of 1.5 mg/kg. Mode of action studies showed that compound 1 diffuses across the plasma membrane, as designed, and targets the mitochondrion of Leishmania parasites. Disruption of the energetic metabolism, with a decrease of intracellular ATP levels as well as mitochondrial depolarization together with a significant reactive oxygen species production, contributes to the leishmanicidal effect of 1. Importantly, this compound was equally effective against antimonials and miltefosine-resistant clinical isolates of Leishmania infantum, indicating its potential as antileishmanial lead.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 measured after 72 hrs by alamar blue dye based fluorimetry analysis
|
Leishmania donovani
|
730.0
nM
|
|
Journal : J Nat Prod
Title : Structure, Biosynthesis, and Bioactivity of Photoditritide from Photorhabdus temperata Meg1.
Year : 2019
Volume : 82
Issue : 12
First Page : 3499
Last Page : 3503
Authors : Zhao L, Awori RM, Kaiser M, Groß J, Opatz T, Bode HB.
Abstract : A new cyclic peptide photoditritide (1), containing two rare amino acid d-homoarginine residues, was isolated from Photorhabdus temperata Meg1 after the nonribosomal peptide synthetase encoding gene pdtS was activated via promoter exchange. The structure of 1 was elucidated by HR-MS and NMR experiments. The absolute configurations of amino acids were determined according to the advanced Marfey's method after hydrolysis of 1. Bioactivity testing of 1 revealed potent antimicrobial activity against Micrococcus luteus with an MIC value of 3.0 μM and weak antiprotozoal activity against Trypanosoma brucei rhodesiense with an IC50 value of 13 μM. Additionally, the biosynthetic pathway of 1 was also proposed.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 amastigotes assessed as growth inhibition after 72 hrs by plate reader based Alamar blue assay
|
Leishmania donovani
|
990.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A new chemotype with promise against Trypanosoma cruzi.
Year : 2020
Volume : 30
Issue : 1
First Page : 126778
Last Page : 126778
Authors : Wang X, Cal M, Kaiser M, Buckner FS, Lepesheva GI, Sanford AG, Wallick AI, Davis PH, Vennerstrom JL.
Abstract : Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure-activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi. Compound 2 and its active analogs had low to moderate metabolic stabilities in human and mouse liver microsomes.
|
Antileishmanial activity against Leishmania infantum MHOM/MA/67/ITMAP-263 axenic amastigotes expressing luciferase plasmid assessed as reduction in parasite viability incubated for 48 hrs by Steady Glow reagent based luminescence assay
|
Leishmania infantum
|
800.0
nM
|
|
Journal : ACS Med Chem Lett
Title : New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi.
Year : 2020
Volume : 11
Issue : 4
First Page : 464
Last Page : 472
Authors : Pedron J, Boudot C, Brossas JY, Pinault E, Bourgeade-Delmas S, Sournia-Saquet A, Boutet-Robinet E, Destere A, Tronnet A, Bergé J, Bonduelle C, Deraeve C, Pratviel G, Stigliani JL, Paris L, Mazier D, Corvaisier S, Since M, Malzert-Fréon A, Wyllie S, Milne R, Fairlamb AH, Valentin A, Courtioux B, Verhaeghe P.
Abstract : An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.
|
Antileishmanial activity against intracellular amastigote stage of Leishmania donovani fused with LUC infected in human THP1 cells assessed as parasite growth inhibition after 72 hrs post infection by luciferase based assay
|
Leishmania donovani
|
440.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of polyfluoroalkyl sp<sup>2</sup>-iminosugar glycolipids and evaluation of their immunomodulatory properties towards anti-tumor, anti-leishmanial and anti-inflammatory therapies.
Year : 2019
Volume : 182
First Page : 111604
Last Page : 111604
Authors : Sánchez-Fernández EM, García-Moreno MI, Arroba AI, Aguilar-Diosdado M, Padrón JM, Padrón JM, García-Hernández R, Gamarro F, Fustero S, Sánchez-Aparicio JE, Masgrau L, García Fernández JM, Ortiz Mellet C.
Abstract : Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from cancer and infection to autoimmune or neurodegenerative diseases. A main difficulty for those channels is that they often provoke a cytokine storm comprising both pro- and anti-inflammatory mediators that antagonize each other and negatively affect the immune response. The synthesis of analogues with narrower cytokine secretion-inducing capabilities is hampered by the intrinsic difficulty at controlling the stereochemical outcome in glycosidation reactions, particularly if targeting the α-anomer, which seriously hampers drug optimization strategies. Here we show that replacing the monosaccharide glycone by a sp<sup>2</sup>-iminosugar glycomimetic moiety allows accessing N-linked sp<sup>2</sup>-iminosugar glycolipids (sp<sup>2</sup>-IGLs) with total α-stereocontrol in a single step with no need of protecting groups or glycosidation promotors. The lipid tail has been then readily tailored by incorporating polyfluoroalkyl segments of varied lengths in view of favouring binding to the lipid binding site of the master p38 mitogen activated protein kinase (p38 MAPK), thereby polarizing the immune response in a cell-context dependent manner. The compounds have been evaluated for their antiproliferative, anti-leishmanial and anti-inflammatory activities in different cell assays. The size of the fluorous segment was found to be critical for the biological activity, probably by regulating the aggregation and membrane-crossing properties, whereas the hydroxylation profile (gluco or galacto-like) was less relevant. Biochemical and computational data further support a mechanism of action implying binding to the allosteric lipid binding site of p38 MAPK and subsequent activation of the noncanonical autophosphorylation route. The ensemble of results provide a proof of concept of the potential of sp<sup>2</sup>-IGLs as immunoregulators.
|
Antileishmanial activity against intracellular amastigote stage of Leishmania braziliensis MHOM/IT/2006/ISS2848 assessed as reduction in parasite viability measured after 72 hrs by MTT assay
|
Leishmania braziliensis
|
890.0
nM
|
|
Journal : Eur J Med Chem
Title : 4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania.
Year : 2019
Volume : 180
First Page : 28
Last Page : 40
Authors : Manzano JI, Konstantinović J, Scaccabarozzi D, Perea A, Pavić A, Cavicchini L, Basilico N, Gamarro F, Šolaja BA.
Abstract : Among neglected tropical diseases, leishmaniasis is one of the most relevant with an estimated 30,000 deaths annually. Existing therapies have serious drawbacks in safety, drug resistance, field-adapted application and cost; therefore, new safer and shorter treatments are needed for this disease. Here we report on the synthesis of novel 4-amino-7-chloroquinoline-based compounds with leishmanicidal activity, together with deeper insight into the mechanism of action of our previously published hit compound 1. New derivatives showed comparable activity to 1 against both promastigote and intracellular amastigote forms of Leishmania infantum, with IC<sub>50</sub> < 1 μM. Furthermore, we have determined that compound 1 induced a decrease of intracellular ATP levels, as well as a mitochondrial depolarization, together with an alteration of plasma membrane permeability and a significant ROS production. The inhibition of the energy metabolism of Leishmania plays an important role in the leishmanicidal mechanism of this compound. In all, these results support the consideration of compound 1 for the future development of new leishmanicidal drugs.
|
Antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
0.36
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Antiprotozoal alkaloid principles of the plant family Amaryllidaceae.
Year : 2019
Volume : 29
Issue : 20
First Page : 126642
Last Page : 126642
Authors : Nair JJ, van Staden J.
Abstract : Protozoan-borne diseases are prominent amongst diseases caused by parasites. Given their alarming morbidity and mortality statistics, there is ever growing interest in new therapies against these diseases. Whilst synthetic drugs such as benznidazole and melarsoprol have had a profound influence on the clinical setup, there has been significant interest in the phytochemical platform to also deliver such drug candidates. The plant family Amaryllidaceae is recognizable for its isoquinoline alkaloids, which exhibit attractive molecular architectures and interesting biological properties. This survey focuses on the antiprotozoal activities of 73 of such substances described in 18 different species of the Amaryllidaceae. Of these, 2-O-acetyllycorine was identified as the most potent (IC<sub>50</sub> 0.15 μg/mL against Trypansoma brucei brucei). Also considered are structure-activity relationships which have served to modulate activities, as well as the plausible mechanisms that underpin these effects and afford insight to the Amaryllidaceae alkaloid antiprotozoal pharmacophore.
|
Antitrypanosomal activity against Leishmania donovani
|
Leishmania donovani
|
0.2
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Antiprotozoal alkaloid principles of the plant family Amaryllidaceae.
Year : 2019
Volume : 29
Issue : 20
First Page : 126642
Last Page : 126642
Authors : Nair JJ, van Staden J.
Abstract : Protozoan-borne diseases are prominent amongst diseases caused by parasites. Given their alarming morbidity and mortality statistics, there is ever growing interest in new therapies against these diseases. Whilst synthetic drugs such as benznidazole and melarsoprol have had a profound influence on the clinical setup, there has been significant interest in the phytochemical platform to also deliver such drug candidates. The plant family Amaryllidaceae is recognizable for its isoquinoline alkaloids, which exhibit attractive molecular architectures and interesting biological properties. This survey focuses on the antiprotozoal activities of 73 of such substances described in 18 different species of the Amaryllidaceae. Of these, 2-O-acetyllycorine was identified as the most potent (IC<sub>50</sub> 0.15 μg/mL against Trypansoma brucei brucei). Also considered are structure-activity relationships which have served to modulate activities, as well as the plausible mechanisms that underpin these effects and afford insight to the Amaryllidaceae alkaloid antiprotozoal pharmacophore.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.04
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Antiprotozoal alkaloid principles of the plant family Amaryllidaceae.
Year : 2019
Volume : 29
Issue : 20
First Page : 126642
Last Page : 126642
Authors : Nair JJ, van Staden J.
Abstract : Protozoan-borne diseases are prominent amongst diseases caused by parasites. Given their alarming morbidity and mortality statistics, there is ever growing interest in new therapies against these diseases. Whilst synthetic drugs such as benznidazole and melarsoprol have had a profound influence on the clinical setup, there has been significant interest in the phytochemical platform to also deliver such drug candidates. The plant family Amaryllidaceae is recognizable for its isoquinoline alkaloids, which exhibit attractive molecular architectures and interesting biological properties. This survey focuses on the antiprotozoal activities of 73 of such substances described in 18 different species of the Amaryllidaceae. Of these, 2-O-acetyllycorine was identified as the most potent (IC<sub>50</sub> 0.15 μg/mL against Trypansoma brucei brucei). Also considered are structure-activity relationships which have served to modulate activities, as well as the plausible mechanisms that underpin these effects and afford insight to the Amaryllidaceae alkaloid antiprotozoal pharmacophore.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes after 72 hrs by alamar blue staining based fluorescence assay
|
Leishmania donovani
|
900.0
nM
|
|
Journal : J Nat Prod
Title : Antiprotozoal Isoprenoids from Salvia hydrangea.
Year : 2018
Volume : 81
Issue : 12
First Page : 2682
Last Page : 2691
Authors : Tabefam M, Moridi Farimani M, Danton O, Ramseyer J, Nejad Ebrahimi S, Neuburger M, Kaiser M, Salehi P, Potterat O, Hamburger M.
Abstract : Fractionation of the n-hexane extract of Salvia hydrangea afforded seven isoprenoids including six new compounds (1-6) and salvadione A (7). Their structures were established by comprehensive spectroscopic and spectrometric data analysis (1D and 2D NMR, HRMS). The absolute configuration of salvadione A (7) was established by single-crystal X-ray diffraction analysis with Cu/Kα radiation. In addition, the absolute configuration of all compounds was determined by electronic circular dichroism spectroscopy. A biosynthetic pathway for the formation of the scaffold of 1 is proposed. The antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum was determined, and cytotoxicity was assessed in rat myoblast L6 cells. Perovskone C (2) exhibited good activity against P. falciparum (IC50 0.6 μM) and a selectivity index of 62.2.
|
Antileishmanial activity against Leishmania infantum axenic amastigotes after 48 hrs by steady-glo luciferase reporter gene assay
|
Leishmania infantum
|
800.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Nongenotoxic 3-Nitroimidazo[1,2-<i>a</i>]pyridines Are NTR1 Substrates That Display Potent <i>in Vitro</i> Antileishmanial Activity.
Year : 2019
Volume : 10
Issue : 1
First Page : 34
Last Page : 39
Authors : Fersing C, Basmaciyan L, Boudot C, Pedron J, Hutter S, Cohen A, Castera-Ducros C, Primas N, Laget M, Casanova M, Bourgeade-Delmas S, Piednoel M, Sournia-Saquet A, Belle Mbou V, Courtioux B, Boutet-Robinet É, Since M, Milne R, Wyllie S, Fairlamb AH, Valentin A, Rathelot P, Verhaeghe P, Vanelle P, Azas N.
Abstract : Twenty nine original 3-nitroimidazo[1,2-<i>a</i>]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. <i>In vitro</i> evaluation highlighted compound <b>5</b> as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC<sub>50</sub> > 100 μM) alongside good antileishmanial activities (IC<sub>50</sub> = 1-2.1 μM) against <i>L. donovani</i>, <i>L. infantum</i>, and <i>L. major</i>; and good antitrypanosomal activities (IC<sub>50</sub> = 1.3-2.2 μM) against <i>T. brucei brucei</i> and <i>T. cruzi</i>, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC<sub>50</sub> = 0.6 to 13.3 μM). Molecule <b>5</b>, presenting a low reduction potential (<i>E</i>° = -0.63 V), was shown to be selectively bioactivated by the <i>L. donovani</i> type 1 nitroreductase (NTR1). Importantly, molecule <b>5</b> was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule <b>5</b> showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making <b>5</b> a good candidate for further <i>in vivo</i> studies.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coliDH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured soluble pig heart MDH refolding by measuring MDH enzyme activity using sodium mesoxalate as substrate after 20 to 40 mins by malachite green dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
79.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coli DH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured rhodanese refolding by measuring rhodanese enzyme activity after 45 mins by Fe(SCN)3 dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
65.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 promastigotes harboring luciferase reporter gene at 50 uM after 48 hrs by Steady-Glo luminescence assay relative to control
|
Leishmania donovani
|
99.5
%
|
|
Journal : J Med Chem
Title : Synthesis, Biological Evaluation, Structure-Activity Relationship, and Mechanism of Action Studies of Quinoline-Metronidazole Derivatives Against Experimental Visceral Leishmaniasis.
Year : 2019
Volume : 62
Issue : 11
First Page : 5655
Last Page : 5671
Authors : Upadhyay A, Chandrakar P, Gupta S, Parmar N, Singh SK, Rashid M, Kushwaha P, Wahajuddin M, Sashidhara KV, Kar S.
Abstract : In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, a series of quinoline-metronidazole hybrid compounds was synthesized and tested against the murine model of visceral leishmaniasis. Among all synthesized derivatives, 15b and 15i showed significant antileishmanial efficacy against both extracellular promastigote (IC<sub>50</sub> 9.54 and 5.42 μM, respectively) and intracellular amastigote (IC<sub>50</sub> 9.81 and 3.75 μM, respectively) forms of Leishmania donovani with negligible cytotoxicity toward the host (J774 macrophages, Vero cells). However, compound 15i effectively inhibited the parasite burden in the liver and spleen (>80%) of infected BALB/c mice. Mechanistic studies revealed that 15i triggers oxidative stress which induces bioenergetic collapse and apoptosis of the parasite by decreasing ATP production and mitochondrial membrane potential. Structure-activity analyses and pharmacokinetic studies suggest 15i as a promising antileishmanial lead and emphasize the importance of quinoline-metronidazole series as a suitable platform for the future development of antileishmanial agents.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 promastigotes harboring luciferase reporter gene at 25 uM after 48 hrs by Steady-Glo luminescence assay relative to control
|
Leishmania donovani
|
97.2
%
|
|
Journal : J Med Chem
Title : Synthesis, Biological Evaluation, Structure-Activity Relationship, and Mechanism of Action Studies of Quinoline-Metronidazole Derivatives Against Experimental Visceral Leishmaniasis.
Year : 2019
Volume : 62
Issue : 11
First Page : 5655
Last Page : 5671
Authors : Upadhyay A, Chandrakar P, Gupta S, Parmar N, Singh SK, Rashid M, Kushwaha P, Wahajuddin M, Sashidhara KV, Kar S.
Abstract : In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, a series of quinoline-metronidazole hybrid compounds was synthesized and tested against the murine model of visceral leishmaniasis. Among all synthesized derivatives, 15b and 15i showed significant antileishmanial efficacy against both extracellular promastigote (IC<sub>50</sub> 9.54 and 5.42 μM, respectively) and intracellular amastigote (IC<sub>50</sub> 9.81 and 3.75 μM, respectively) forms of Leishmania donovani with negligible cytotoxicity toward the host (J774 macrophages, Vero cells). However, compound 15i effectively inhibited the parasite burden in the liver and spleen (>80%) of infected BALB/c mice. Mechanistic studies revealed that 15i triggers oxidative stress which induces bioenergetic collapse and apoptosis of the parasite by decreasing ATP production and mitochondrial membrane potential. Structure-activity analyses and pharmacokinetic studies suggest 15i as a promising antileishmanial lead and emphasize the importance of quinoline-metronidazole series as a suitable platform for the future development of antileishmanial agents.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 amastigotes harboring luciferase reporter gene infected in mouse J774 cells at 50 uM after 48 hrs by Steady-Glo luminescence assay relative to control
|
Leishmania donovani
|
99.2
%
|
|
Journal : J Med Chem
Title : Synthesis, Biological Evaluation, Structure-Activity Relationship, and Mechanism of Action Studies of Quinoline-Metronidazole Derivatives Against Experimental Visceral Leishmaniasis.
Year : 2019
Volume : 62
Issue : 11
First Page : 5655
Last Page : 5671
Authors : Upadhyay A, Chandrakar P, Gupta S, Parmar N, Singh SK, Rashid M, Kushwaha P, Wahajuddin M, Sashidhara KV, Kar S.
Abstract : In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, a series of quinoline-metronidazole hybrid compounds was synthesized and tested against the murine model of visceral leishmaniasis. Among all synthesized derivatives, 15b and 15i showed significant antileishmanial efficacy against both extracellular promastigote (IC<sub>50</sub> 9.54 and 5.42 μM, respectively) and intracellular amastigote (IC<sub>50</sub> 9.81 and 3.75 μM, respectively) forms of Leishmania donovani with negligible cytotoxicity toward the host (J774 macrophages, Vero cells). However, compound 15i effectively inhibited the parasite burden in the liver and spleen (>80%) of infected BALB/c mice. Mechanistic studies revealed that 15i triggers oxidative stress which induces bioenergetic collapse and apoptosis of the parasite by decreasing ATP production and mitochondrial membrane potential. Structure-activity analyses and pharmacokinetic studies suggest 15i as a promising antileishmanial lead and emphasize the importance of quinoline-metronidazole series as a suitable platform for the future development of antileishmanial agents.
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 amastigotes harboring luciferase reporter gene infected in mouse J774 cells at 25 uM after 48 hrs by Steady-Glo luminescence assay relative to control
|
Leishmania donovani
|
98.3
%
|
|
Journal : J Med Chem
Title : Synthesis, Biological Evaluation, Structure-Activity Relationship, and Mechanism of Action Studies of Quinoline-Metronidazole Derivatives Against Experimental Visceral Leishmaniasis.
Year : 2019
Volume : 62
Issue : 11
First Page : 5655
Last Page : 5671
Authors : Upadhyay A, Chandrakar P, Gupta S, Parmar N, Singh SK, Rashid M, Kushwaha P, Wahajuddin M, Sashidhara KV, Kar S.
Abstract : In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, a series of quinoline-metronidazole hybrid compounds was synthesized and tested against the murine model of visceral leishmaniasis. Among all synthesized derivatives, 15b and 15i showed significant antileishmanial efficacy against both extracellular promastigote (IC<sub>50</sub> 9.54 and 5.42 μM, respectively) and intracellular amastigote (IC<sub>50</sub> 9.81 and 3.75 μM, respectively) forms of Leishmania donovani with negligible cytotoxicity toward the host (J774 macrophages, Vero cells). However, compound 15i effectively inhibited the parasite burden in the liver and spleen (>80%) of infected BALB/c mice. Mechanistic studies revealed that 15i triggers oxidative stress which induces bioenergetic collapse and apoptosis of the parasite by decreasing ATP production and mitochondrial membrane potential. Structure-activity analyses and pharmacokinetic studies suggest 15i as a promising antileishmanial lead and emphasize the importance of quinoline-metronidazole series as a suitable platform for the future development of antileishmanial agents.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigotes after 72 hrs by alamar blue staining based fluorescence assay
|
Leishmania donovani
|
300.0
nM
|
|
Journal : J Nat Prod
Title : Methionine-Containing Rhabdopeptide/Xenortide-like Peptides from Heterologous Expression of the Biosynthetic Gene Cluster kj12ABC in Escherichia coli.
Year : 2018
Volume : 81
Issue : 10
First Page : 2292
Last Page : 2295
Authors : Zhao L, Cai X, Kaiser M, Bode HB.
Abstract : Seven new methionine-containing rhabdopeptide/xenortide-like peptides (1-7) were identified from Escherichia coli expressing the rhabdopeptide/xenortide-like peptide biosynthetic gene cluster kj12ABC from Xenorhabdus KJ12.1. Their structures were elucidated by detailed HPLC-HR-MS/MS analysis and confirmed by chemical synthesis. Bioactivity tests of these first rhabdopeptide/xenortide-like peptide derivatives (2-7) showing methionine building blocks compared to the usually found derivatives containing exclusively hydrophobic amino acids such as valine, leucine, or phenylalanine revealed good activities of 2-7 against protozoan parasites and no cytotoxicity against mammalian L6 cells.
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 axenic amastigote after 72 hrs by inverted microscopic analysis
|
Leishmania donovani
|
560.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of New 1-(Aryl-1 H-pyrrolyl)(phenyl)methyl-1 H-imidazole Derivatives as Antiprotozoal Agents.
Year : 2019
Volume : 62
Issue : 3
First Page : 1330
Last Page : 1347
Authors : Saccoliti F, Madia VN, Tudino V, De Leo A, Pescatori L, Messore A, De Vita D, Scipione L, Brun R, Kaiser M, Mäser P, Calvet CM, Jennings GK, Podust LM, Pepe G, Cirilli R, Faggi C, Di Marco A, Battista MR, Summa V, Costi R, Di Santo R.
Abstract : We have designed and synthesized a series of new imidazole-based compounds structurally related to an antiprotozoal agent with nanomolar activity which we identified recently. The new analogues possess micromolar activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar potency against Plasmodium falciparum. Most of the analogues displayed IC<sub>50</sub> within the low nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure-activity relationships and in vitro biological data for the new compounds are provided against a number of different protozoa. The mechanism of action for the most potent derivatives (5i, 6a-c, and 8b) was assessed by a target-based assay using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits were assessed in a T. cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal administration of 25 mg/kg/day dose for 4 consecutive days.
|
Antiviral activity against HIV-1 3B
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of pentacyclic triterpene conjugates and their use in medicinal research.
Year : 2019
Volume : 182
First Page : 111653
Last Page : 111653
Authors : Hodon J, Borkova L, Pokorny J, Kazakova A, Urban M.
Abstract : Triterpenoids are natural products from plants and many other organisms that have various biological activities, such as antitumor, antiviral, antimicrobial, and protective activities. This review covers the synthesis and biological evaluation of pentacyclic triterpene (PT) conjugates with other molecules that have been found to increase the IC50 or improve the pharmacological profile of the parent PT. Some of these molecules are designed to target specific proteins or cellular organelles, which has resulted in highly selective lead structures for drug development. Other PT conjugates are useful for investigating their mechanism of action. This concept has been very successful: 1) Many compounds, especially mitochondria-targeting PT conjugates, have reached a selective cytotoxicity at low nanomolar concentrations in cancer cells. 2) A number of PT conjugates have had high activity against HIV or the influenza virus. 3) Fluorescent PT conjugates have been able to visualize the PT in living cells, which has allowed quantification of the uptake and distribution of the PT within the cell. 4) Biotinylated PT conjugates have been used to identify target proteins, which may help to show their mechanism of action. 5) A large number of PT conjugates with polyethylene glycol (PEG), polyamines, etc. form nanometer-sized micelles that have a much better pharmacological profile than the PT alone. In summary, the connection of a PT to an appropriate modifying molecule has resulted in extremely useful semisynthetic compounds with a high potential to treat cancer or viral infections or compounds that are useful for the study of the mechanism of action of PTs at the molecular level.
|
Antiprotozoal activity against Leishmania donovani MHOM-ET-67/L82 axenic amastigotes incubated for 72 hrs by Alamar blue staining-based fluorometric analysis
|
Leishmania donovani
|
430.0
nM
|
|
Journal : J Nat Prod
Title : Ealamines A-H, a Series of Naphthylisoquinolines with the Rare 7,8'-Coupling Site, from the Congolese Liana Ancistrocladus ealaensis, Targeting Pancreatic Cancer Cells.
Year : 2019
Volume : 82
Issue : 11
First Page : 3150
Last Page : 3164
Authors : Tshitenge DT, Bruhn T, Feineis D, Schmidt D, Mudogo V, Kaiser M, Brun R, Würthner F, Awale S, Bringmann G.
Abstract : From the twigs and leaves of the Central African liana Ancistrocladus ealaensis (Ancistrocladaceae), a series of ten 7,8'-coupled naphthylisoquinoline alkaloids were isolated, comprising eight new compounds, named ealamines A-H (4a, 4b, 5-10), and two known ones, 6-O-demethylancistrobrevine A (11) and yaoundamine A (12), which had previously been found in related African Ancistrocladus species. Only one of the new compounds within this series, ealamine H (10), is a typical Ancistrocladaceae-type alkaloid, with 3S-configuration at C-3 and an oxygen function at C-6, whereas seven of the new alkaloids are the first 7,8'-linked "hybrid-type" naphthylisoquinoline alkaloids, i.e., 3R-configured and 6-oxygenated in the tetrahydroisoquinoline part. The discovery of such a broad series of 7,8'-coupled naphthyltetrahydroisoquinolines is unprecedented, because representatives of this subclass of alkaloids are normally found in Nature quite rarely. The stereostructures of the new ealamines were assigned by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and quantum-chemical ECD investigations, and-in the case of ealamine A (4a)-also confirmed by X-ray diffraction analysis. Ealamines A-D exhibited distinct-and specific-antiplasmodial activities, and they displayed pronounced preferential cytotoxic effects toward PANC-1 human pancreatic cancer cells in nutrient-deprived medium, without causing toxicity under normal, nutrient-rich conditions, with ealamine C (5) as the most potent agent.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 axenic amastigotes after 70 hrs by resazurin staining based fluorescence assay
|
Leishmania donovani
|
285.0
nM
|
|
Journal : J Nat Prod
Title : HPLC-Based Activity Profiling for Antiprotozoal Compounds in the Endemic Iranian Medicinal Plant Helichrysum oocephalum.
Year : 2019
Volume : 82
Issue : 4
First Page : 958
Last Page : 969
Authors : Akaberi M, Danton O, Tayarani-Najaran Z, Asili J, Iranshahi M, Emami SA, Hamburger M.
Abstract : In a screening of Iranian plants for antiprotozoal activity a dichlomethane extract from the aerial parts of Helichrysum oocephalum showed in vitro antiprotozoal activity against Plasmodium falciparum and Leishmania donovani, with IC50 values of 4.01 ± 0.50 and 5.08 ± 0.07 μg/mL, respectively. The activity in the extract was tracked by HPLC-based activity profiling, and subsequent targeted preparative isolation afforded 24 compounds, including pyrones 22-24, phloroglucinol derivatives 12-19, and compounds containing both structural motifs (1-11, 20, and 21). Of these, 15 compounds were new natural products. The in vitro antiprotozoal activity of isolates was determined. Compound 3 showed good potency and selectivity in vitro against L. donovani (IC50 1.79 ± 0.17 μM; SI 53).
|
Growth inhibiting activity of Naegleria gruberi in vitro
|
Naegleria gruberi
|
4.0
%
|
|
Title : Naegleria gruberi Pathogen Box compounds screening
Authors : Sarink, M; Mykytyn, A; Tielens, A; van Hellemond, J
Abstract : 400 compounds from the Pathogen box were screened for inhibitory activity against Naegleria gruberi strain NEG-M. N. gruberi was grown in modified PYNFH medium in 96-wells plates. Compounds were added in 10 uM concentrations in triplicate wells. Optical density was measured daily, after 6 days area under the curve was calculated and compared to 0.1 % DMSO control.
|
Antileishmanial activity against Leishmania orientalis MHOM/TH/2010/PCM2 promastigote at 0.25 uM incubated for 72 hrs by resazurin dye based colorimetric assay relative to control
|
Leishmania orientalis
|
4.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and antileishmanial activity of fluorinated rhodacyanine analogues: The 'fluorine-walk' analysis.
Year : 2020
Volume : 28
Issue : 1
First Page : 115187
Last Page : 115187
Authors : Lasing T, Phumee A, Siriyasatien P, Chitchak K, Vanalabhpatana P, Mak KK, Hee Ng C, Vilaivan T, Khotavivattana T.
Abstract : In a search for potent antileishmanial drug candidates, eighteen rhodacyanine analogues bearing fluorine or perfluoroalkyl substituents at various positions were synthesized. These compounds were tested for their inhibitory activities against Leishmania martiniquensis and L. orientalis. This 'fluorine-walk' analysis revealed that the introduction of fluorine atom at C-5, 6, 5', or 6' on the benzothiazole units led to significant enhancement of the activity, correlating with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. On the other hand, CF<sub>3</sub> and OCF<sub>3</sub> groups were found to have detrimental effects, which agreed with the poor aqueous solubility predicted by the in silico ADMET analysis. In addition, some of the analogues including the difluorinated species showed exceptional potency against the promastigote and axenic amastigote stages (IC<sub>50</sub> = 40-85 nM), with the activities surpassing both amphotericin B and miltefosine.
|
Antileishmanial activity against Leishmania orientalis MHOM/TH/2010/PCM2 axenic amastigotes at 0.25 uM incubated for 72 hrs by resazurin dye based colorimetric assay relative to control
|
Leishmania orientalis
|
24.9
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and antileishmanial activity of fluorinated rhodacyanine analogues: The 'fluorine-walk' analysis.
Year : 2020
Volume : 28
Issue : 1
First Page : 115187
Last Page : 115187
Authors : Lasing T, Phumee A, Siriyasatien P, Chitchak K, Vanalabhpatana P, Mak KK, Hee Ng C, Vilaivan T, Khotavivattana T.
Abstract : In a search for potent antileishmanial drug candidates, eighteen rhodacyanine analogues bearing fluorine or perfluoroalkyl substituents at various positions were synthesized. These compounds were tested for their inhibitory activities against Leishmania martiniquensis and L. orientalis. This 'fluorine-walk' analysis revealed that the introduction of fluorine atom at C-5, 6, 5', or 6' on the benzothiazole units led to significant enhancement of the activity, correlating with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. On the other hand, CF<sub>3</sub> and OCF<sub>3</sub> groups were found to have detrimental effects, which agreed with the poor aqueous solubility predicted by the in silico ADMET analysis. In addition, some of the analogues including the difluorinated species showed exceptional potency against the promastigote and axenic amastigote stages (IC<sub>50</sub> = 40-85 nM), with the activities surpassing both amphotericin B and miltefosine.
|
Antileishmanial activity against Leishmania donovani MHOM-ET-67/L82 axenic amastigotes assessed as parasite growth inhibition measured after 72 hrs by Alamar blue based inverted microscopy analysis
|
Leishmania donovani
|
700.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis, in-vitro antiprotozoal activity and molecular docking study of isothiocyanate derivatives.
Year : 2020
Volume : 28
Issue : 1
First Page : 115185
Last Page : 115185
Authors : Babanezhad Harikandei K, Salehi P, Ebrahimi SN, Bararjanian M, Kaiser M, Al-Harrasi A.
Abstract : Novel isothiocyanate derivatives were synthesized starting from noscapine, bile acids, amino acids, and some aromatic compounds. Antiparasitic activities of the synthesized derivatives were tested against four unicellular protozoa, i.e., Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. Interestingly, seven isothiocyanate analogues displayed promising antiparasitic activity against Leishmania donovani with IC<sub>50</sub> values between 0.4 and 1.0 µM and selectivity index (SI) ranged from 7.8 to 18.4, comparable to the standard drug miltefosine (IC<sub>50</sub> = 0.7 μM). Compound 7h demonstrated the best antileishmanial activity with an IC<sub>50</sub> value of 0.4 µM. Seven products exhibited inhibition activity against T. brucei rhodesiense with IC<sub>50</sub>s below 2.0 μM and SI between 2.7 and 29.3. Four primary amine derivatives of noscapine and five isothiocyanate derivatives exhibited antiplasmodial activity with IC<sub>50</sub>s in the range of 1.1-2.7 µM and SI values between 1.1 and 14.5. The isothiocyanate derivative 7c showed against T. cruzi with an IC<sub>50</sub> value of 1.9 µM and SI 4. Molecular docking and ADMET studies were performed to investigate the interaction between active ligands and T. brucei trypanothione reductase active site. The docking studies showed significant binding affinity of noscapine derivatives to enzyme active site and good compatibility with experimental data.
|
Antileishmanial activity against Leishmania donovani promastigotes
|
Leishmania donovani
|
4.54
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Green recipes to quinoline: A review.
Year : 2019
Volume : 164
First Page : 121
Last Page : 170
Authors : Nainwal LM, Tasneem S, Akhtar W, Verma G, Khan MF, Parvez S, Shaquiquzzaman M, Akhter M, Alam MM.
Abstract : The quinoline core possesses a vast number of biological activities such as anticancer, antimalarial, antimicrobial, antifungal, antitubercular and antileishmanial. The conventional classical synthetic methods require the use of expensive and harsh conditions such as high temperature. Currently the scientific communities are searching new methodology to eliminate the use of chemicals, solvents and catalysts, which are hazardous to human health as well as to environment. This review provides a concise overview of new dimensions of green chemistry approaches in designing quinoline scaffold that would encourage the researchers towards green chemistry as well as future application of these greener, non-toxic, environment friendly methods in designing quinoline scaffold.
|
Antileishmanial activity against Leishmania donovani amastigotes
|
Leishmania donovani
|
8.2
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Green recipes to quinoline: A review.
Year : 2019
Volume : 164
First Page : 121
Last Page : 170
Authors : Nainwal LM, Tasneem S, Akhtar W, Verma G, Khan MF, Parvez S, Shaquiquzzaman M, Akhter M, Alam MM.
Abstract : The quinoline core possesses a vast number of biological activities such as anticancer, antimalarial, antimicrobial, antifungal, antitubercular and antileishmanial. The conventional classical synthetic methods require the use of expensive and harsh conditions such as high temperature. Currently the scientific communities are searching new methodology to eliminate the use of chemicals, solvents and catalysts, which are hazardous to human health as well as to environment. This review provides a concise overview of new dimensions of green chemistry approaches in designing quinoline scaffold that would encourage the researchers towards green chemistry as well as future application of these greener, non-toxic, environment friendly methods in designing quinoline scaffold.
|
Antileishmanial activity against Leishmania donovani amastigotes infected in golden hamster assessed as reduction in parasite burden in spleen at 30 mg/kg, po initiated after 2 days of pre-treatment biopsy administered for 5 days and measured on day 7 by giemsa staining based assay relative to control
|
Leishmania donovani
|
97.32
%
|
|
Journal : RSC Med Chem
Title : Antileishmanial assessment of isoxazole derivatives against L. donovani
Year : 2020
Volume : 11
Issue : 9
First Page : 1053
Last Page : 1062
Authors : Mukhopadhyay, Sushobhan, Barak, Dinesh S., Karthik, R., Verma, Sarvesh K., Bhatta, Rabi S., Goyal, Neena, Batra, Sanjay
Abstract : A chemical library comprising substituted 3-nitroisoxazoles and 3-aminoisoxazoles was prepared and screened for their antileishmanial activity against L. donovani. As compared to Miltefosine, the standard drug used in bioassays, several compounds displayed remarkably better inhibition of the promastigote and amastigote stages of parasites. The in vivo evaluation of a few compounds in a golden hamster model showed significant reduction of the parasite load post treatment via the intraperitoneal route by several compounds. The preliminary pharmacokinetic evaluation of a representative compound 4mfvia the oral route, however, indicated high systemic clearance from the body.
|
Antileishmanial activity against Leishmania donovani amastigotes infected in golden hamster assessed as reduction in parasite burden in spleen at 30 mg/kg, po initiated after 2 days of pre-treatment biopsy administered for 5 days and measured on day 28 by giemsa staining based assay relative to control
|
Leishmania donovani
|
98.41
%
|
|
Journal : RSC Med Chem
Title : Antileishmanial assessment of isoxazole derivatives against L. donovani
Year : 2020
Volume : 11
Issue : 9
First Page : 1053
Last Page : 1062
Authors : Mukhopadhyay, Sushobhan, Barak, Dinesh S., Karthik, R., Verma, Sarvesh K., Bhatta, Rabi S., Goyal, Neena, Batra, Sanjay
Abstract : A chemical library comprising substituted 3-nitroisoxazoles and 3-aminoisoxazoles was prepared and screened for their antileishmanial activity against L. donovani. As compared to Miltefosine, the standard drug used in bioassays, several compounds displayed remarkably better inhibition of the promastigote and amastigote stages of parasites. The in vivo evaluation of a few compounds in a golden hamster model showed significant reduction of the parasite load post treatment via the intraperitoneal route by several compounds. The preliminary pharmacokinetic evaluation of a representative compound 4mfvia the oral route, however, indicated high systemic clearance from the body.
|
Antiprotozoal activity against Leishmania donovani MHOM/ET/67/L82 alamar blue staining-based fluorometric analysis
|
Leishmania donovani
|
156.0
nM
|
|
Journal : Eur J Med Chem
Title : Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity.
Year : 2016
Volume : 123
First Page : 895
Last Page : 904
Authors : Papadopoulou MV,Bloomer WD,Rosenzweig HS,Wilkinson SR,Szular J,Kaiser M
Abstract : 3-Nitro-1H-1,2,4-triazole-based acetamides bearing a biphenyl- or a phenoxyphenyl moiety have shown remarkable antichagasic activity both in vitro and in an acute murine model, as well as substantial in vitro antileishmanial activity but lacked activity against human African trypanosomiasis. We have shown now that by inserting a methylene group in the linkage to obtain the corresponding propanamides, both antichagasic and in particular anti-human African trypanosomiasis potency was increased. Therefore, IC50 values at low nM concentrations against both T. cruzi and T. b. rhodesiense, along with huge selectivity indices were obtained. Although several propanamides were active against Leishmania donovani, they were slightly less potent than their corresponding acetamides. There was a good correlation between lipophilicity (clogP value) and trypanocidal activity, for all new compounds. Type I nitroreductase, an enzyme absent from the human host, played a role in the activation of the new compounds, which may function as prodrugs. Antichagasic activity in vivo was also demonstrated with representative propanamides.
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 amastigotes assessed as growth inhibition incubated for 70 hrs by resazurin based inverted microscopic analysis
|
Leishmania donovani
|
770.0
nM
|
|
Journal : Eur J Med Chem
Title : (±)-trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents: Synthesis, in vitro evaluation and SAR analysis.
Year : 2020
Volume : 205
First Page : 112493
Last Page : 112493
Authors : Bernal FA,Gerhards M,Kaiser M,Wünsch B,Schmidt TJ
Abstract : Leishmaniasis, a neglected tropical disease caused by parasites of the genus Leishmania, causes a serious burden of disease around the world, represents a threat to the life of millions of people, and therefore is a major public health problem. More effective and non-toxic new treatments are required, especially for visceral leishmaniasis, the most severe form of the disease. On the backdrop that dihydrobenzofurans have previously shown antileishmanial activity, we present here the synthesis of a set of seventy trans-2-phenyl-2,3-dihydrobenzofurans and evaluation of their in vitro activity against Leishmania donovani as well as a discussion of structure-activity relationships. Compounds 8m-o and 8r displayed the highest potency (IC < 2 μmol/L) and interesting selectivity of the antileishmanial activity over cytotoxicity against mammalian cells (SI > 4.6). Nonetheless, structural optimization as further requirement was inferred from the high clearance of the most potent compound (8m) observed during determination in vitro of its metabolic stability. On the other hand, chiral separation of 8m and subsequent biological evaluation of its enantiomers demonstrated no effect of chirality on activity and cytotoxicity. Holistic analysis of in silico ADME-like properties and ligand efficiency metrics by a simple scoring function estimating druglikeness highlighted compounds 16c, 18 and 23 as promising candidates for further development. Overall, the potential of trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents was confirmed.
|
Antileishmanial activity against Leishmania infantum MHOM/MA/67/ITMAP-263 axenic amastigotes assessed as inhibition of parasitic metabolic activity incubated for 48 hrs by steady Glow reagent based luminescence assay
|
Leishmania infantum
|
800.0
nM
|
|
Journal : Eur J Med Chem
Title : Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.
Year : 2020
Volume : 206
First Page : 112668
Last Page : 112668
Authors : Fersing C,Boudot C,Paoli-Lombardo R,Primas N,Pinault E,Hutter S,Castera-Ducros C,Kabri Y,Pedron J,Bourgeade-Delmas S,Sournia-Saquet A,Stigliani JL,Valentin A,Azqueta A,Muruzabal D,Destere A,Wyllie S,Fairlamb AH,Corvaisier S,Since M,Malzert-Fréon A,Di Giorgio C,Rathelot P,Azas N,Courtioux B,Vanelle P,Verhaeghe P
Abstract : To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
|
Antileishmanial activity against intramacrophage form of Leishmania donovani LV9 assessed as reduction in parasite growth
|
Leishmania donovani
|
610.0
nM
|
|
|
Leishmanicidal activity against axenic amastigote stage of Leishmania infantum MCAN/ES/89/IPZ229/1/89 infected in human THP-1 macrophage cells assessed as reduction in intracellular amastigotes incubated for 24 hrs by propidium iodide staining based flow cytometry
|
Leishmania infantum
|
600.0
nM
|
|
|
Antileishmanial activity against intracellular Leishmania infantum MHOM/MA/67/ITMAP-263 amastigotes infected in BALB/c mouse peritoneal macrophage assessed as reduced parasite growth incubated for 72 hrs by PANOTIC staining based assay
|
Leishmania infantum
|
500.0
nM
|
|
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 amastigotes assessed as inhibition of parasite growth measured after 72 hrs by alamar blue dye based fluorometric analysis
|
Leishmania donovani
|
390.0
nM
|
|
|
Antileishmanial activity against Leishmania donovani MHOM/Br/79/Maria promastigotes assessed as reduction in parasites for 48 hrs by resazurin dye based assay
|
Leishmania donovani
|
150.0
nM
|
|
|
Antileishmanial activity against Leishmania donovani MHOM/Br/79/Maria amastigotes infected in mouse J774 cells assessed as reduction in parasites for 48 hrs by resazurin dye based assay
|
Leishmania donovani
|
370.0
nM
|
|
|
Antileishmanial activity against log phase of Leishmania donovani MHOM/IN/80/Dd8 promastigotes assessed as reduction in cell viability at 50 uM incubated for 72 hrs by MTT assay
|
Leishmania donovani
|
99.7
%
|
|
|
Antileishmanial activity against log phase of Leishmania donovani MHOM/IN/80/Dd8 promastigotes assessed as reduction in cell viability at 25 uM incubated for 72 hrs by MTT assay
|
Leishmania donovani
|
99.4
%
|
|
|
Antileishmanial activity against amastigote stage of Leishmania donovani MHOM/IN/80/Dd8 harboring luciferase gene infected in mouse J774 cells assessed as parasite growth inhibition at 50 uM incubated for 72 hrs by Steady-Glo reagent based luciferase assay
|
Leishmania donovani
|
95.3
%
|
|
|
Antileishmanial activity against amastigote stage of Leishmania donovani MHOM/IN/80/Dd8 harboring luciferase gene infected in mouse J774 cells assessed as parasite growth inhibition at 25 uM incubated for 72 hrs by Steady-Glo reagent based luciferase assay
|
Leishmania donovani
|
91.2
%
|
|
|
Antileishmanial activity against Leishmania donovani MHOM/IN/80/Dd8 infected in BALB/c mouse assessed as reduction in organ intracellular amastigote burden at 25 mg/kg, po for 5 days and measured at 1 week post-treatment by Giemsa staining based assay relative to control
|
Leishmania donovani
|
97.0
%
|
|
|
Antileishmanial activity against Leishmania donovani MHOM/ET/67/L82 amastigotes measured after 70 hrs by resazurin dye based fluorometric analysis
|
Leishmania donovani
|
0.555
ug.mL-1
|
|
|
Antileishmanial activity against Leishmania infantum amastigotes infected in golden hamster assessed as reduction in parasite load in liver tissue at 40 mg/kg, po administered once daily for 5 days relative to control
|
Leishmania infantum
|
98.5
%
|
|
|
Antileishmanial activity against Leishmania infantum amastigotes infected in golden hamster assessed as reduction in parasite load in spleen tissue at 40 mg/kg, po administered once daily for 5 days relative to control
|
Leishmania infantum
|
99.7
%
|
|
|
Antileishmanial activity against Leishmania infantum amastigotes infected in golden hamster assessed as reduction in parasite load in bone marrow tissue at 40 mg/kg, po administered once daily for 5 days relative to control
|
Leishmania infantum
|
94.9
%
|
|
