|
Inhibitory concentration against Epimastigotes (Tulahuen strain) of Trypanosoma cruzi
|
Trypanosoma cruzi
|
7.4
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-Trypanosoma activity of some natural stilbenoids and synthetic related heterocyclic compounds.
Year : 2001
Volume : 11
Issue : 20
First Page : 2755
Last Page : 2757
Authors : del Olmo E, Armas MG, López-Pérez JL, Ruiz G, Vargas F, Giménez A, Deharo E, San Feliciano A.
Abstract : We report the anti-Chagasic activity of the natural dihydrostilbenoid isonotholaenic acid and several simple derivatives, as well as that of some representative compounds of related synthetic series, with basic structures of benzalphthalides, dihydrostilbamides, isoindoles, phthalazin-1-ones, imidazo[2,1-a]isoindoles and pyrimido[2,1-a]isoindoles. The evaluation was performed in vitro on cultures of epimastigote and trypomastigote forms of Trypanosoma cruzi. Some of the tested compounds resulted to be as potent as benznidazole (epimastigotes), and others were shown to be more active than gentian violet (trypomastigotes), used as reference drugs.
|
Compound was evaluated for anti-parasitic activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy.
Year : 2001
Volume : 44
Issue : 6
First Page : 909
Last Page : 916
Authors : Martin MB, Grimley JS, Lewis JC, Heath HT, Bailey BN, Kendrick H, Yardley V, Caldera A, Lira R, Urbina JA, Moreno SN, Docampo R, Croft SL, Oldfield E.
Abstract : We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar IC(50) activity values against parasite replication (e.g. o-risedronate, IC(50) = 220 nM for T. brucei rhodesiense; risedronate, IC(50) = 490 nM for T. gondii). In T. cruzi, the nitrogen-containing bisphosphonate risedronate is shown to inhibit sterol biosynthesis at a pre-squalene level, most likely by inhibiting farnesylpyrophosphate synthase. Bisphosphonates therefore appear to have potential in treating parasitic protozoan diseases.
|
Trypanocidal activity against amastigote forms of Y strain of Trypanosoma cruzi
|
Trypanosoma cruzi
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Trypanocidal activity of (-)-cubebin derivatives against free amastigote forms of Trypanosoma cruzi.
Year : 2005
Volume : 15
Issue : 2
First Page : 303
Last Page : 307
Authors : de Souza VA, da Silva R, Pereira AC, Royo Vde A, Saraiva J, Montanheiro M, de Souza GH, da Silva Filho AA, Grando MD, Donate PM, Bastos JK, Albuquerque S, e Silva ML.
Abstract : Five (-)-cubebin derivative compounds, (-)-O-acetyl cubebin (3), (-)-O-benzyl cubebin (4), (-)-O-(N,N-dimethylaminoethyl)-cubebin (5), (-)-hinokinin (6) and (-)-6,6'-dinitrohinokinin (7), previously synthesised by our research group, were evaluated on in vitro assay against free amastigote forms of Trypanosoma cruzi, the asogic agent of Chagas' disease. It was observed that 6 was the most active compound (IC(50)=0.7 microM), and that 4 and 5 displayed moderate activity against the parasite, giving IC(50) values of 5.7 and 4.7 microM, respectively. In contrast, it was observed that compound 3 was inactive and that 7 displayed low activity with IC(50) values of congruent with 1.5 x 10(4) and 95.3 microM, respectively.
|
In vivo percent inhibition of compound at a dose of 45 mg/kg, p.o., for 5 doses in rodent model with Trypanosoma brucei brucei STIB 795 strain [ND = not determined]
|
Trypanosoma brucei brucei
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of a series of melamine-based nitroheterocycles with activity against Trypanosomatid parasites.
Year : 2005
Volume : 48
Issue : 17
First Page : 5570
Last Page : 5579
Authors : Baliani A, Bueno GJ, Stewart ML, Yardley V, Brun R, Barrett MP, Gilbert IH.
Abstract : The parasites that give rise to human African trypanosomiasis (HAT) are auxotrophs for various nutrients from the human host, including purines. They have specialist nucleoside transporters to import these metabolites. In addition to uptake of purine nucleobases and purine nucleosides, one of these transporters, the P2 transporter, can carry melamine derivatives; these derivatives are not substrates for the corresponding mammalian transporters. In this paper, we report the coupling of the melamine moiety to selected nitro heterocycles with the aim of selectively delivering these compounds to the parasites. Some compounds prepared have similar in vitro trypanocidal activities as melarsoprol, the principal drug used against late-stage HAT, with 50% growth inhibitory concentrations in the submicromolar range. Selected compounds were also evaluated in vivo in rodent models infected with Trypanosoma brucei brucei and T. brucei rhodesiense and showed pronounced activity and in two cases were curative without overt signs of toxicity. Compounds were also tested against other trypanosomatid pathogens, Leishmania donovani and Trypanosoma cruzi, and significant activity in vitro was noted for T. cruzi against which various nitro heterocycles are already registered for use.
|
Antiprotozoal activity against Trypanosoma cruzi Tulahuen C2C4 trypomastigotes in L6 cells
|
Trypanosoma cruzi
|
0.74
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.
|
Inhibition of Trypanosoma cruzi Maracay epimastigotes after 72 hrs
|
Trypanosoma cruzi
|
4.12
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : 1,4-Bis(alkylamino)benzo[g]phthalazines able to form dinuclear complexes of Cu(II) which as free ligands behave as SOD inhibitors and show efficient in vitro activity against Trypanosoma cruzi.
Year : 2007
Volume : 15
Issue : 5
First Page : 2081
Last Page : 2091
Authors : Rodríguez-Ciria M, Sanz AM, Yunta MJ, Gómez-Contreras F, Navarro P, Sánchez-Moreno M, Boutaleb-Charki S, Osuna A, Castiñeiras A, Pardo M, Cano C, Campayo L.
Abstract : The synthesis of a new series of 1,4-bis(alkylamino)benzo[g]phthalazines 1-3 is reported, and their ability to form dinuclear complexes with Cu(II) assayed. The geometry of the complexes is dependent on the nature of the electron-donor sites at the sidechains. Compounds 1 and 2, that contain sp3 or sp2 nitrogens at the end of the alkylamino groups, originate monopodal dinuclear complexes which seem to include endogenous OH bridges, and the sidechains seem to actively participate in complexation. However, the substitution of nitrogen by oxygen in 3 leads to a tripodal dinuclear complex in which the sidechains are not involved. The in vitro antiparasitic activity on Trypanosoma cruzi epimastigotes and amastigotes and the SOD activity inhibition have been evaluated for compounds 1-3, and, as expected, 1 and 2 show in all cases relevant results, whereas 3 is always the less active among the three substrates tested.
|
Toxicity against Vero cells after 72 hrs
|
Chlorocebus sabaeus
|
3.53
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : 1,4-Bis(alkylamino)benzo[g]phthalazines able to form dinuclear complexes of Cu(II) which as free ligands behave as SOD inhibitors and show efficient in vitro activity against Trypanosoma cruzi.
Year : 2007
Volume : 15
Issue : 5
First Page : 2081
Last Page : 2091
Authors : Rodríguez-Ciria M, Sanz AM, Yunta MJ, Gómez-Contreras F, Navarro P, Sánchez-Moreno M, Boutaleb-Charki S, Osuna A, Castiñeiras A, Pardo M, Cano C, Campayo L.
Abstract : The synthesis of a new series of 1,4-bis(alkylamino)benzo[g]phthalazines 1-3 is reported, and their ability to form dinuclear complexes with Cu(II) assayed. The geometry of the complexes is dependent on the nature of the electron-donor sites at the sidechains. Compounds 1 and 2, that contain sp3 or sp2 nitrogens at the end of the alkylamino groups, originate monopodal dinuclear complexes which seem to include endogenous OH bridges, and the sidechains seem to actively participate in complexation. However, the substitution of nitrogen by oxygen in 3 leads to a tripodal dinuclear complex in which the sidechains are not involved. The in vitro antiparasitic activity on Trypanosoma cruzi epimastigotes and amastigotes and the SOD activity inhibition have been evaluated for compounds 1-3, and, as expected, 1 and 2 show in all cases relevant results, whereas 3 is always the less active among the three substrates tested.
|
Antitrypanosomal activity against Trypanosoma cruzi after 72 hrs
|
Trypanosoma cruzi
|
0.17
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.
|
Antitrypanosomal activity against Trypanosoma cruzi Y infected in human LLC-MK2 cells after 24 hrs by MTT assay
|
Trypanosoma cruzi
|
36.3
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antiparasitic, antineuroinflammatory, and cytotoxic polyketides from the marine sponge Plakortis angulospiculatus collected in Brazil.
Year : 2008
Volume : 71
Issue : 3
First Page : 334
Last Page : 339
Authors : Kossuga MH, Nascimento AM, Reimão JQ, Tempone AG, Taniwaki NN, Veloso K, Ferreira AG, Cavalcanti BC, Pessoa C, Moraes MO, Mayer AM, Hajdu E, Berlinck RG.
Abstract : Investigation of the bioactive crude extract from the sponge Plakortis angulospiculatus from Brazil led to the isolation of plakortenone ( 1) as a new polyketide, along with five known polyketides ( 2- 6) previously isolated from other Plakortis sponges. The known polyketides were tested in antileishmanial, antitrypanosomal, antineuroinflammatory, and cytotoxicity assays. The results show that plakortide P ( 3) is a potent antiparasitic compound, against both Leishmania chagasi and Trypanosona cruzi, and exhibited antineuroinflammatory activity. The known polyketides 2- 6 were tested for cytotoxicity against four human cancer cell lines, but displayed only moderate cytotoxic activity.
|
Antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
0.55
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.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen strain C2C4 containing galactosidase gene in rat L6 cells after 4 days
|
Trypanosoma cruzi
|
0.382
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Ancistrocongolines A-D, new naphthylisoquinoline alkaloids from ancistrocladus congolensis.
Year : 2002
Volume : 65
Issue : 8
First Page : 1096
Last Page : 1101
Authors : Bringmann G, Messer K, Brun R, Mudogo V.
Abstract : Four new naphthylisoquinoline alkaloids, ancistrocongolines A-D (4-7) were isolated from Ancistrocladus congolensis, along with the known compound korupensamine A (8). Structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. Their biological activities against the pathogens of malaria, Leishmaniasis, Chagas disease, and African sleeping sickness were evaluated.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen C4
|
Trypanosoma cruzi
|
0.14
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.
|
Antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
0.42
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.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen
|
Trypanosoma cruzi
|
7.4
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Benzoic acid derivatives from Piper species and their antiparasitic activity.
Year : 2008
Volume : 71
Issue : 9
First Page : 1538
Last Page : 1543
Authors : Flores N, Jiménez IA, Giménez A, Ruiz G, Gutiérrez D, Bourdy G, Bazzocchi IL.
Abstract : Piper glabratum and P. acutifolium were analyzed for their content of main secondary constituents, affording nine new benzoic acid derivatives (1, 2, 4, 5, 7, and 10-13), in addition to four known compounds (3, 6, 8, and 9). Their structures were elucidated on the basis of spectroscopic data. Riguera ester reactions and optical rotation measurements established the new compounds as racemates. In the search for antiparasitic agents, the compounds were evaluated in vitro against the promastigote forms of Leishmania spp., Trypanosoma cruzi, and Plasmodium falciparum. Among the evaluated compounds, methyl 3,4-dihydroxy-5-(3'-methyl-2'-butenyl)benzoate (7) exhibited leishmanicidal effect (IC50 13.8-18.5 microg/mL) against the three Leishmania strains used, and methyl 3,4-dihydroxy-5-(2-hydroxy-3-methylbutenyl)benzoate (1), methyl 4-hydroxy-3-(2-hydroxy-3-methyl-3-butenyl)benzoate (3), and methyl 3,4-dihydroxy-5-(3-methyl-2-butenyl) benzoate (7) showed significant trypanocidal activity, with IC50 values of 16.4, 15.6, and 18.5 microg/mL, respectively.
|
Antiprotozoal activity against Trypanosoma cruzi Tulahuen C4 in rat L6 cells
|
Trypanosoma cruzi
|
0.317
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.
|
Antitrypanosomal activity against trypomastigotes of Trypanosoma cruzi Tulahuen C2C4 containing lacZ gene in rat L6 cells after 4 days
|
Trypanosoma cruzi
|
0.83
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, in vitro antitrypanosomal and antibacterial activity of phenoxy, phenylthio or benzyloxy substituted quinolones.
Year : 2009
Volume : 19
Issue : 3
First Page : 986
Last Page : 989
Authors : Ma X, Zhou W, Brun R.
Abstract : Chagas' disease, caused by Trypanosoma cruzi(T. cruzi), is one of the most serious parasitic diseases in Latin America. The currently available chemotherapy, based on nifurtimox or benznidazole, is unsatisfactory due to the limited efficacy in the prevalent chronic stage of the disease and toxic side effects. In order to address these deficiencies, a series of quinolones based novel molecules have been synthesized and evaluated as potential antitrypanosomal agents. The most active analogue 10 inhibited T. cruzi with an IC(50) of 1.3 microg/mL. The results of this study have implications in the development of novel quinolone's antitrypanosomal agents.
|
Antitrypanosomal activity against galactosidase gene containing Trypanosoma cruzi Tulahuen C2C4 trypomastigotes in rat L6 cells after 4 days
|
Trypanosoma cruzi
|
0.3
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Ancistroealaines A and B, two new bioactive naphthylisoquinolines, and related naphthoic acids from Ancistrocladus ealaensis.
Year : 2000
Volume : 63
Issue : 11
First Page : 1465
Last Page : 1470
Authors : Bringmann G, Hamm A, Günther C, Michel M, Brun R, Mudogo V.
Abstract : Two new 5,8'-coupled naphthylisoquinoline alkaloids, ancistroealaines A (1) and B (2), eleutherolic acid (3), and two naphthoic acids, ancistronaphthoic acid A (4) and B (5), have been isolated from Ancistrocladus ealaensis. Their structures were determined by spectroscopic, chemical, and chiroptical methods. Ancistroealaine A (1) exhibited activity against Leishmania donovani and Trypanosoma cruzi in vitro.
|
Antiplasmodial activity against Plasmodium falciparum K1 infected human erythrocytes after 48 hrs as [3H]hypoxanthine uptake
|
Plasmodium falciparum
|
0.25
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.
|
Antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
0.29
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.
|
Antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
1.5
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.
|
Antitrypanosomal activity against Trypanosoma cruzi in rat L6 cells
|
Trypanosoma cruzi
|
0.55
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : ent-Dioncophylleine A and related dehydrogenated naphthylisoquinoline alkaloids, the first Asian dioncophyllaceae-type alkaloids, from the "new"plant species Ancistrocladus benomensis.
Year : 2005
Volume : 68
Issue : 5
First Page : 686
Last Page : 690
Authors : Bringmann G, Dreyer M, Kopff H, Rischer H, Wohlfarth M, Hadi HA, Brun R, Meimberg H, Heubl G.
Abstract : Three new fully dehydrogenated naphthylisoquinoline alkaloids, the 7,1'-coupled ent-dioncophylleine A (3a), the likewise 7,1'-coupled 5'-O-demethyl-ent-dioncophylleine A (4), and the 7,8'-linked dioncophylleine D (5), have been isolated from the leaves of the recently described Malaysian highland liana Ancistrocladusbenomensis. All of them lack an oxygen function at C-6; this so-called Dioncophyllaceae-type structural subclass had previously been found only in naphthylisoquinoline alkaloids from West and Central African plants. Moreover, compounds 3a and 4 are the first fully dehydrogenated, i.e., only axially chiral, naphthylisoquinoline alkaloids of this type that are optically active; compound 5, by contrast, is fully racemic, due to its configurationally unstable biaryl axis. The structural elucidation was achieved by spectroscopic and chiroptical methods. Biological activities of these alkaloids against different protozoan parasites are described.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen C2C4
|
Trypanosoma cruzi
|
86.0
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.
|
Antimicrobial activity against Trypanosoma cruzi Tulahuen C2C4 amastigote forms infected in rat L6 cells
|
Trypanosoma cruzi
|
521.0
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.
|
Antiprotozoal activity against Trypanosoma cruzi Tulahuen C2C4 infected in rat skeletal myoblast at 4.8 ug/ml after 48 hrs
|
Trypanosoma cruzi
|
89.6
%
|
|
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.
|
Trypanocidal activity against intracellular amastigotes of Trypanosoma cruzi Tulahuen C2C4 expressing LacZ gene infected in rat L6 cells after 96 hrs
|
Trypanosoma cruzi
|
0.489
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.
|
Antitrypanosomal activity against epimastigotes of Trypanosoma cruzi Y assessed as viability at 40 uM after 11 days by trypan blue exclusion assay
|
Trypanosoma cruzi
|
97.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents.
Year : 2010
Volume : 18
Issue : 22
First Page : 7826
Last Page : 7835
Authors : Hernandes MZ, Rabello MM, Leite AC, Cardoso MV, Moreira DR, Brondani DJ, Simone CA, Reis LC, Souza MA, Pereira VR, Ferreira RS, McKerrow JH.
Abstract : In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.
|
Antitrypanosomal activity against epimastigotes of Trypanosoma cruzi Y assessed as viability at 40 uM after 15 hrs by trypan blue exclusion assay
|
Trypanosoma cruzi
|
43.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents.
Year : 2010
Volume : 18
Issue : 22
First Page : 7826
Last Page : 7835
Authors : Hernandes MZ, Rabello MM, Leite AC, Cardoso MV, Moreira DR, Brondani DJ, Simone CA, Reis LC, Souza MA, Pereira VR, Ferreira RS, McKerrow JH.
Abstract : In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.
|
Antitrypanosomal activity against epimastigotes of Trypanosoma cruzi Y assessed as viability at 40 uM after 7 days by trypan blue exclusion assay
|
Trypanosoma cruzi
|
85.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents.
Year : 2010
Volume : 18
Issue : 22
First Page : 7826
Last Page : 7835
Authors : Hernandes MZ, Rabello MM, Leite AC, Cardoso MV, Moreira DR, Brondani DJ, Simone CA, Reis LC, Souza MA, Pereira VR, Ferreira RS, McKerrow JH.
Abstract : In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.
|
Inhibition of Trypanosoma cruzi triosephosphate isomerase at 400 uM after 2 hrs
|
Trypanosoma cruzi
|
18.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Massive screening yields novel and selective Trypanosoma cruzi triosephosphate isomerase dimer-interface-irreversible inhibitors with anti-trypanosomal activity.
Year : 2010
Volume : 45
Issue : 12
First Page : 5767
Last Page : 5772
Authors : Alvarez G, Aguirre-López B, Varela J, Cabrera M, Merlino A, López GV, Lavaggi ML, Porcal W, Di Maio R, González M, Cerecetto H, Cabrera N, Pérez-Montfort R, de Gómez-Puyou MT, Gómez-Puyou A.
Abstract : Triosephosphate isomerase from Trypanosoma cruzi (TcTIM), an enzyme in the glycolytic pathway that exhibits high catalytic rates of glyceraldehyde-3-phosphate- and dihydroxyacetone-phosphate-isomerization only in its dimeric form, was screened against an in-house chemical library containing nearly 230 compounds belonging to different chemotypes. After secondary screening, twenty-six compounds from eight different chemotypes were identified as screening positives. Four compounds displayed selectivity for TcTIM over TIM from Homo sapiens and, concomitantly, in vitro activity against T. cruzi.
|
Antiprotozoal activity against Trypanosoma cruzi Tulahuen C2C4 amastigotes
|
Trypanosoma cruzi
|
1.8
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.
|
Antitrypanosomal activity against metacyclic forms of Trypanosoma cruzi infected in vero cells assessed as inhibition of infection at IC25 concentration after 12 hrs
|
Trypanosoma cruzi
|
39.0
%
|
|
Journal : J. Nat. Prod.
Title : In vitro and in vivo trypanocidal activity of flavonoids from Delphinium staphisagria against Chagas disease.
Year : 2011
Volume : 74
Issue : 4
First Page : 744
Last Page : 750
Authors : Marín C, Ramírez-Macías I, López-Céspedes A, Olmo F, Villegas N, Díaz JG, Rosales MJ, Gutiérrez-Sánchez R, Sánchez-Moreno M.
Abstract : The in vitro and in vivo trypanocidal activities of nine flavonoids (1-9) isolated from the aerial parts of Delphinium staphisagria have been studied in both the acute and chronic phases of Chagas disease. The antiproliferative activity of these substances against Trypanosoma cruzi (epimastigote, amastigote, and trypomastigote forms) in some cases exhibited more potent antitrypanosomatid activity and lower toxicity than the reference drug, benznidazole. Studies in vitro using ultrastructural analysis together with metabolism-excretion studies were also performed in order to identify the possible action mechanism of the compounds tested. Alterations mainly at the level of the mitochondria may explain metabolic changes in succinate and acetate production, perhaps due to the disturbance of the enzymes involved in sugar metabolism within the mitochondrion. In vivo studies provided results consistent with those observed in vitro. No signs of toxicity were detected in mice treated with the flavonoids tested, and the parasitic charge was significantly lower than in the control assay with benznidazole. The effects of these compounds were also demonstrated with the change in the anti-T. cruzi antibody levels during the chronic stage.
|
Antiprotozoal activity against Trypanosoma cruzi Tulahuen C4 at pH 7.4 by microplate assay
|
Trypanosoma cruzi
|
886.0
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.
|
Trypanocidal activity against trypomastigote Trypanosoma cruzi Tulahuen C2C4 infected in L6 cells after 96 hrs by beta-galactosidase reporter gene assay
|
Trypanosoma cruzi
|
0.464
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.
|
Antitrypanosomal activity against intracellular amastigote stage of Trypanosoma cruzi Tulahuen C2C4 infected in rat L6 cells after 96 hrs by spectrophotometric analysis
|
Trypanosoma cruzi
|
0.48
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.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen C2C4 intracellular amastigotes infected in rat L6 cells after 4 days by photometry
|
Trypanosoma cruzi
|
122.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents.
Year : 2012
Volume : 54
First Page : 512
Last Page : 521
Authors : Carvalho SA, Feitosa LO, Soares M, Costa TE, Henriques MG, Salomão K, de Castro SL, Kaiser M, Brun R, Wardell JL, Wardell SM, Trossini GH, Andricopulo AD, da Silva EF, Fraga CA.
Abstract : We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N-acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action.
|
Trypanosomicidal activity against Trypanosoma cruzi epimastigotes assessed as inhibition of acetate metabolite excretion after 96 hrs by NMR analysis
|
Trypanosoma cruzi
|
6.0
%
|
|
Journal : J. Med. Chem.
Title : In vitro and in vivo trypanosomicidal activity of pyrazole-containing macrocyclic and macrobicyclic polyamines: their action on acute and chronic phases of Chagas disease.
Year : 2012
Volume : 55
Issue : 9
First Page : 4231
Last Page : 4243
Authors : Sánchez-Moreno M, Marín C, Navarro P, Lamarque L, García-España E, Miranda C, Huertas O, Olmo F, Gómez-Contreras F, Pitarch J, Arrebola F.
Abstract : The in vitro and in vivo anti- Trypanosoma cruzi activity of the pyrazole-containing macrobicyclic polyamine 1 and N-methyl- and N-benzyl-substituted monocyclic polyamines 2 and 3 was studied. Activity against both the acute and chronic phases of Chagas disease was considered. The compounds were more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, but 1 and 2 were especially effective, where cryptand 1 was the most active, particularly in the chronic phase. The activity results found for these compounds were complemented and discussed by considering their inhibitory effect on the iron superoxide dismutase enzyme of the parasite, the nature of the metabolites excreted after treatment, and the ultrastructural alterations produced. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug and that 1 and 2 exhibited lower levels of damage than 3.
|
Antitrypanosomal activity against Trypanosoma cruzi IRHOD/VO/2008/SN3 metacyclic forms infected in african green monkey Vero cells assessed as inhibition of trypomastigotes level at IC25 level 0.5 to 10 days
|
Trypanosoma cruzi
|
41.6
%
|
|
Journal : J. Med. Chem.
Title : Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection.
Year : 2012
Volume : 55
Issue : 22
First Page : 9900
Last Page : 9913
Authors : Sánchez-Moreno M, Gómez-Contreras F, Navarro P, Marín C, Olmo F, Yunta MJ, Sanz AM, Rosales MJ, Cano C, Campayo L.
Abstract : A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.
|
Antitrypanosomal activity against Trypanosoma cruzi IRHOD/VO/2008/SN3 metacyclic forms infected in african green monkey Vero cells assessed as inhibition of intracellular amastigotes replication at IC25 level 0.5 to 10 days
|
Trypanosoma cruzi
|
12.5
%
|
|
Journal : J. Med. Chem.
Title : Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection.
Year : 2012
Volume : 55
Issue : 22
First Page : 9900
Last Page : 9913
Authors : Sánchez-Moreno M, Gómez-Contreras F, Navarro P, Marín C, Olmo F, Yunta MJ, Sanz AM, Rosales MJ, Cano C, Campayo L.
Abstract : A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.
|
Antitrypanosomal activity against Trypanosoma cruzi IRHOD/VO/2008/SN3 metacyclic forms infected in african green monkey Vero cells assessed as inhibition of infection rate at IC25 level 0.5 to 10 days
|
Trypanosoma cruzi
|
39.4
%
|
|
Journal : J. Med. Chem.
Title : Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection.
Year : 2012
Volume : 55
Issue : 22
First Page : 9900
Last Page : 9913
Authors : Sánchez-Moreno M, Gómez-Contreras F, Navarro P, Marín C, Olmo F, Yunta MJ, Sanz AM, Rosales MJ, Cano C, Campayo L.
Abstract : A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.
|
Antitrypanosomal activity against trypomastigote form of Trypanosoma cruzi INC5 after 24 hr by Neubauer counting method
|
Trypanosoma cruzi
|
204.64
ug.mL-1
|
|
Journal : Med Chem Res
Title : Synthesis and theoretic calculations of benzoxazoles and docking studies of their interactions with triosephosphate isomerase
Year : 2013
Volume : 22
Issue : 6
First Page : 2768
Last Page : 2777
Authors : Flores Sandoval CA, Cuevas Hernandez RI, Correa Basurto J, Beltran Conde HI, Padilla Martinez II, Farfan Garcia JN, Nogueda Torres B, Trujillo Ferrara JG
|
Antitrypanosomal activity against trypomastigote form of Trypanosoma cruzi NINOA after 24 hr by Neubauer counting method
|
Trypanosoma cruzi
|
116.61
ug.mL-1
|
|
Journal : Med Chem Res
Title : Synthesis and theoretic calculations of benzoxazoles and docking studies of their interactions with triosephosphate isomerase
Year : 2013
Volume : 22
Issue : 6
First Page : 2768
Last Page : 2777
Authors : Flores Sandoval CA, Cuevas Hernandez RI, Correa Basurto J, Beltran Conde HI, Padilla Martinez II, Farfan Garcia JN, Nogueda Torres B, Trujillo Ferrara JG
|
Antitrypanosomal activity against Trypanosoma cruzi Y epimastigotes at 8 uM incubated for 48 hrs by resazurin dye reduction based ELISA method
|
Trypanosoma cruzi
|
51.0
%
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Antitrypanosomal activity against Trypanosoma cruzi Y epimastigotes at 16 uM incubated for 48 hrs by resazurin dye reduction based ELISA method
|
Trypanosoma cruzi
|
66.0
%
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Antitrypanosomal activity against Trypanosoma cruzi Y epimastigotes at 32 uM incubated for 48 hrs by resazurin dye reduction based ELISA method
|
Trypanosoma cruzi
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Antitrypanosomal activity against Trypanosoma cruzi Y epimastigotes at 64 uM incubated for 48 hrs by resazurin dye reduction based ELISA method
|
Trypanosoma cruzi
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Antitrypanosomal activity against Trypanosoma cruzi Y epimastigotes at 128 uM incubated for 48 hrs by resazurin dye reduction based ELISA method
|
Trypanosoma cruzi
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Antitrypanosomal activity against Trypanosoma cruzi Y epimastigotes at 256 uM incubated for 48 hrs by resazurin dye reduction based ELISA method
|
Trypanosoma cruzi
|
91.0
%
|
|
Journal : J. Med. Chem.
Title : Cloning, characterization, and sulfonamide and thiol inhibition studies of an α-carbonic anhydrase from Trypanosoma cruzi, the causative agent of Chagas disease.
Year : 2013
Volume : 56
Issue : 4
First Page : 1761
Last Page : 1771
Authors : Pan P, Vermelho AB, Capaci Rodrigues G, Scozzafava A, Tolvanen ME, Parkkila S, Capasso C, Supuran CT.
Abstract : An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
|
Antiparasitic activity against amastigotes of Trypanosoma cruzi CL Brener expressing Escherichia coli lacZ gene infected in mouse NCTC-929 cells assessed as parasite growth inhibition after 7 days by colorimetric assay
|
Trypanosoma cruzi strain CL Brener
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective activity of 2,4-diaryl-1,2,3,4-tetrahydroquinolines on Trypanosoma cruzi epimastigotes and amastigotes expressing β-galactosidase.
Year : 2013
Volume : 23
Issue : 17
First Page : 4851
Last Page : 4856
Authors : Fonseca-Berzal C, Merchán Arenas DR, Romero Bohórquez AR, Escario JA, Kouznetsov VV, Gómez-Barrio A.
Abstract : The growth inhibitory effect on Trypanosoma cruzi epimastigotes and the unspecific cytotoxicity over NCTC-929 fibroblasts of two series of previously synthesized 2,4-diaryl-1,2,3,4-tetrahydroquinolines (THQ), have been studied in vitro and compared with those of benznidazole (BZ). Derivatives AR39, AR40, AR41, AR91 and DM15 achieved outstanding selectivity indexes (SI) on the extracellular form (SITHQ>SIBZ>9.44) and thus, were tested in a more specific in vitro assay against amastigotes, showing less effectiveness than the reference drug (SIBZ>320) but also accomplishing great selectivity on the intracellular stage (SITHQ>25). These promising results, supported by the in silico prediction of high bioavailability and less potential risk than benznidazole, reveal several tetrahydroquinolines as prototypes of potential antichagasic drugs.
|
Antiparasitic activity against epimastigotes of Trypanosoma cruzi assessed as inhibition of parasite proliferation
|
Trypanosoma cruzi
|
2.5
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Preparation and antitrypanosomal activity of secochiliolide acid derivatives.
Year : 2013
Volume : 23
Issue : 17
First Page : 4964
Last Page : 4967
Authors : Siless GE, Lozano E, Sánchez M, Mazzuca M, Sosa MA, Palermo JA.
Abstract : Secochiliolide acid (1) isolated from the Patagonian shrub Nardophyllum bryoides, was used as a scaffold for the preparation of a series of nine derivatives. Compound 1 and its derivatives were tested against Trypanosoma cruzi epimastigotes grown in liquid media. It was first observed that secochiliolide acid (1) inhibited the proliferation of the parasites, with an IC50 of 2 μg/mL. Six of the synthesized derivatives were also active with IC50's between 2 and 7 μg/mL which are comparable to that of the commercial drug benznidazole (2.5 μg/mL). These results indicate that the carboxyl group is not essential for the bioactivity of 1, while the presence of the tetrasubstituted exocyclic double bond seems to be important. Moreover, the presence of the furan and spirolactone rings is not essential for the bioactivity per se, but is important in combination with other structural fragments present in the molecule.
|
Trypanocidal activity against trypomastigote form of Trypanosoma cruzi IRHOD/CO/2008/SN3 infected in African green monkey Vero cells assessed as inhibition of trypomastigotes released in culture medium at IC25 relative to control
|
Trypanosoma cruzi
|
27.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model.
Year : 2013
Volume : 70
First Page : 189
Last Page : 198
Authors : Olmo F, Marín C, Clares MP, Blasco S, Albelda MT, Soriano C, Gutiérrez-Sánchez R, Arrebola-Vargas F, García-España E, Sánchez-Moreno M.
Abstract : Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in vitro and in vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T. cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by (1)H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug.
|
Trypanocidal activity against amastigote form of Trypanosoma cruzi IRHOD/CO/2008/SN3 infected in African green monkey Vero cells assessed as inhibition of amastigotes load per cell at IC25 preincubated for 12 hrs followed by compound washout measured after 10 days by Giemsa staining-based microscopic analysis relative to control
|
Trypanosoma cruzi
|
12.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model.
Year : 2013
Volume : 70
First Page : 189
Last Page : 198
Authors : Olmo F, Marín C, Clares MP, Blasco S, Albelda MT, Soriano C, Gutiérrez-Sánchez R, Arrebola-Vargas F, García-España E, Sánchez-Moreno M.
Abstract : Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in vitro and in vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T. cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by (1)H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug.
|
Trypanocidal activity against amastigote form of Trypanosoma cruzi IRHOD/CO/2008/SN3 infected in African green monkey Vero cells assessed as inhibition of parasite infection rate at IC25 preincubated for 12 hrs followed by compound washout measured after 10 days by Giemsa staining-based microscopic analysis relative to control
|
Trypanosoma cruzi
|
39.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model.
Year : 2013
Volume : 70
First Page : 189
Last Page : 198
Authors : Olmo F, Marín C, Clares MP, Blasco S, Albelda MT, Soriano C, Gutiérrez-Sánchez R, Arrebola-Vargas F, García-España E, Sánchez-Moreno M.
Abstract : Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in vitro and in vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T. cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by (1)H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug.
|
Antimicrobial activity against amastigote stage of Trypanosoma cruzi CL Brener infected in mouse NCTC-929 cells assessed as growth inhibition after 7 days by beta-galactosidase reporter gene assay
|
Trypanosoma cruzi strain CL Brener
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents.
Year : 2014
Volume : 24
Issue : 4
First Page : 1209
Last Page : 1213
Authors : Fonseca-Berzal C, Rojas Ruiz FA, Escario JA, Kouznetsov VV, Gómez-Barrio A.
Abstract : In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI=12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.
|
Cytotoxicity against mouse NCTC-929 cells at 256 uM after 48 hrs by resazurin staining-based fluorescence assay
|
Mus musculus
|
17.38
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents.
Year : 2014
Volume : 24
Issue : 4
First Page : 1209
Last Page : 1213
Authors : Fonseca-Berzal C, Rojas Ruiz FA, Escario JA, Kouznetsov VV, Gómez-Barrio A.
Abstract : In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI=12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.
|
Antitrypanosomal activity against Trypanosoma cruzi (IRHOD/CO/2008/SN3) infected in African green monkey Vero cells assessed as reduction in number of trypomastigotes at IC25 treated for 12 hrs followed by compound-washout measured after 10 days by microscopic analysis relative to control
|
Trypanosoma cruzi
|
41.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New perspectives on the synthesis and antichagasic activity of 3-alkoxy-1-alkyl-5-nitroindazoles.
Year : 2014
Volume : 74
First Page : 124
Last Page : 134
Authors : Muro B, Reviriego F, Navarro P, Marín C, Ramírez-Macías I, Rosales MJ, Sánchez-Moreno M, Arán VJ.
Abstract : The synthesis and antiprotozoal activity of some 3-alkoxy-1-alkyl- (1, 4) and 3-alkoxy-1-(ω-aminoalkyl)-5-nitroindazoles (2, 3, 5-8) against different morphological forms of Trypanosoma cruzi are reported. These compounds were prepared using simple alkylation reactions and, usually, taking advantage of the reactivity of some indazole-derived betaines previously studied by us. Most indazole derivatives showed in vitro activities similar or higher than those of the reference drug benznidazole; this fact, along with low unspecific cytotoxicities against Vero cells shown by some of them, led to very good selectivity indexes (SI). The high efficiency of 5-nitroindazoles 1 and 2 against T. cruzi was confirmed by further in vitro studies on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. Complementary analyses of the changes in the metabolites excreted by the parasite and on the ultrastructural alterations induced after treatment with indazole derivatives 1 and 2 were also conducted.
|
Antitrypanosomal activity against Trypanosoma cruzi (IRHOD/CO/2008/SN3) infected in African green monkey Vero cells assessed as reduction in infection rate at IC25 treated for 12 hrs followed by compound-washout measured after 10 days by microscopic analysis relative to control
|
Trypanosoma cruzi
|
19.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New perspectives on the synthesis and antichagasic activity of 3-alkoxy-1-alkyl-5-nitroindazoles.
Year : 2014
Volume : 74
First Page : 124
Last Page : 134
Authors : Muro B, Reviriego F, Navarro P, Marín C, Ramírez-Macías I, Rosales MJ, Sánchez-Moreno M, Arán VJ.
Abstract : The synthesis and antiprotozoal activity of some 3-alkoxy-1-alkyl- (1, 4) and 3-alkoxy-1-(ω-aminoalkyl)-5-nitroindazoles (2, 3, 5-8) against different morphological forms of Trypanosoma cruzi are reported. These compounds were prepared using simple alkylation reactions and, usually, taking advantage of the reactivity of some indazole-derived betaines previously studied by us. Most indazole derivatives showed in vitro activities similar or higher than those of the reference drug benznidazole; this fact, along with low unspecific cytotoxicities against Vero cells shown by some of them, led to very good selectivity indexes (SI). The high efficiency of 5-nitroindazoles 1 and 2 against T. cruzi was confirmed by further in vitro studies on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. Complementary analyses of the changes in the metabolites excreted by the parasite and on the ultrastructural alterations induced after treatment with indazole derivatives 1 and 2 were also conducted.
|
Antitrypanosomal activity against Trypanosoma cruzi (IRHOD/CO/2008/SN3) infected in African green monkey Vero cells assessed as reduction in number of amastigotes at IC25 treated for 12 hrs followed by compound-washout measured after 10 days by microscopic analysis relative to control
|
Trypanosoma cruzi
|
37.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New perspectives on the synthesis and antichagasic activity of 3-alkoxy-1-alkyl-5-nitroindazoles.
Year : 2014
Volume : 74
First Page : 124
Last Page : 134
Authors : Muro B, Reviriego F, Navarro P, Marín C, Ramírez-Macías I, Rosales MJ, Sánchez-Moreno M, Arán VJ.
Abstract : The synthesis and antiprotozoal activity of some 3-alkoxy-1-alkyl- (1, 4) and 3-alkoxy-1-(ω-aminoalkyl)-5-nitroindazoles (2, 3, 5-8) against different morphological forms of Trypanosoma cruzi are reported. These compounds were prepared using simple alkylation reactions and, usually, taking advantage of the reactivity of some indazole-derived betaines previously studied by us. Most indazole derivatives showed in vitro activities similar or higher than those of the reference drug benznidazole; this fact, along with low unspecific cytotoxicities against Vero cells shown by some of them, led to very good selectivity indexes (SI). The high efficiency of 5-nitroindazoles 1 and 2 against T. cruzi was confirmed by further in vitro studies on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. Complementary analyses of the changes in the metabolites excreted by the parasite and on the ultrastructural alterations induced after treatment with indazole derivatives 1 and 2 were also conducted.
|
Trypanocidal activity against metacyclic trypomastigote stage of Trypanosoma cruzi infected in BALB/c albino mouse acute chagas disease model assessed as inhibition of parasitemia at 25 mg/kg, ip administered on day 7 to 12 post-infection measured every 2 days until day 40 by ELISA relative to control
|
Trypanosoma cruzi
|
26.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of N,N'-squaramides with high in vivo efficacy and low toxicity: toward a low-cost drug against Chagas disease.
Year : 2014
Volume : 57
Issue : 3
First Page : 987
Last Page : 999
Authors : Olmo F, Rotger C, Ramírez-Macías I, Martínez L, Marín C, Carreras L, Urbanová K, Vega M, Chaves-Lemaur G, Sampedro A, Rosales MJ, Sánchez-Moreno M, Costa A.
Abstract : Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.
|
Antitrypanosomal activity against trypomastigote stage of Trypanosoma cruzi IRHOD/CO/2008/SN3 assessed as reduction of trypomastigote number per mililiter of culture medium at IC25 preincubated for 12 hrs followed by compound washout measured every 48 hrs for 10 days by Neubauer hemocytometric chamber analysis relative to control
|
Trypanosoma cruzi
|
21.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of N,N'-squaramides with high in vivo efficacy and low toxicity: toward a low-cost drug against Chagas disease.
Year : 2014
Volume : 57
Issue : 3
First Page : 987
Last Page : 999
Authors : Olmo F, Rotger C, Ramírez-Macías I, Martínez L, Marín C, Carreras L, Urbanová K, Vega M, Chaves-Lemaur G, Sampedro A, Rosales MJ, Sánchez-Moreno M, Costa A.
Abstract : Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.
|
Antitrypanosomal activity against amastigote stage of Trypanosoma cruzi IRHOD/CO/2008/SN3 infected in African green monkey Vero cells assessed as reduction of amastigote number per cell at IC25 preincubated for 12 hrs followed by compound washout measured every 48 hrs for 10 days by Neubauer hemocytometric chamber analysis relative to control
|
Trypanosoma cruzi
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of N,N'-squaramides with high in vivo efficacy and low toxicity: toward a low-cost drug against Chagas disease.
Year : 2014
Volume : 57
Issue : 3
First Page : 987
Last Page : 999
Authors : Olmo F, Rotger C, Ramírez-Macías I, Martínez L, Marín C, Carreras L, Urbanová K, Vega M, Chaves-Lemaur G, Sampedro A, Rosales MJ, Sánchez-Moreno M, Costa A.
Abstract : Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.
|
Antitrypanosomal activity against amastigote stage of Trypanosoma cruzi IRHOD/CO/2008/SN3 infected in African green monkey Vero cells assessed as decrease in infection rate at IC25 preincubated for 12 hrs followed by compound washout measured every 48 hrs for 10 days by Neubauer hemocytometric chamber analysis relative to control
|
Trypanosoma cruzi
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of N,N'-squaramides with high in vivo efficacy and low toxicity: toward a low-cost drug against Chagas disease.
Year : 2014
Volume : 57
Issue : 3
First Page : 987
Last Page : 999
Authors : Olmo F, Rotger C, Ramírez-Macías I, Martínez L, Marín C, Carreras L, Urbanová K, Vega M, Chaves-Lemaur G, Sampedro A, Rosales MJ, Sánchez-Moreno M, Costa A.
Abstract : Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.
|
Antiprotozoal activity against Trypanosoma cruzi Tulahuen C2C4
|
Trypanosoma cruzi
|
886.0
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
|
Antitrypanosomal activity against Trypanosoma cruzi assessed as growth inhibition
|
Trypanosoma cruzi
|
409.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Exploring in vitro and in vivo Hsp90 inhibitors activity against human protozoan parasites.
Year : 2015
Volume : 25
Issue : 3
First Page : 462
Last Page : 465
Authors : Giannini G, Battistuzzi G.
Abstract : A set of compounds, previously selected as potent Hsp90α inhibitors, has been studied on a panel of human parasites. 5-Aryl-3,4-isoxazolediamide derivatives (1) were active against two protozoa, Trypanosoma brucei rhodesiense and Plasmodium falciparum, with a good tolerability toward cytotoxicity on non-malignant L6 rat myoblast cell line, unlike the 1,5-diaryl,4-carboxamides-1,2,3-triazole derivatives (2) which, while showing a single-digit nM range activity against the same protozoa, were also highly cytotoxic on L6 cells. In a subsequent in vivo study, two isoxazolediamide derivatives, 1a and 1b, were very efficacious on the sleeping sickness-causing agent with a clear parasitaemia during treatment. These data, however, showed that not all protozoa are sensitive to Hsp90 inhibitors, as well as not all Hsp90 inhibitors are equally active on parasites.
|
Antimicrobial activity against trypomastigote form of Trypanosoma cruzi Tulahuen C2C4 infected in rat L6 cells after 96 hrs by microscopic analysis
|
Trypanosoma cruzi
|
0.38
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.
|
Antitrypanosomal activity against amastigote stage of Trypanosoma cruzi Tulahuen infected in human U937 cells assessed as parasite growth inhibition after 72 hrs by beta-galactosidase reporter gene assay
|
Trypanosoma cruzi
|
10.7
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : An efficient synthesis of new caffeine-based chalcones, pyrazolines and pyrazolo[3,4-b][1,4]diazepines as potential antimalarial, antitrypanosomal and antileishmanial agents.
Year : 2015
Volume : 93
First Page : 401
Last Page : 413
Authors : Insuasty B, Ramírez J, Becerra D, Echeverry C, Quiroga J, Abonia R, Robledo SM, Vélez ID, Upegui Y, Muñoz JA, Ospina V, Nogueras M, Cobo J.
Abstract : A new series of chalcones 5a-f were synthesized from caffeine-based aldehyde 3 and substituted acetophenones 4a-f. Treatment of compounds 5a-f with hydrazine hydrate led to pyrazolines 6a-f, and their subsequent reaction with acetic anhydride or formic acid afforded the corresponding N-substituted pyrazolines 7a-f and 8a-f respectively. Additionally, the regioselective cyclocondensation reaction of chalcones 5a-f with 4,5-diaminopyrazole 9 afforded the diazepine derivatives 10a-f. Synthesis of the above novel compounds was carried out through a simple procedure involving an easy work-up and mild reaction conditions. In vitro antimalarial activity against Plasmodium falciparum was evaluated for the obtained compounds. Among of them, just pirazoline 6a showed an outstanding growth inhibition percentage 85.2 ± 5.4%, while diazepines 10a-f showed remarkable growth inhibitions in the range of 80.3 ± 13.5 to 94.2 ± 0.2% when were tested at 20 μg/mL. Compounds 5b, 5e, 7c and 7f showed remarkable activities against Leishmania panamensis with growth inhibition of 88.3 ± 1.5, 82.6 ± 2.2, 82.8 ± 1.7 and 87.6 ± 0.5% respectively, at 20 μg/mL. In vitro assays against Trypanozoma cruzi showed that pyrazoline 6d displayed a growth inhibition of 61.9 ± 7.8% at 20 μg/mL while chalcone 5f was considered especially active with a growth inhibition of 9.7 ± 1.5% for a very low concentration of 1.0 μg/mL.
|
Trypanocidal activity against intracellular amastigotes of Trypanosoma cruzi Tulahuen infected in human U937 cells assessed as reduction of viability of intracellular amastigotes by measuring beta-galactosidase activity at 20 ug/ml after 72 hrs by spectrophotometry analysis
|
Trypanosoma cruzi
|
87.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline-hydrazone hybrids.
Year : 2015
Volume : 101
First Page : 746
Last Page : 753
Authors : Coa JC, Castrillón W, Cardona W, Carda M, Ospina V, Muñoz JA, Vélez ID, Robledo SM.
Abstract : Cutaneous leishmaniasis and Chagas disease are vector-borne parasitic disease causing serious risks to million people living in poverty-stricken areas. Both diseases are a major health problem in Latin America, and currently drugs for the effective treatment of these diseases have important concerns related with efficacy or toxicity than need to be addressed. We report herein the synthesis and biological activities (cytotoxicity, leishmanicidal and trypanocidal activities) of ten quinolone-hydrazone hybrids. The structure of the products was elucidated by spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis which is the most prevalent Leishmania species in Colombia and Trypanosoma cruzi that is the major pathogenic species to humans; in turn, cytotoxicity was evaluated against human U-937 macrophages. Compounds 6b, 6c and 8 showed activity against L. (V) panamensis with EC50 of 6.5 ± 0.8 μg/mL (21.2 μM), 0.8 ± 0.0 μg/mL (2.6 μM) and 3.4 ± 0.6 μg/mL (11.1 μM), respectively, while compounds 6a and 6c had activity against T. cruzi. with EC50 values of 1.4 ± 0.3 μg/mL (4.8 μM) and 6.6 ± 0.3 μg/mL (4.6 μM), respectively. Even compound 6a showed better activity against T. cruzi than the standard drug benznidazole with EC50 = 10.5 ± 1.8 μg/mL (40.3 μM). Analysis of the results obtained against leishmaniasis indicates that antiparasite activity is related to the presence of 2-substituted quinoline (isoquinolinic core) and the hydroxyl group in positions 3 and 4 of the aromatic ring. Although the majority of these compounds were highly cytotoxic, the antiparasite activity was higher than cytotoxicity and therefore, they still have potential to be considered as hit molecules for leishmanicidal and trypanocidal drug development.
|
Trypanocidal activity against intracellular amastigotes of Trypanosoma cruzi Tulahuen infected in human U937 cells assessed as reduction of viability of intracellular amastigotes by measuring beta-galactosidase activity after 72 hrs by spectrophotometry analysis
|
Trypanosoma cruzi
|
10.5
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline-hydrazone hybrids.
Year : 2015
Volume : 101
First Page : 746
Last Page : 753
Authors : Coa JC, Castrillón W, Cardona W, Carda M, Ospina V, Muñoz JA, Vélez ID, Robledo SM.
Abstract : Cutaneous leishmaniasis and Chagas disease are vector-borne parasitic disease causing serious risks to million people living in poverty-stricken areas. Both diseases are a major health problem in Latin America, and currently drugs for the effective treatment of these diseases have important concerns related with efficacy or toxicity than need to be addressed. We report herein the synthesis and biological activities (cytotoxicity, leishmanicidal and trypanocidal activities) of ten quinolone-hydrazone hybrids. The structure of the products was elucidated by spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis which is the most prevalent Leishmania species in Colombia and Trypanosoma cruzi that is the major pathogenic species to humans; in turn, cytotoxicity was evaluated against human U-937 macrophages. Compounds 6b, 6c and 8 showed activity against L. (V) panamensis with EC50 of 6.5 ± 0.8 μg/mL (21.2 μM), 0.8 ± 0.0 μg/mL (2.6 μM) and 3.4 ± 0.6 μg/mL (11.1 μM), respectively, while compounds 6a and 6c had activity against T. cruzi. with EC50 values of 1.4 ± 0.3 μg/mL (4.8 μM) and 6.6 ± 0.3 μg/mL (4.6 μM), respectively. Even compound 6a showed better activity against T. cruzi than the standard drug benznidazole with EC50 = 10.5 ± 1.8 μg/mL (40.3 μM). Analysis of the results obtained against leishmaniasis indicates that antiparasite activity is related to the presence of 2-substituted quinoline (isoquinolinic core) and the hydroxyl group in positions 3 and 4 of the aromatic ring. Although the majority of these compounds were highly cytotoxic, the antiparasite activity was higher than cytotoxicity and therefore, they still have potential to be considered as hit molecules for leishmanicidal and trypanocidal drug development.
|
Antichagasic activity against firefly luciferase expressing trypamastigote forms of transgenic Trypanosoma cruzi Y infected in Balb/c mouse assessed as reduction in parasite level at 15 mg/kg/day, ip dosed for 10 days by luciferase reporter gene assay
|
Trypanosoma cruzi
|
99.0
%
|
|
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.
|
Trypanocidal activity against Trypanosoma cruzi Tulahuen 2 epimastigotes at 25 uM after 5 days
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of quinoxaline di-N-oxide derivatives with in vitro trypanocidal activity.
Year : 2016
Volume : 26
Issue : 3
First Page : 903
Last Page : 906
Authors : Pérez-Silanes S, Torres E, Arbillaga L, Varela J, Cerecetto H, González M, Azqueta A, Moreno-Viguri E.
Abstract : We report the synthesis and in vitro activity against Trypanosoma cruzi epimastigotes of 15 novel quinoxaline derivatives. Ten of the derivatives presented IC50 values lower than the reference drugs Nfx and Bzn; four of them standed out with IC50 values lower than 1.5 μM. Moreover, unspecific cytotoxicity and genotoxicity studies are also reported. Compound 14 showed a SI higher than 24, whereas compound 10 was the only one that was negative in the genotoxicity screening.
|
Antichagasic activity against Trypanosoma cruzi CL-B5 intracellular amastigotes in mouse L929 cells assessed as growth inhibition after 7 days by beta galactosidase reporter gene assay
|
Trypanosoma cruzi
|
680.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles.
Year : 2016
Volume : 115
First Page : 295
Last Page : 310
Authors : Fonseca-Berzal C, Ibáñez-Escribano A, Reviriego F, Cumella J, Morales P, Jagerovic N, Nogal-Ruiz JJ, Escario JA, da Silva PB, Soeiro Mde N, Gómez-Barrio A, Arán VJ.
Abstract : Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6-29, series A) and 3-alkoxy-2-benzyl-2H-indazoles (30-37, series B), containing differently functionalized chains at position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological agents of Chagas disease and trichomonosis, respectively. Many indazolinones of series A were efficient against different morphological forms of T. cruzi CL Brener strain (compounds 6, 7, 9, 10 and 19-21: IC50 = 1.58-4.19 μM for epimastigotes; compounds 6, 19-21 and 24: IC50 = 0.22-0.54 μM for amastigotes) being as potent as the reference drug benznidazole. SAR analysis suggests that electron-donating groups at position 1 of indazolinone ring are associated with an improved antichagasic activity. Moreover, compounds of series A displayed low unspecific toxicities against an in vitro model of mammalian cells (fibroblasts), which were reflected in high values of the selectivity indexes (SI). Compound 20 was also very efficient against amastigotes from Tulahuen and Y strains of T. cruzi (IC50 = 0.81 and 0.60 μM, respectively), showing low toxicity towards cardiac cells (LC50 > 100 μM). In what concerns compounds of series B, some of them displayed moderate activity against trophozoites of a metronidazole-sensitive isolate of T. vaginalis (35 and 36: IC50 = 9.82 and 7.25 μM, respectively), with low unspecific toxicity towards Vero cells. Compound 36 was also active against a metronidazole-resistant isolate (IC50 = 9.11 μM) and can thus be considered a good prototype for the development of drugs directed to T. vaginalis resistant to 5-nitroimidazoles.
|
Antitrypanosomal activity against trypomastigote stage of Trypanosoma cruzi Y at 25 uM measured after 24 hrs using propidium iodide by neubauer chamber method relative to control
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi.
Year : 2016
Volume : 24
Issue : 18
First Page : 4228
Last Page : 4240
Authors : Silva-Júnior EF, Silva EP, França PH, Silva JP, Barreto EO, Silva EB, Ferreira RS, Gatto CC, Moreira DR, Siqueira-Neto JL, Mendonça-Júnior FJ, Lima MC, Bortoluzzi JH, Scotti MT, Scotti L, Meneghetti MR, Aquino TM, Araújo-Júnior JX.
Abstract : In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03μM. The 8c derivative showed the highest potency against cruzain (IC50=2.4μM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
|
Antitrypanosomal activity against amastigote stage of Trypanosoma cruzi CA-I/72 infected in mouse C2C12 cells at 10 uM measured after 3 days by DAPI staining-based assay relative to control
|
Trypanosoma cruzi
|
94.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi.
Year : 2016
Volume : 24
Issue : 18
First Page : 4228
Last Page : 4240
Authors : Silva-Júnior EF, Silva EP, França PH, Silva JP, Barreto EO, Silva EB, Ferreira RS, Gatto CC, Moreira DR, Siqueira-Neto JL, Mendonça-Júnior FJ, Lima MC, Bortoluzzi JH, Scotti MT, Scotti L, Meneghetti MR, Aquino TM, Araújo-Júnior JX.
Abstract : In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03μM. The 8c derivative showed the highest potency against cruzain (IC50=2.4μM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen amastigotes infected in mouse 3T3 cells after 6 days by beta galactosidase reporter asay
|
Trypanosoma cruzi
|
690.0
nM
|
|
Journal : ACS Med Chem Lett
Title : New Class of Antitrypanosomal Agents Based on Imidazopyridines.
Year : 2017
Volume : 8
Issue : 7
First Page : 766
Last Page : 770
Authors : Silva DG, Gillespie JR, Ranade RM, Herbst ZM, Nguyen UTT, Buckner FS, Montanari CA, Gelb MH.
Abstract : The present work describes the synthesis of 22 new imidazopyridine analogues arising from medicinal chemistry optimization at different sites on the molecule. Seven and 12 compounds exhibited an in vitro EC50 ≤ 1 μM against Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) parasites, respectively. Based on promising results of in vitro activity (EC50 < 100 nM), cytotoxicity, metabolic stability, protein binding, and pharmacokinetics (PK) properties, compound 20 was selected as a candidate for in vivo efficacy studies. This compound was screened in an acute mouse model against T.cruzi (Tulahuen strain). After established infection, mice were dosed twice a day for 5 days, and then monitored for 6 weeks using an in vivo imaging system (IVIS). Compound 20 demonstrated parasite inhibition comparable to the benznidazole treatment group. Compound 20 represents a potential lead for the development of drugs to treat trypanosomiasis.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen intracellular amastigote harboring LacZ infected in human U937 cells after 72 hrs by CPRG/Nonidet reagent based spectrophotometric method
|
Trypanosoma cruzi
|
10.7
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel quinoline-based 4,5-dihydro-1H-pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents.
Year : 2017
Volume : 131
First Page : 237
Last Page : 254
Authors : Ramírez-Prada J, Robledo SM, Vélez ID, Crespo MDP, Quiroga J, Abonia R, Montoya A, Svetaz L, Zacchino S, Insuasty B.
Abstract : A new series of N-substituted 2-pyrazolines 9a-f, 10a-f, 11a-f, 12a-f and 13a-f were obtained from the cyclocondensation reaction of [(7-chloroquinolin-4-yl)amino]chalcones 8a-f with hydrazine hydrate and its derivatives. Fourteen of the synthesized compounds including the starting chalcones were selected by US National Cancer Institute (NCI) for testing their anticancer activity against 60 different human cancer cell lines, with the most important GI50 values ranging from 0.28 to 11.7 μM (0.13-6.05 μg/mL) and LC50 values ranging from 2.6 to > 100 μM (1.2 to > 51.7 μg/mL), for chalcones 8a,d and pyrazolines 10c,d. All compounds were assessed for antibacterial activity against wild type and multidrug resistant gram negative and gram positive bacteria, with MIC values ranging from 31.25 to 500 μg/mL. Additionally, the novel compounds were tested for antifungal and antiparasitic properties. Although these compounds showed mild activity against Candida albicans, chalcones 8a and 8e showed high activity against Cryptococcus neoformans with MIC50 = 7.8 μg/mL. For anti-Plasmodium falciparum activity the 2-pyrazoline 11b was the most active with EC50 = 5.54 μg/mL. Regarding the activity against Trypanosoma cruzi, compound 10a was highly active with EC50 = 0.70 μg/mL. Chalcone 8a had good activity against Leishmania panamensis amastigotes with EC50 = 0.79 μg/mL.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen amastigotes infected in mouse L929 cells assessed as reduction in infection level at 10 uM after 96 hrs by beta galactosidase reporter assay relative to control
|
Trypanosoma cruzi
|
89.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification and preliminary structure-activity relationship studies of novel pyridyl sulfonamides as potential Chagas disease therapeutic agents.
Year : 2018
Volume : 28
Issue : 11
First Page : 2018
Last Page : 2022
Authors : Peres RB, Ullah AI, de Almeida Fiuza LF, Silva PB, Batista MM, Corcoran O, Reddy TRK, de Nazaré Correia Soeiro M.
Abstract : Chagas disease is a neglected pathology responsible for about 12,000 deaths every year across Latin America. Although six million people are infected by the Trypanosoma cruzi, current therapeutic options are limited, highlighting the need for new drugs. Here we report the preliminary structure activity relationships of a small library of 17 novel pyridyl sulfonamide derivatives. Analogues 4 and 15 displayed significant potency against intracellular amastigotes with EC50 of 5.4 µM and 8.6 µM. In cytotoxicity assays using mice fibroblast L929 cell lines, both compounds indicated low toxicity with decent selectivity indices (SI) >36 and >23 respectively. Hence these compounds represent good starting points for further lead optimization.
|
Induction of mitochondrial membrane potential disruption in Trypanosoma cruzi MHOM/Pe/2011/Arequipa DTU 5 epimastigotes assessed as inhibition of DNA replication and RNA synthesis at IC25 after 72 hrs by acridine orange staining based flow cytometry relative to control
|
Trypanosoma cruzi
|
22.4
%
|
|
Journal : J Med Chem
Title : Second Generation of Mannich Base-Type Derivatives with in Vivo Activity against Trypanosoma cruzi.
Year : 2018
Volume : 61
Issue : 13
First Page : 5643
Last Page : 5663
Authors : Martín-Escolano R, Moreno-Viguri E, Santivañez-Veliz M, Martin-Montes A, Medina-Carmona E, Paucar R, Marín C, Azqueta A, Cirauqui N, Pey AL, Pérez-Silanes S, Sánchez-Moreno M.
Abstract : Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives. Compounds 7, 9, and 10 showed improved in vitro efficiency and lower toxicity than benznidazole, in addition to no genotoxicity; thus, they were applied in in vivo assays to assess their activity in both acute and chronic phases of the disease. Compound 10 presented a similar profile to benznidazole from the parasitological perspective but also yielded encouraging data, as no toxicity was observed. Moreover, compound 9 showed lower parasitaemia and higher curative rates than benznidazole, also with lower toxicity in both acute and chronic phases. Therefore, further studies should be considered to optimize compound 9 to promote its further preclinical evaluation.
|
Antitrypanosomal activity against Trypanosoma cruzi clone CL B5 amastigotes harboring lacZ infected in mouse NCTC-929 cells after 7 days by beta-galactosidase reporter gene assay
|
Trypanosoma cruzi
|
800.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel Imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxides as antiproliferative trypanosoma cruzi drugs: Computational screening from neural network, synthesis and in vivo biological properties.
Year : 2017
Volume : 136
First Page : 223
Last Page : 234
Authors : Guerra A, Gonzalez-Naranjo P, Campillo NE, Varela J, Lavaggi ML, Merlino A, Cerecetto H, González M, Gomez-Barrio A, Escario JA, Fonseca-Berzal C, Yaluf G, Paniagua-Solis J, Páez JA.
Abstract : A new family of imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxide with antiproliferative Trypanosoma cruzi properties was identified from a neural network model published by our group. The synthesis and evaluation of this new class of trypanocidal agents are described. These compounds inhibit the growth of Trypanosoma cruzi, comparable with benznidazole or nifurtimox. In vitro assays were performed to study their effects on the growth of the epimastigote form of the Tulahuen 2 strain, as well as the epimastigote and amastigote forms of CL clone B5 of Trypanosoma cruzi. To verify selectivity towards parasite cells, the non-specific cytotoxicity of the most relevant compounds was studied in mammalian cells, i.e. J774 murine macrophages and NCTC clone 929 fibroblasts. Furthermore, these compounds were assayed regarding the inhibition of cruzipain. In vivo studies revealed that one of the compounds, 19, showed interesting trypanocidal activity, and could be a very promising candidate for the treatment of Chagas disease.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen amastigote forms infected in human U937 cells after 72 hrs by beta-galactosidase reporter gene assay
|
Trypanosoma cruzi
|
10.7
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : A Schmidt rearrangement-mediated synthesis of novel tetrahydro-benzo[1,4]diazepin-5-ones as potential anticancer and antiprotozoal agents.
Year : 2017
Volume : 141
First Page : 567
Last Page : 583
Authors : Insuasty D, Robledo SM, Vélez ID, Cuervo P, Insuasty B, Quiroga J, Nogueras M, Cobo J, Abonia R.
Abstract : Novel tetrahydro-5H-benzo[e][1,4]diazepin-5-ones, several of them, containing the quinoline pharmacophore, were synthesized via a Schmidt rearrangement from their corresponding 1,2,3,4-tetrahydro-4-quinolones mediated by the NaN3/H2SO4 reaction conditions. Twelve of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines, where compound 24a presented a remarkable activity against 58 of the 60 cancer cell lines, with the most important GI50 values ranging from 0.047 to 8.16 μM and LC50 values ranging from 9.4 to > 100 μM. Additionally, some of them were evaluated as antimalarial, antitrypanosomal and antileishmanial agents. The best antimalarial response was observed for compound 22g with an EC50 = 13.61 μg/mL for Plasmodium falciparum, while compound 24d exhibited high activity against Trypanosoma cruzi. and Leishmania (V) panamensis with EC50 = 2.78 μg/mL and 3.35 μg/mL respectively.
|
Antitrypanosomal activity against Trypanosoma cruzi Y trypomastigotes
|
Trypanosoma cruzi
|
0.04
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and 2D-QSAR studies of neolignan-based diaryl-tetrahydrofuran and -furan analogues with remarkable activity against Trypanosoma cruzi and assessment of the trypanothione reductase activity.
Year : 2017
Volume : 140
First Page : 187
Last Page : 199
Authors : Hartmann AP, de Carvalho MR, Bernardes LSC, Moraes MH, de Melo EB, Lopes CD, Steindel M, da Silva JS, Carvalho I.
Abstract : Two series of diaryl-tetrahydrofuran and -furan were synthesised and screened for anti-trypanosomal activity against trypomastigote and amastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. Based on evidence that modification of a natural product may result in a more effective drug than the natural product itself, and using known neolignan inhibitors veraguensin 1 and grandisin 2 as templates to synthesise simpler analogues, remarkable anti-trypanosomal activity and selectivity were found for 3,5-dimethoxylated diaryl-furan 5c and 2,4-dimethoxylated diaryl-tetrahydrofuran 4e analogues with EC50 0.01 μM and EC50 0.75 μM, respectively, the former being 260-fold more potent than veraguensin 1 and 150-fold better than benznidazole, the current available drugs for Chagas disease treatment. The ability of the most potent anti-trypanosomal compounds to penetrate LLC-MK2 cells infected with T. cruzi amastigotes parasite was tested, which revealed 4e and 5e analogues as the most effective, causing no damage to mammalian cells. In particular, the majority of the derivatives were non-toxic against mice spleen cells. 2D-QSAR studies show the rigid central core and the position of dimethoxy-aryl substituents dramatically affect the anti-trypanosomal activity. The mode of action of the most active anti-trypanosomal derivatives was investigated by exploring the anti-oxidant functions of Trypanothione reductase (TR). As a result, diarylfuran series displayed the strongest inhibition, highlighting compounds 5d-e (IC50 19.2 and 17.7 μM) and 5f-g (IC50 8.9 and 7.4 μM), respectively, with similar or 2-fold higher than the reference inhibitor clomipramine (IC50 15.2 μM).
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen strain C2C4 amastigote forms harboring LacZ infected in rat L6 cells after 96 hrs by CPRG/Nonidet reagent based photometric method
|
Trypanosoma cruzi
|
0.5
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : Antiprotozoal and cysteine proteases inhibitory activity of dipeptidyl enoates.
Year : 2018
Volume : 26
Issue : 16
First Page : 4624
Last Page : 4634
Authors : Royo S, Schirmeister T, Kaiser M, Jung S, Rodríguez S, Bautista JM, González FV.
Abstract : A family of dipeptidyl enoates has been prepared and tested against the parasitic cysteine proteases rhodesain, cruzain and falcipain-2 related to sleeping sickness, Chagas disease and malaria, respectively. They have also been tested against human cathepsins B and L1 for selectivity. Dipeptidyl enoates resulted to be irreversible inhibitors of these enzymes. Some of the members of the family are very potent inhibitors of parasitic cysteine proteases displaying k2nd (M-1s-1) values of seven orders of magnitude. In vivo antiprotozoal testing was also performed. Inhibitors exhibited IC50 values in the micromolar range against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi and even more promising lower values against Leishmania donovanii.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen intracellular amastigote harboring beta-galactosidase infected in mouse NIH/3T3 cells after 96 hrs by CPRG reagent based assay
|
Trypanosoma cruzi
|
790.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation.
Year : 2018
Volume : 9
Issue : 10
First Page : 996
Last Page : 1001
Authors : Woodring JL, Behera R, Sharma A, Wiedeman J, Patel G, Singh B, Guyett P, Amata E, Erath J, Roncal N, Penn E, Leed SE, Rodriguez A, Sciotti RJ, Mensa-Wilmot K, Pollastri MP.
Abstract : Discovery of new chemotherapeutic lead agents can be accelerated by optimizing chemotypes proven to be effective in other diseases to act against parasites. One such medicinal chemistry campaign has focused on optimizing the anilinoquinazoline drug lapatinib (1) and the alkynyl thieno[3,2-d]pyrimidine hit GW837016X (NEU-391, 3) into leads for antitrypanosome drugs. We now report the structure-activity relationship studies of 3 and its analogs against Trypanosoma brucei, which causes human African trypanosomiasis (HAT). The series was also tested against Trypanosoma cruzi, Leishmania major, and Plasmodium falciparum. In each case, potent antiparasitic hits with acceptable toxicity margins over mammalian HepG2 and NIH3T3 cell lines were identified. In a mouse model of HAT, 3 extended life of treated mice by 50%, compared to untreated controls. At the cellular level, 3 inhibited mitosis and cytokinesis in T. brucei. Thus, the alkynylthieno[3,2-d]pyrimidine chemotype is an advanced hit worthy of further optimization as a potential chemotherapeutic agent for HAT.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
21.81
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
9.92
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
18.48
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
15.47
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
13.69
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.82
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-2.09
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
0.65
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Antitrypanosomal activity against Trypanosoma brucei bloodstream form assessed as parasite growth inhibition incubated for 72 hrs by resazurin dye based assay
|
Trypanosoma brucei
|
16.0
nM
|
|
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.
|
Antitrypanosomal activity against intracellular amastigote stage of Trypanosoma cruzi 92.80 cl2 infected in human U2OS cells measured after 96 hrs by DRAQ5 dye based microscopic analysis
|
Trypanosoma cruzi
|
600.0
nM
|
|
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.
|
Antitrypanosomal activity against Trypanosoma cruzi CL Brener amastigotes infected in African green monkey Vero cells assessed as reduction in parasite growth incubated for 120 hrs at 24 hrs post-infection and measured on day 6 post-infection by hemocytometer based light microscopy
|
Trypanosoma cruzi
|
500.0
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.
|
Trypanocidal activity against intracellular amastigote stage of Trypanosoma cruzi Y strain infected in Swiss webster cardiac cells assessed as reduction in parasite viability after 24 hrs by Celltiter-Glo assay
|
Trypanosoma cruzi
|
900.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease.
Year : 2019
Volume : 182
First Page : 111610
Last Page : 111610
Authors : Monteiro ME, Lechuga G, Lara LS, Souto BA, Viganó MG, Bourguignon SC, Calvet CM, Oliveira FOR, Alves CR, Souza-Silva F, Santos MS, Pereira MCS.
Abstract : Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease.
|
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 Trypanosoma brucei rhodesiense after 48 hrs by [3H]-hypoxanthine incorporation assay
|
Trypanosoma brucei rhodesiense
|
0.001
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 cruzi after 48 hrs by [3H]-hypoxanthine incorporation assay
|
Trypanosoma cruzi
|
5.42
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 after 48 hrs by [3H]-hypoxanthine incorporation assay
|
Leishmania donovani
|
33.26
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.
|
Trypanocidal activity against Trypanosoma cruzi Y strain intracellular amastigotes infected in mouse cardiac cells assessed as parasite death after 168 hrs by Giemsa-staining based assay
|
Trypanosoma cruzi
|
354.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel 7-Aryl 7-Deazapurine 3'-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi.
Year : 2018
Volume : 61
Issue : 20
First Page : 9287
Last Page : 9300
Authors : Hulpia F, Van Hecke K, França da Silva C, da Gama Jaen Batista D, Maes L, Caljon G, de Nazaré C Soeiro M, Van Calenbergh S.
Abstract : Chagas disease is the leading cause of cardiac-related mortality in Latin American countries where it is endemic. Trypanosoma cruzi, the disease-causing pathogen, is unable to synthesize purines de novo, necessitating salvage of preformed host purines. Therefore, purine and purine-nucleoside analogues might constitute an attractive source for identifying antitrypanosomal hits. In this study, structural elements of two purine-nucleoside analogues (i.e., cordycepin and a recently discovered 7-substituted 7-deazaadenosine) led to the identification of novel nucleoside analogues with potent in vitro activity. The structure-activity relationships of substituents at C-7 were investigated, ultimately leading to the selection of compound 5, with a C-7 para-chlorophenyl group, for in vivo evaluation. This derivative showed complete suppression of T. cruzi Y-strain blood parasitemia when orally administered twice daily for 5 days at 25 mg/kg and was able to protect infected mice from parasite-induced mortality. However, sterile cure by immunosuppression could not be demonstrated.
|
Antitrypanosomal activity against Trypanosoma cruzi MHOM/MX/1994/INC5 epimastigotes assessed as metabolic inhibition at 10 ug/ml after 24 hrs by MTT assay relative to control
|
Trypanosoma cruzi
|
77.4
%
|
|
Journal : Eur J Med Chem
Title : Novel prenyloxy chalcones as potential leishmanicidal and trypanocidal agents: Design, synthesis and evaluation.
Year : 2019
Volume : 167
First Page : 402
Last Page : 413
Authors : Espinoza-Hicks JC, Chacón-Vargas KF, Hernández-Rivera JL, Nogueda-Torres B, Tamariz J, Sánchez-Torres LE, Camacho-Dávila A.
Abstract : The available drugs for treating Leishmaniasis and American trypanosomiasis have high toxicity and multiple side effects, among other problems. More effective and less toxic treatments are urgently needed. A series of chalcones that contained a prenyloxy or geranyloxy substituent was synthesized and characterized. Each substituent was attached to the A ring in some compounds and to the B ring in others, with additional substituents placed on the chalcone moiety. The present aim was to evaluate the effect of the substitution pattern on leishmanicidal and trypanocidal activity. When tested at a single concentration, the compounds exerting a metabolic inhibition close to or exceeding 50% for Leishmania mexicana were 11, 17 and 12, and for Trypanosoma cruzi were 11, 17, 15 and 26. Upon determining the selectivity index (SI =IC<sub>50</sub>/CC<sub>50</sub>), the values were 80.9, 1.24 and 55.12 for 11, 17 and 12 (respectively) versus L. mexicana, and 75.1, 1.43, 27.36 and 33.52 for 11, 17, 15 and 26 (respectively) versus T. cruzi. Structural isomers 11 and 17 showed activity for both the L. mexicana and T. cruzi strains, though the greater cytotoxic activity of 17 led to a lower SI. Compounds 12, 15 and 26 were species specific. For T. cruzi, the SI was higher for 11, 15 and 26 than for the reference drugs nifurtimox and benznidazole. The examination of promastigote morphology after exposing L. mexicana and T. cruzi to 11 revealed a decrease in cell density. The current findings suggest that 11 could be a useful lead compound for further SAR studies.
|
Induction of mitochondrial membrane potential disruption Trypanosoma cruzi MHOM/Pe/2011/Arequipa DTU 5 epimastigotes assessed as inhibition of DNA and RNA levels at IC25 after 72 hrs by acridine orange staining based flow cytometry relative to control
|
Trypanosoma cruzi
|
22.4
%
|
|
Journal : Eur J Med Chem
Title : New polyamine drugs as more effective antichagas agents than benznidazole in both the acute and chronic phases.
Year : 2019
Volume : 164
First Page : 27
Last Page : 46
Authors : Martín-Escolano R, Molina-Carreño D, Delgado-Pinar E, Martin-Montes Á, Clares MP, Medina-Carmona E, Pitarch-Jarque J, Martín-Escolano J, Rosales MJ, García-España E, Sánchez-Moreno M, Marín C.
Abstract : Despite the continuous research effort that has been made in recent years to find ways to treat the potentially life threatening Chagas disease (CD), this remains the third most important infectious disease in Latin America. CD is an important public health problem affecting 6-7 million people. Since the need to search for new drugs for the treatment of DC persists, in this article we present a panel of new polyamines based on the tripodal structure of tris(2-aminomethyl)amine (tren) that can be prepared at low cost with high yields. Moreover, these polyamines present the characteristic of being water-soluble and resistant to the acidic pH values of stomach, which would allow their potential oral administration. In vitro and in vivo assays permitted to identify the compound with the tren moiety functionalized with one fluorene unit (7) as a potential antichagas agent. Compound 7 has broader spectrum of action, improved efficacy in acute and chronic phases of the disease and lower toxicity than the reference drug benznidazole. Finally, the action mechanisms studied at metabolic and mitochondrial levels shows that the trypanocidal activity of compound 7 could be related to its effect at the glycosomal level. Therefore, this work allowed us to select compound 7 as a promising candidate to perform preclinical evaluation studies.
|
Antitrypanosomal activity against Trypanosoma cruzi MHOM/Pe/2011/Arequipa DTU 5 epimastigotes assessed as reduction in DNA and RNA levels at IC25 after 72 hrs by acridine orange staining based flow cytometry relative to control
|
Trypanosoma cruzi
|
22.38
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological evaluation of new long-chain squaramides as anti-chagasic agents in the BALB/c mouse model.
Year : 2019
Volume : 27
Issue : 5
First Page : 865
Last Page : 879
Authors : Martín-Escolano R, Marín C, Vega M, Martin-Montes Á, Medina-Carmona E, López C, Rotger C, Costa A, Sánchez-Moreno M.
Abstract : Chagas Disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi and affects more than 10 million people. It is a paradigmatic example of a chronic disease without an effective treatment in Latin America where the current therapies, based on Benznidazole and Nifurtimox, are characterised by limited efficacy, toxic side-effects and frequent failures in the treatment. We present a series of new long-chain squaramides, identified based on their 1H and 13C NMR spectra, and their trypanocidal activity and cytotoxicity were tested in vitro through the determination of IC50 values. Compounds 4 and 7 were more active and less toxic than the reference drug Benznidazole, and these results were the basis of promoting in vivo assays, where parasitaemia levels, assignment of cure, reactivation of parasitaemia and others parameters were determined in mice treated in both the acute and chronic phases. Finally, the mechanisms of action were elucidated at metabolic and mitochondrial levels and superoxide dismutase inhibition. The experiments allowed us to select compound 7 as a promising candidate for treating Chagas Disease, where the activity, stability and low cost make long-chain squaramides appropriate molecules for the development of an affordable anti-chagasic agent versus current treatments.
|
Antitrypanosomal activity against Trypanosoma cruzi Y amastigotes infected in Swiss mouse primary cardiac cells replenished for every 48 hrs for 168 hrs by geimsa staining based assay
|
Trypanosoma cruzi
|
350.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Pyrrolo[2,3-<i>b</i>]pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-<i>Trypanosoma cruzi</i> Agents.
Year : 2019
Volume : 62
Issue : 19
First Page : 8847
Last Page : 8865
Authors : Lin C, Hulpia F, da Silva CF, Batista DDGJ, Van Hecke K, Maes L, Caljon G, Soeiro MNC, Van Calenbergh S.
Abstract : <i>Trypanosoma cruzi</i> is the causative pathogen of Chagas disease and the main culprit for cardiac-related mortality in Latin-America triggered by an infective agent. Incapable of synthesizing purines de novo, this parasite depends on acquisition and processing of host-derived purines, making purine (nucleoside) analogues a potential source of antitrypanosomal agents. In this respect, hitherto 7-deazaadenosine (tubercidin) analogues attracted most attention. Here, we investigated analogues with an additional nitrogen (N1) removed. Structure-activity relationship investigation showed that C7 modification afforded analogues with potent antitrypanosomal activity. Halogens and small, linear carbon-based substituents were preferred. Compound <b>11</b> proved most potent in vitro, showed full suppression of parasitemia in a mouse model of acute infection, and elicited 100% animal survival after oral dosing at 25 mg/kg b.i.d. for 5 and 15 days. Cyclophosphamide-induced immunosuppression led to recrudescence. Washout experiments demonstrated a lack of complete clearance of infected cell cultures, potentially explaining the in vivo results.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
2.226
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.15
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Growth inhibiting activity of Naegleria gruberi in vitro
|
Naegleria gruberi
|
37.4
%
|
|
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.
|
Reduction in inflammatory cell infiltration in heart of BALB/c mouse infected with blood trypomastigote form of Trypanosoma cruzi strain Y at 25 mg/kg, po administered via gavage daily for 15 days starting from 2 days post-infection and measured on 16th day post-infection by haematoxylin and eosin staining based microscopic analysis relative to control
|
Mus musculus
|
76.0
%
|
|
Journal : Bioorg Med Chem
Title : Trypanocidal activity of new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine derivatives: Synthesis, in vitro and in vivo studies.
Year : 2021
Volume : 29
First Page : 115855
Last Page : 115855
Authors : Ribeiro JLS,Soares JCAV,Portapilla GB,Providello MV,Lima CHS,Muri EMF,de Albuquerque S,Dias LRS
Abstract : Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
|
Antitrypanosomal activity against blood trypomastigote form of Trypanosoma cruzi strain Y infected in BALB/c mouse assessed as reduction in amastigote nest in host heart at 25 mg/kg, po administered via gavage daily for 15 days starting from 2 days post-infection and measured on 16th day post-infection by haematoxylin and eosin staining based microscopic analysis
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg Med Chem
Title : Trypanocidal activity of new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine derivatives: Synthesis, in vitro and in vivo studies.
Year : 2021
Volume : 29
First Page : 115855
Last Page : 115855
Authors : Ribeiro JLS,Soares JCAV,Portapilla GB,Providello MV,Lima CHS,Muri EMF,de Albuquerque S,Dias LRS
Abstract : Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
|
Antitrypanosomal activity against blood trypomastigote form of Trypanosoma cruzi strain Y infected in BALB/c mouse assessed as reduction in parasite DNA load in host heart at 25 mg/kg, po administered via gavage daily for 15 days starting from 2 days post-infection and measured on 16th day post-infection by qPCR analysis relative to control
|
Trypanosoma cruzi
|
99.0
%
|
|
Journal : Bioorg Med Chem
Title : Trypanocidal activity of new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine derivatives: Synthesis, in vitro and in vivo studies.
Year : 2021
Volume : 29
First Page : 115855
Last Page : 115855
Authors : Ribeiro JLS,Soares JCAV,Portapilla GB,Providello MV,Lima CHS,Muri EMF,de Albuquerque S,Dias LRS
Abstract : Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
|
Inhibition of nucleic acid level in Trypanosoma cruzi MHOM/Pe/2011/Arequipa(DTU V) epimastigote form at IC25 concentration after 72 hrs by Rho (FITC-A) staining based flow cytometric analysis
|
Trypanosoma cruzi
|
22.4
%
|
|
Journal : J Nat Prod
Title : In Vivo Biological Evaluation of a Synthetic Royleanone Derivative as a Promising Fast-Acting Trypanocidal Agent by Inducing Mitochondrial-Dependent Necrosis.
Year : 2020
Volume : 83
Issue : 12
First Page : 3571
Last Page : 3583
Authors : Martín-Escolano R,Guardia JJ,Martín-Escolano J,Cirauqui N,Fernández A,Rosales MJ,Chahboun R,Sánchez-Moreno M,Alvarez-Manzaneda E,Marín C
Abstract : The life-long and life-threatening Chagas disease is one of the most neglected tropical diseases caused by the protozoan parasite Trypanosoma cruzi. It is a major public health problem in Latin America, as six to seven million people are infected, being the principal cause of mortality in many endemic regions. Moreover, Chagas disease has become widespread due to migrant populations. Additionally, there are no vaccines nor effective treatments to fight the disease because of its long-term nature and complex pathology. Therefore, these facts emphasize how crucial the international effort for the development of new treatments against Chagas disease is. Here, we present the in vitro and in vivo trypanocidal activity of some oxygenated abietane diterpenoids and related compounds. The 1,4-benzoquinone 15, not yet reported, was identified as a fast-acting trypanocidal drug with efficacy against different strains in vitro and higher activity and lower toxicity than benznidazole in both phases of murine Chagas disease. The mode of action was also evaluated, suggesting that quinone 15 kills T. cruzi by inducing mitochondrion-dependent necrosis through a bioenergetics collapse caused by a mitochondrial membrane depolarization and iron-containing superoxide dismutase inhibition. Therefore, the abietane 1,4-benzoquinone 15 can be considered as a new candidate molecule for the development of an appropriate and commercially accessible anti-Chagas drug.
|
Inhibition of mitochondrial membrane potential in Trypanosoma cruzi MHOM/Pe/2011/Arequipa(DTU V) epimastigote form at IC25 concentration after 72 hrs by Rho (FITC-A) staining based flow cytometric analysis
|
Trypanosoma cruzi
|
35.4
%
|
|
Journal : J Nat Prod
Title : In Vivo Biological Evaluation of a Synthetic Royleanone Derivative as a Promising Fast-Acting Trypanocidal Agent by Inducing Mitochondrial-Dependent Necrosis.
Year : 2020
Volume : 83
Issue : 12
First Page : 3571
Last Page : 3583
Authors : Martín-Escolano R,Guardia JJ,Martín-Escolano J,Cirauqui N,Fernández A,Rosales MJ,Chahboun R,Sánchez-Moreno M,Alvarez-Manzaneda E,Marín C
Abstract : The life-long and life-threatening Chagas disease is one of the most neglected tropical diseases caused by the protozoan parasite Trypanosoma cruzi. It is a major public health problem in Latin America, as six to seven million people are infected, being the principal cause of mortality in many endemic regions. Moreover, Chagas disease has become widespread due to migrant populations. Additionally, there are no vaccines nor effective treatments to fight the disease because of its long-term nature and complex pathology. Therefore, these facts emphasize how crucial the international effort for the development of new treatments against Chagas disease is. Here, we present the in vitro and in vivo trypanocidal activity of some oxygenated abietane diterpenoids and related compounds. The 1,4-benzoquinone 15, not yet reported, was identified as a fast-acting trypanocidal drug with efficacy against different strains in vitro and higher activity and lower toxicity than benznidazole in both phases of murine Chagas disease. The mode of action was also evaluated, suggesting that quinone 15 kills T. cruzi by inducing mitochondrion-dependent necrosis through a bioenergetics collapse caused by a mitochondrial membrane depolarization and iron-containing superoxide dismutase inhibition. Therefore, the abietane 1,4-benzoquinone 15 can be considered as a new candidate molecule for the development of an appropriate and commercially accessible anti-Chagas drug.
|
Antitrypanosomal activity against Trypanosoma cruzi MHOM/Pe/2011/Arequipa(DTU V) amastigote form infected in Vero cells assessed as parasite growth inhibition at 50 uM incubated for 72 hrs by Giemsa-staining based assay relative to control
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : J Nat Prod
Title : In Vivo Biological Evaluation of a Synthetic Royleanone Derivative as a Promising Fast-Acting Trypanocidal Agent by Inducing Mitochondrial-Dependent Necrosis.
Year : 2020
Volume : 83
Issue : 12
First Page : 3571
Last Page : 3583
Authors : Martín-Escolano R,Guardia JJ,Martín-Escolano J,Cirauqui N,Fernández A,Rosales MJ,Chahboun R,Sánchez-Moreno M,Alvarez-Manzaneda E,Marín C
Abstract : The life-long and life-threatening Chagas disease is one of the most neglected tropical diseases caused by the protozoan parasite Trypanosoma cruzi. It is a major public health problem in Latin America, as six to seven million people are infected, being the principal cause of mortality in many endemic regions. Moreover, Chagas disease has become widespread due to migrant populations. Additionally, there are no vaccines nor effective treatments to fight the disease because of its long-term nature and complex pathology. Therefore, these facts emphasize how crucial the international effort for the development of new treatments against Chagas disease is. Here, we present the in vitro and in vivo trypanocidal activity of some oxygenated abietane diterpenoids and related compounds. The 1,4-benzoquinone 15, not yet reported, was identified as a fast-acting trypanocidal drug with efficacy against different strains in vitro and higher activity and lower toxicity than benznidazole in both phases of murine Chagas disease. The mode of action was also evaluated, suggesting that quinone 15 kills T. cruzi by inducing mitochondrion-dependent necrosis through a bioenergetics collapse caused by a mitochondrial membrane depolarization and iron-containing superoxide dismutase inhibition. Therefore, the abietane 1,4-benzoquinone 15 can be considered as a new candidate molecule for the development of an appropriate and commercially accessible anti-Chagas drug.
|
Antitrypanosomal activity against Trypanosoma cruzi infected in African green monkey Vero cells assessed as reduction in number of trypomastigotes measured up to 10 days by Giemsa staining based hemocytometry
|
Trypanosoma cruzi
|
20.0
%
|
|
Journal : J Med Chem
Title : In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives.
Year : 2016
Volume : 59
Issue : 24
First Page : 10929
Last Page : 10945
Authors : Moreno-Viguri E,Jiménez-Montes C,Martín-Escolano R,Santivañez-Veliz M,Martin-Montes A,Azqueta A,Jimenez-Lopez M,Zamora Ledesma S,Cirauqui N,López de Ceráin A,Marín C,Sánchez-Moreno M,Pérez-Silanes S
Abstract : Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.
|
Antitrypanosomal activity against Trypanosoma cruzi infected in African green monkey Vero cells assessed as reduction in number of amastigotes per infected cell measured up to 10 days by Giemsa staining based hemocytometry
|
Trypanosoma cruzi
|
30.0
%
|
|
Journal : J Med Chem
Title : In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives.
Year : 2016
Volume : 59
Issue : 24
First Page : 10929
Last Page : 10945
Authors : Moreno-Viguri E,Jiménez-Montes C,Martín-Escolano R,Santivañez-Veliz M,Martin-Montes A,Azqueta A,Jimenez-Lopez M,Zamora Ledesma S,Cirauqui N,López de Ceráin A,Marín C,Sánchez-Moreno M,Pérez-Silanes S
Abstract : Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.
|
Antitrypanosomal activity against Trypanosoma cruzi infected in African green monkey Vero cells assessed as reduction in infection rate measured up to 10 days by Giemsa staining based hemocytometry
|
Trypanosoma cruzi
|
22.0
%
|
|
Journal : J Med Chem
Title : In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives.
Year : 2016
Volume : 59
Issue : 24
First Page : 10929
Last Page : 10945
Authors : Moreno-Viguri E,Jiménez-Montes C,Martín-Escolano R,Santivañez-Veliz M,Martin-Montes A,Azqueta A,Jimenez-Lopez M,Zamora Ledesma S,Cirauqui N,López de Ceráin A,Marín C,Sánchez-Moreno M,Pérez-Silanes S
Abstract : Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.
|
Antitrypanosomal activity against Trypanosoma cruzi (MHOM/CH/00/Tulahuen C2, lacZ) amastigotes infected in HFF-1 cells assessed as reduction in parasite growth at 300 uM incubated for 120 hrs by CPRG/Igepal substrate based photometric method relative to control
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids.
Year : 2020
Volume : 201
First Page : 112418
Last Page : 112418
Authors : Fernandes FS,Santos H,Lima SR,Conti C,Rodrigues MT,Zeoly LA,Ferreira LLG,Krogh R,Andricopulo AD,Coelho F
Abstract : A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC values of 3.89, 2.38, 2.50 and 2.85 μM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC values of 6.20, 2.20, 2.30 and 2.20 μM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.
|
Antitrypanosomal activity against Trypanosoma cruzi (MHOM/CH/00/Tulahuen C2, lacZ) amastigotes infected in HFF-1 cells assessed as reduction in parasite growth at 150 uM incubated for 120 hrs by CPRG/Igepal substrate based photometric method relative to control
|
Trypanosoma cruzi
|
92.77
%
|
|
Journal : Eur J Med Chem
Title : Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids.
Year : 2020
Volume : 201
First Page : 112418
Last Page : 112418
Authors : Fernandes FS,Santos H,Lima SR,Conti C,Rodrigues MT,Zeoly LA,Ferreira LLG,Krogh R,Andricopulo AD,Coelho F
Abstract : A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC values of 3.89, 2.38, 2.50 and 2.85 μM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC values of 6.20, 2.20, 2.30 and 2.20 μM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.
|
Antitrypanosomal activity against Trypanosoma cruzi (MHOM/CH/00/Tulahuen C2, lacZ) amastigotes infected in HFF-1 cells assessed as reduction in parasite growth at 75 uM incubated for 120 hrs by CPRG/Igepal substrate based photometric method relative to control
|
Trypanosoma cruzi
|
85.47
%
|
|
Journal : Eur J Med Chem
Title : Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids.
Year : 2020
Volume : 201
First Page : 112418
Last Page : 112418
Authors : Fernandes FS,Santos H,Lima SR,Conti C,Rodrigues MT,Zeoly LA,Ferreira LLG,Krogh R,Andricopulo AD,Coelho F
Abstract : A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC values of 3.89, 2.38, 2.50 and 2.85 μM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC values of 6.20, 2.20, 2.30 and 2.20 μM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.
|
Antitrypanosomal activity against Trypanosoma cruzi trypomastigotes infected in African green monkey Vero cells incubated for 120 hrs measured on day 6 cells followed by trypomastigotes release by haemocytometer-based light microscopy
|
Trypanosoma cruzi
|
500.0
nM
|
|
Journal : Eur J Med Chem
Title : 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.
Year : 2020
Volume : 202
First Page : 112558
Last Page : 112558
Authors : Fersing C,Boudot C,Castera-Ducros C,Pinault E,Hutter S,Paoli-Lombardo R,Primas N,Pedron J,Seguy L,Bourgeade-Delmas S,Sournia-Saquet A,Stigliani JL,Brossas JY,Paris L,Valentin A,Wyllie S,Fairlamb AH,Boutet-Robinet É,Corvaisier S,Since M,Malzert-Fréon A,Destere A,Mazier D,Rathelot P,Courtioux B,Azas N,Verhaeghe P,Vanelle P
Abstract : An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen C4 strain amastigotes infected in rat L6 cells measured after 96 hrs by inverted microscopy analysis
|
Trypanosoma cruzi
|
0.757
ug.mL-1
|
|
|
Antitrypanosomal activity against Trypanosoma cruzi amastigotes infected in BSR cells assessed as inhibition of replication of intracellular amastigotes incubated for 72 hrs by fluorescence based analysis
|
Trypanosoma cruzi
|
500.0
nM
|
|
