|
50% antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
0.6
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Lepadins D-F: antiplasmodial and antitrypanosomal decahydroquinoline derivatives from the tropical marine tunicate Didemnum sp.
Year : 2002
Volume : 45
Issue : 14
First Page : 3067
Last Page : 3072
Authors : Wright AD, Goclik E, König GM, Kaminsky R.
Abstract : From a new tunicate species, belonging to the genus Didemnum, three alkaloids possessing an unusual and extremely rare decahydroquinoline skeleton and showing significant and selective antiplasmodial and antitrypanosomal activity were obtained as follows: (2R*,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methylquinoline (lepadin D,1), its quaternary nitrogen derivative (2), (2R*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin E, 3), and (2S*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin F, 4). These isolates may well serve as lead structures for the development of new antimalarial drugs.
|
50% antitrypanosomal activity against Trypanosoma rhodesiense
|
trypanosoma rhodesiense
|
0.0026
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Lepadins D-F: antiplasmodial and antitrypanosomal decahydroquinoline derivatives from the tropical marine tunicate Didemnum sp.
Year : 2002
Volume : 45
Issue : 14
First Page : 3067
Last Page : 3072
Authors : Wright AD, Goclik E, König GM, Kaminsky R.
Abstract : From a new tunicate species, belonging to the genus Didemnum, three alkaloids possessing an unusual and extremely rare decahydroquinoline skeleton and showing significant and selective antiplasmodial and antitrypanosomal activity were obtained as follows: (2R*,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methylquinoline (lepadin D,1), its quaternary nitrogen derivative (2), (2R*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin E, 3), and (2S*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin F, 4). These isolates may well serve as lead structures for the development of new antimalarial drugs.
|
In Vitro inhibition concentration against Trypomastigote form of Trypanosoma brucei
|
Trypanosoma brucei
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Antimalarial, antitrypanosomal, and antileishmanial activities and cytotoxicity of bis(9-amino-6-chloro-2-methoxyacridines): influence of the linker.
Year : 2000
Volume : 43
Issue : 14
First Page : 2646
Last Page : 2654
Authors : Girault S, Grellier P, Berecibar A, Maes L, Mouray E, Lemière P, Debreu MA, Davioud-Charvet E, Sergheraert C.
Abstract : Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 microM upon MRC-5 cells, one displayed IC(50) values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 microM.
|
Inhibitory concentration in vitro against blood stream Trypanosoma brucei rhodesiense incubated for 72 hr at 37 degree C
|
Trypanosoma brucei rhodesiense
|
6.0
nM
|
|
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.
|
In vitro inhibitory concentration against intracellular amastigotes of Trypanosoma cruzi in rat skeletal myoblasts incubated for 37 degree C for 4 days
|
Trypanosoma cruzi
|
6.0
nM
|
|
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.
|
In vitro inhibitory concentration against blood stream Trypanosoma brucei brucei AT1 wild type incubated for 72 h at 37 degree C
|
Trypanosoma brucei brucei
|
53.0
nM
|
|
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.
|
In vitro inhibitory concentration against blood stream Trypanosoma brucei brucei AT1 knockout mutant with a non functional P2 transporter incubated for 72 h at 37 degree C
|
Trypanosoma brucei brucei
|
120.0
nM
|
|
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.
|
Inhibition of Trypanosoma brucei rhodesiense rhodesain at 200 uM
|
Trypanosoma brucei rhodesiense
|
94.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents.
Year : 2006
Volume : 16
Issue : 10
First Page : 2753
Last Page : 2757
Authors : Vicik R, Hoerr V, Glaser M, Schultheis M, Hansell E, McKerrow JH, Holzgrabe U, Caffrey CR, Ponte-Sucre A, Moll H, Stich A, Schirmeister T.
Abstract : The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new trypanocidal drugs. Series of aziridine-2,3-dicarboxylate-based cysteine protease inhibitors have been tested, most of them inhibiting rhodesain in the low micromolar range. Among these, only dibenzyl aziridine-2,3-dicarboxylates display trypanocidal activity being equipotent to the drug eflornithine. The Leu-Pro-containing aziridinyl tripeptides 13a-f are the most promising as they are not cytotoxic to macrophages up to concentrations of 125microM.
|
Trypanocidal activity against Trypanosoma brucei brucei after 48 hrs
|
Trypanosoma brucei brucei
|
2.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents.
Year : 2006
Volume : 16
Issue : 10
First Page : 2753
Last Page : 2757
Authors : Vicik R, Hoerr V, Glaser M, Schultheis M, Hansell E, McKerrow JH, Holzgrabe U, Caffrey CR, Ponte-Sucre A, Moll H, Stich A, Schirmeister T.
Abstract : The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new trypanocidal drugs. Series of aziridine-2,3-dicarboxylate-based cysteine protease inhibitors have been tested, most of them inhibiting rhodesain in the low micromolar range. Among these, only dibenzyl aziridine-2,3-dicarboxylates display trypanocidal activity being equipotent to the drug eflornithine. The Leu-Pro-containing aziridinyl tripeptides 13a-f are the most promising as they are not cytotoxic to macrophages up to concentrations of 125microM.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiprotozoal activities of new bis-chlorophenyl derivatives of bicyclic octanes and aza-nonanes.
Year : 2006
Volume : 16
Issue : 20
First Page : 5457
Last Page : 5461
Authors : Berger H, Seebacher W, Saf R, Kaiser M, Brun R, Weis R.
Abstract : The in vitro activity of newly synthesized bis-(chlorophenyl)-azabicyclo[3.2.2]nonanes and bis-(chlorophenyl)-bicyclo[2.2.2]octanes against Plasmodium falciparum K(1) (resistant to chloroquine and pyrimethamine) and Trypanosoma brucei rhodesiense was investigated. Especially the bis-(chlorophenyl)-azabicyclo[3.2.2]nonanes exhibit promising antitrypanosomal activity and were tested in vivo against Trypanosoma brucei brucei featuring moderate activities.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
0.004
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.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
6.4
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro antiprotozoal activities of dicationic 3,5-diphenylisoxazoles.
Year : 2007
Volume : 50
Issue : 10
First Page : 2468
Last Page : 2485
Authors : Patrick DA, Bakunov SA, Bakunova SM, Kumar EV, Lombardy RJ, Jones SK, Bridges AS, Zhirnov O, Hall JE, Wenzler T, Brun R, Tidwell RR.
Abstract : 3,5-bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general synthetic pathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. brucei rhodesiense) STIB900, Plasmodium falciparum (P. falciparum) K1, and rat myoblast L6 cells (for cytotoxicity) in vitro. Eleven compounds (3, 13, 16-18, 22, 26, 29, 31, 37, and 41) exhibited antitrypanosomal IC50 values less than 10 nM, five of which displayed cytotoxic indices (ratios of cytotoxic IC50 to antiprotozoal IC50 values) at least 10 times higher than that of furamidine. Eighteen compounds (4-8, 12, 14, 18-22, 25, 26, 28, 29, 32, and 43) were more active against P. falciparum than furamidine, with IC50 values less than 15 nM. Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher than that of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense after 72 hrs by microplate assay
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Bicyclo[2.2.2]octyl esters of dialkylamino acids as antiprotozoals.
Year : 2007
Volume : 15
Issue : 16
First Page : 5543
Last Page : 5550
Authors : Schlapper C, Seebacher W, Kaiser M, Brun R, Saf R, Weis R.
Abstract : A couple of bicyclo[2.2.2]octyl esters of 2-dialkylaminoacetic acids were prepared. Their antiplasmodial and antitrypanosomal activities against Trypanosoma brucei rhodesiense (STIB 900) and the K(1) strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine) were determined using microplate assays. Structure-activity relationships were discussed. The antiprotozoal activities were remarkably increased by insertion of a second basic centre. The selectivity indices of the most active compounds are superior in the bicyclo-octane series.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro antiprotozoal activity of bisbenzofuran cations.
Year : 2007
Volume : 50
Issue : 23
First Page : 5807
Last Page : 5823
Authors : Bakunova SM, Bakunov SA, Wenzler T, Barszcz T, Werbovetz KA, Brun R, Hall JE, Tidwell RR.
Abstract : Forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with alpha-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. In vitro antiprotozoal activities of compounds 1-43 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicity against mammalian cells were influenced by the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. One bisamidine displayed an antitrypanosomal efficacy comparable to that of pentamidine and melarsoprol. Twenty two compounds were more potent than pentamidine and seven dications were more effective than artemisinin against P. falciparum. Eight bisbenzofurans displayed activity against L. donovani superior to that of pentamidine. Overall, bisamidines connected by two-carbon linkers exhibited the highest efficacies against T. b. rhodesiense, P. falciparum, and L. donovani.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900 in blood
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of antiparasitic activities of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives.
Year : 2007
Volume : 50
Issue : 23
First Page : 5833
Last Page : 5839
Authors : Kuettel S, Zambon A, Kaiser M, Brun R, Scapozza L, Perozzo R.
Abstract : A series of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives, prepared by two synthetic routes, were in vitro assayed against three Trypanosoma strains, Leishmania donovani, and Plasmodium falciparum K1. Seven out of 17 compounds showed moderate to very good activity against blood stage T. b. rhodesiense, with 10 and 17 exhibiting highest potency (IC50 of 1.0 and 1.1 microM, respectively). Interestingly, the beta-diketone precursors 1-3 had good antitrypanosomal activity toward the insect stage, with IC50 values of 1.0-3.4 microM. Among different compounds with moderate activity against T. cruzi, compound 17 showed the lowest IC50 value of 9.5 microM; thus, the series seemed to act selectively toward the different Trypanosoma parasites. Eight compounds were moderately active against L. donovani, with 2, 3, and 12 being the most promising ones (IC50 values of 2.3-5.2 microM), whereas compound 14 was the only derivative with good activity against P. falciparum (IC50 of 3.7 microM).
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900 in procyclic stage
|
Trypanosoma brucei rhodesiense
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of antiparasitic activities of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives.
Year : 2007
Volume : 50
Issue : 23
First Page : 5833
Last Page : 5839
Authors : Kuettel S, Zambon A, Kaiser M, Brun R, Scapozza L, Perozzo R.
Abstract : A series of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives, prepared by two synthetic routes, were in vitro assayed against three Trypanosoma strains, Leishmania donovani, and Plasmodium falciparum K1. Seven out of 17 compounds showed moderate to very good activity against blood stage T. b. rhodesiense, with 10 and 17 exhibiting highest potency (IC50 of 1.0 and 1.1 microM, respectively). Interestingly, the beta-diketone precursors 1-3 had good antitrypanosomal activity toward the insect stage, with IC50 values of 1.0-3.4 microM. Among different compounds with moderate activity against T. cruzi, compound 17 showed the lowest IC50 value of 9.5 microM; thus, the series seemed to act selectively toward the different Trypanosoma parasites. Eight compounds were moderately active against L. donovani, with 2, 3, and 12 being the most promising ones (IC50 values of 2.3-5.2 microM), whereas compound 14 was the only derivative with good activity against P. falciparum (IC50 of 3.7 microM).
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.0027
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.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
5.8
nM
|
|
Journal : J. Nat. Prod.
Title : Antiprotozoal polyacetylenes from the Tanzanian medicinal plant Cussonia zimmermannii.
Year : 2007
Volume : 70
Issue : 10
First Page : 1565
Last Page : 1569
Authors : Senn M, Gunzenhauser S, Brun R, Séquin U.
Abstract : From the petroleum ether extract of the root bark of Cussonia zimmermannii four polyacetylenes, 1- 4, were isolated, three of which ( 1- 3) were active against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Plasmodium falciparum, and Leishmania donovani.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes by microplate assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity.
Year : 2008
Volume : 18
Issue : 7
First Page : 2272
Last Page : 2276
Authors : Bolognesi ML, Lizzi F, Perozzo R, Brun R, Cavalli A.
Abstract : Taking advantage of the structural features of natural products showing anti-trypanosomatid activity, we designed and synthesized a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives. The library was obtained following a parallel approach and using readily available synthons. All the derivatives showed inhibitory activity toward either Trypanosoma or Leishmania species, with 8, 10, and 16 being the most active compounds against Trypanosoma brucei rhodesiense, Leishmania donovani, and Trypanosoma cruzi cells (IC(50)=50nM, IC(50)=0.28microM, and IC(50)=1.26microM, respectively).
|
Antimicrobial activity against Trypanosoma brucei brucei clone 427-221a after 48 hrs
|
Trypanosoma brucei brucei
|
16.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2164
Last Page : 2172
Authors : Caffrey CR, Steverding D, Swenerton RK, Kelly B, Walshe D, Debnath A, Zhou YM, Doyle PS, Fafarman AT, Zorn JA, Land KM, Beauchene J, Schreiber K, Moll H, Ponte-Sucre A, Schirmeister T, Saravanamuthu A, Fairlamb AH, Cohen FE, McKerrow JH, Weisman JL, May BC.
Abstract : Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 A. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC(50)) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC(50) values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.00095
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 brucei rhodesiense after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.003
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 brucei brucei Lab110 EATRO after 48 hrs
|
Trypanosoma brucei brucei
|
0.002
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Trypanocidal diarylheptanoids from Aframomum letestuianum.
Year : 2003
Volume : 66
Issue : 3
First Page : 364
Last Page : 367
Authors : Kamnaing P, Tsopmo A, Tanifum EA, Tchuendem MH, Tane P, Ayafor JF, Sterner O, Rattendi D, Iwu MM, Schuster B, Bacchi C.
Abstract : Three new diarylheptanoids, (4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hepta-4,6-dien-3-one, letestuianin A (1), (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-4,6-dien-3-one, letestuianin B (2), and 1,7-bis(4-hydroxyphenyl)heptan-3,5-dione, letestuianin C (3), as well as the known (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxyphenyl)hepta-4,6-dien-3-one (5) were isolated from Aframomum letestuianum. The known flavonoids 3-acetoxy-5,7,4'-trihydroxyflavanone, 3-acetoxy-7-methoxy-5,4'-dihydroxyflavanone, 7-methoxy-3,5,4'-trihydroxyflavone, and 3,3',4',5,7-pentahydroxyflavan were also obtained from this plant. Their structures were determined using a combination of 1D and 2D NMR techniques. The four diarylheptanoids were tested for growth inhibitory activity in vitro versus bloodstream forms of African trypanosomes. IC(50) values in the range of 1-3 microg/mL were found for compounds 3 and 5.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense KETRI 243 isolate after 48 hrs
|
Trypanosoma brucei rhodesiense
|
0.0005
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Trypanocidal diarylheptanoids from Aframomum letestuianum.
Year : 2003
Volume : 66
Issue : 3
First Page : 364
Last Page : 367
Authors : Kamnaing P, Tsopmo A, Tanifum EA, Tchuendem MH, Tane P, Ayafor JF, Sterner O, Rattendi D, Iwu MM, Schuster B, Bacchi C.
Abstract : Three new diarylheptanoids, (4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hepta-4,6-dien-3-one, letestuianin A (1), (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-4,6-dien-3-one, letestuianin B (2), and 1,7-bis(4-hydroxyphenyl)heptan-3,5-dione, letestuianin C (3), as well as the known (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxyphenyl)hepta-4,6-dien-3-one (5) were isolated from Aframomum letestuianum. The known flavonoids 3-acetoxy-5,7,4'-trihydroxyflavanone, 3-acetoxy-7-methoxy-5,4'-dihydroxyflavanone, 7-methoxy-3,5,4'-trihydroxyflavone, and 3,3',4',5,7-pentahydroxyflavan were also obtained from this plant. Their structures were determined using a combination of 1D and 2D NMR techniques. The four diarylheptanoids were tested for growth inhibitory activity in vitro versus bloodstream forms of African trypanosomes. IC(50) values in the range of 1-3 microg/mL were found for compounds 3 and 5.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense KETRI 243 As 10-3 isolate after 48 hrs
|
Trypanosoma brucei rhodesiense
|
0.005
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Trypanocidal diarylheptanoids from Aframomum letestuianum.
Year : 2003
Volume : 66
Issue : 3
First Page : 364
Last Page : 367
Authors : Kamnaing P, Tsopmo A, Tanifum EA, Tchuendem MH, Tane P, Ayafor JF, Sterner O, Rattendi D, Iwu MM, Schuster B, Bacchi C.
Abstract : Three new diarylheptanoids, (4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hepta-4,6-dien-3-one, letestuianin A (1), (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-4,6-dien-3-one, letestuianin B (2), and 1,7-bis(4-hydroxyphenyl)heptan-3,5-dione, letestuianin C (3), as well as the known (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxyphenyl)hepta-4,6-dien-3-one (5) were isolated from Aframomum letestuianum. The known flavonoids 3-acetoxy-5,7,4'-trihydroxyflavanone, 3-acetoxy-7-methoxy-5,4'-dihydroxyflavanone, 7-methoxy-3,5,4'-trihydroxyflavone, and 3,3',4',5,7-pentahydroxyflavan were also obtained from this plant. Their structures were determined using a combination of 1D and 2D NMR techniques. The four diarylheptanoids were tested for growth inhibitory activity in vitro versus bloodstream forms of African trypanosomes. IC(50) values in the range of 1-3 microg/mL were found for compounds 3 and 5.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
0.003
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 brucei rhodesiense after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiplasmodial and antitrypanosomal activity of bicyclic amides and esters of dialkylamino acids.
Year : 2009
Volume : 17
Issue : 10
First Page : 3595
Last Page : 3603
Authors : Faist J, Seebacher W, Schlapper C, Kaiser M, Brun R, Saf R, Weis R.
Abstract : Several bicyclic amides and esters of dialkylamino acids were prepared. Their activities against a multiresistant strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900) were examined. Structure-activity relationships were discussed. Particularly the ester compounds showed good antiplasmodial and antitrypanosomal activity and a single compound was tested in vivo against Plasmodium berghei.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.001
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.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
0.004
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.
|
Trypanocidal activity against Trypanosoma brucei rhodesiense STIB 900 infected in mouse macrophage by reporter dye assay
|
Trypanosoma brucei rhodesiense
|
5.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : 2,N6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities.
Year : 2007
Volume : 51
Issue : 11
First Page : 3796
Last Page : 3802
Authors : Rodenko B, van der Burg AM, Wanner MJ, Kaiser M, Brun R, Gould M, de Koning HP, Koomen GJ.
Abstract : A library of 2,N(6)-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and N(6)-m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substitutions, such as N(6)-2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of Plasmodium spp. The activities against Trypanosoma cruzi trypomastigotes and Leishmania donovani amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against Trypanosoma brucei rhodesiense and T. b. brucei bloodstream forms in vitro. The most active were 2-cyclopentylamino-N(6)-cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-N(6)-cyclopentyladenine (compound NA134), with the nucleobase an order of magnitude more potent than the nucleoside, at 26 +/- 4 nM. It was determined that the mode of action of these purines was trypanostatic, with the compounds becoming trypanocidal only at much higher concentrations. Those 2,N(6)-disubstituted purines tested for their effects on purine transport in T. b. brucei displayed at best a moderate affinity for the transporters. It is highly probable that the large hydrophobic substitutions, which bestow high calculated octanol-water coefficient values on the analogs, allow them to diffuse across the membrane. Consistent with this view, the analogs were as effective against a T. b. brucei strain lacking the P2 nucleoside transporter as they were against the parental strain. As the analogs were not toxic to human cell lines, the purine analogs are likely to act on a trypanosome-specific target.
|
Antitrypanosomal activity against wild type Trypanosoma cruzi BS221 infected in mouse macrophage by reporter dye assay
|
Trypanosoma cruzi
|
4.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : 2,N6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities.
Year : 2007
Volume : 51
Issue : 11
First Page : 3796
Last Page : 3802
Authors : Rodenko B, van der Burg AM, Wanner MJ, Kaiser M, Brun R, Gould M, de Koning HP, Koomen GJ.
Abstract : A library of 2,N(6)-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and N(6)-m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substitutions, such as N(6)-2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of Plasmodium spp. The activities against Trypanosoma cruzi trypomastigotes and Leishmania donovani amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against Trypanosoma brucei rhodesiense and T. b. brucei bloodstream forms in vitro. The most active were 2-cyclopentylamino-N(6)-cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-N(6)-cyclopentyladenine (compound NA134), with the nucleobase an order of magnitude more potent than the nucleoside, at 26 +/- 4 nM. It was determined that the mode of action of these purines was trypanostatic, with the compounds becoming trypanocidal only at much higher concentrations. Those 2,N(6)-disubstituted purines tested for their effects on purine transport in T. b. brucei displayed at best a moderate affinity for the transporters. It is highly probable that the large hydrophobic substitutions, which bestow high calculated octanol-water coefficient values on the analogs, allow them to diffuse across the membrane. Consistent with this view, the analogs were as effective against a T. b. brucei strain lacking the P2 nucleoside transporter as they were against the parental strain. As the analogs were not toxic to human cell lines, the purine analogs are likely to act on a trypanosome-specific target.
|
Antitrypanosomal activity against tbat1 knockout Trypanosoma cruzi BS221 infected in mouse macrophage by reporter dye assay
|
Trypanosoma cruzi
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : 2,N6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities.
Year : 2007
Volume : 51
Issue : 11
First Page : 3796
Last Page : 3802
Authors : Rodenko B, van der Burg AM, Wanner MJ, Kaiser M, Brun R, Gould M, de Koning HP, Koomen GJ.
Abstract : A library of 2,N(6)-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and N(6)-m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substitutions, such as N(6)-2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of Plasmodium spp. The activities against Trypanosoma cruzi trypomastigotes and Leishmania donovani amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against Trypanosoma brucei rhodesiense and T. b. brucei bloodstream forms in vitro. The most active were 2-cyclopentylamino-N(6)-cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-N(6)-cyclopentyladenine (compound NA134), with the nucleobase an order of magnitude more potent than the nucleoside, at 26 +/- 4 nM. It was determined that the mode of action of these purines was trypanostatic, with the compounds becoming trypanocidal only at much higher concentrations. Those 2,N(6)-disubstituted purines tested for their effects on purine transport in T. b. brucei displayed at best a moderate affinity for the transporters. It is highly probable that the large hydrophobic substitutions, which bestow high calculated octanol-water coefficient values on the analogs, allow them to diffuse across the membrane. Consistent with this view, the analogs were as effective against a T. b. brucei strain lacking the P2 nucleoside transporter as they were against the parental strain. As the analogs were not toxic to human cell lines, the purine analogs are likely to act on a trypanosome-specific target.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
0.003
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiparasitic and antifungal evaluation of 2'-arylsubstituted-1H,1'H-[2,5']bisbenzimidazolyl-5-carboxamidines.
Year : 2009
Volume : 44
Issue : 5
First Page : 2002
Last Page : 2008
Authors : Alp M, Göker H, Brun R, Yildiz S.
Abstract : A series of 2'-arylsubstituted-1H,1'H-[2,5']-bisbenzimidazolyl-5-carboxamidines were prepared in a six-step process starting from 4-amino-3-nitrobenzonitrile. The antiparasitic activity against Trypanosoma brucei rhodesiense (T.b.r.), Plasmodium falciparum (P.f.), Leishmania donovani (L.d.) and Trypanosoma cruzi (T.c.) and antifungal activity against Candida albicans and Candida krusei were evaluated in vitro. Several compounds showed promising in vitro activity against T.b.r., P.f. and C. albicans and had superior activity against P.f. as compared to chloroquine.
|
Antitrypanosomal activity against Trypanosoma rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.0026
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Pelorol from the tropical marine sponge Dactylospongia elegans.
Year : 2000
Volume : 63
Issue : 8
First Page : 1150
Last Page : 1152
Authors : Goclik E, König GM, Wright AD, Kaminsky R.
Abstract : From the dichloromethane solubles of the tropical marine sponge Dactylospongia elegans, a new aromatic substituted sesquiterpene, pelorol (1), and the known sesquiterpene, ilimaquinone (2), were isolated. The structures of 1 and 2 were deduced from their spectroscopic data. The biological activities of compounds 1 and 2 were assessed in a variety of bioassays, and both compounds were found to have weak antitrypanosomal and antiplasmodial effects.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.0063
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.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Epimers of bicyclo[2.2.2]octan-2-ol derivatives with antiprotozoal activity.
Year : 2008
Volume : 43
Issue : 4
First Page : 800
Last Page : 807
Authors : Schlapper C, Seebacher W, Kaiser M, Brun R, Saf R, Weis R.
Abstract : (2SR,6RS,7RS)-4-Dialkylaminobicyclo[2.2.2]octan-2-ols and several of their esters have shown promising activity against the causative organisms for malaria and sleeping sickness. The base-catalyzed epimerization of the alcohols was carried out by different methods giving their (2RS,6RS,7RS)-isomers. Best results were obtained by the consecutive use of potassium tert-butoxide and sodium. The isomeric alcohols were converted to selected esters. All new compounds were tested for their activity against Trypanosoma brucei rhodesiense (STIB 900) and a multiresistant strain of Plasmodium falciparum. The antitrypanosomal activity and the cytotoxicity were in general increased. The most active antitrypanosomal agents were the benzoate 8b and the 4-chlorobenzoate 9b of the 4-pyrrolidino series. The nicotinate 10a and the isonicotinate 11a showed the highest antiplasmodial activities.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 bloodstream trypomastigotes
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiprotozoal activity of cationic 2-phenylbenzofurans.
Year : 2008
Volume : 51
Issue : 21
First Page : 6927
Last Page : 6944
Authors : Bakunov SA, Bakunova SM, Wenzler T, Barszcz T, Werbovetz KA, Brun R, Tidwell RR.
Abstract : A series of cationically substituted 2-phenylbenzofurans 1- 49 have been synthesized, and their in vitro antiprotozoal properties against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, as well as cytotoxicity against mammalian cells, have been evaluated. Eight dications exhibited antitrypanosomal activities comparable to that of pentamidine and melarsoprol. Twenty-six compounds were more active than pentamidine, and seven dications demonstrated increased activities against P. falciparum than artemisinin. Five congeners were more active against L. donovani than pentamidine. Introduction of methoxy or hydroxy groups in the 7- and/or 2'-position afforded derivatives that were highly selective against T. b. rhodesiense, P. falciparum, and L. donovani. Fourteen 2-phenylbenzofurans displayed excellent in vivo efficacies in the acute mouse model of trypanosomiasis, curing 3/4 or 4/4 animals at 4 x 5 mg/kg. Diamidine 1 and di( N-isopropyl)amidine 45, administered at 4 x 1 mg/kg, exhibited potency comparable to that of melarsoprol, providing 3/4 and 2/4 cures, respectively.
|
Antitrypanosomal activity against blood stream form of Trypanosoma brucei rhodesiense STIB 900
|
Trypanosoma brucei rhodesiense
|
0.0004
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Total synthesis and biological activities of (+)- and (-)-boscialin and their 1'-epimers.
Year : 1998
Volume : 61
Issue : 5
First Page : 591
Last Page : 597
Authors : Busch J, Grether Y, Ochs D, Séquin U.
Abstract : Natural (-)-boscialin [(-)-1] has recently been described as one of the constituents of various medicinal plants. To obtain more material for investigations of its biological activities, we carried out the synthesis of (-)-1 and its isomers. Starting from the chiral building block 2, the key steps of the synthesis involved a regioselective reduction and a nucleophilic addition. The enantiomer of the natural product, (+)-boscialin [(+)-1], could be obtained via acid-catalyzed epimerization of hydroxyketone 4 to (+)-3. Starting the synthesis with (-)-3 led to (-)-boscialin [(-)-1] with the natural absolute configuration. In addition to (+)- and (-)-boscialin, the corresponding 1'-epimers (+)- and (-)-epiboscialin were also obtained. In vitro assays with (-)-boscialin [(-)-1] and its three stereoisomers were carried out to test for activity against microbes, parasites, and human fibroblasts. The investigations revealed activity against various microbes and against Trypanosoma brucei rhodesiense and also revealed cytotoxicity against human cancer cells.
|
Cytotoxicity against human HT-29 cells
|
Homo sapiens
|
3.6
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Total synthesis and biological activities of (+)- and (-)-boscialin and their 1'-epimers.
Year : 1998
Volume : 61
Issue : 5
First Page : 591
Last Page : 597
Authors : Busch J, Grether Y, Ochs D, Séquin U.
Abstract : Natural (-)-boscialin [(-)-1] has recently been described as one of the constituents of various medicinal plants. To obtain more material for investigations of its biological activities, we carried out the synthesis of (-)-1 and its isomers. Starting from the chiral building block 2, the key steps of the synthesis involved a regioselective reduction and a nucleophilic addition. The enantiomer of the natural product, (+)-boscialin [(+)-1], could be obtained via acid-catalyzed epimerization of hydroxyketone 4 to (+)-3. Starting the synthesis with (-)-3 led to (-)-boscialin [(-)-1] with the natural absolute configuration. In addition to (+)- and (-)-boscialin, the corresponding 1'-epimers (+)- and (-)-epiboscialin were also obtained. In vitro assays with (-)-boscialin [(-)-1] and its three stereoisomers were carried out to test for activity against microbes, parasites, and human fibroblasts. The investigations revealed activity against various microbes and against Trypanosoma brucei rhodesiense and also revealed cytotoxicity against human cancer cells.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.0031
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 brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.0038
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 brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.00095
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 brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
6.0
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.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by microplate alamar blue assay
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel azabicyclo[3.2.2]nonane derivatives and their activities against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense.
Year : 2008
Volume : 16
Issue : 12
First Page : 6371
Last Page : 6378
Authors : Berger H, Weis R, Kaiser M, Brun R, Saf R, Seebacher W.
Abstract : New diaryl substituted 2-azabicyclo[3.2.2]nonane derivatives have been synthesized in order to investigate the influence of the aromatic substitution and of N substitution on the antiprotozoal activities of those compounds. Following a manual method for the Hansch approach, different 4-substituted aryl rings were systematically inserted, and moieties with varying basicity and polarity were attached to the ring nitrogen. All compounds were investigated for their activities against Trypanosoma brucei rhodesiense (STIB 900) and the K(1) strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine) and for their cytotoxicity using microplate assays. Some of the new compounds are amongst the most active antitrypanosomal agents in this series, and the selectivity index of a single derivative is superior in the 2-azabicyclo-nonane series.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 by microplate assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Antiplasmodial and antitrypanosomal activities of aminobicyclo[2.2.2]octyl omega-aminoalkanoates.
Year : 2009
Volume : 44
Issue : 2
First Page : 736
Last Page : 744
Authors : Schlapper C, Seebacher W, Faist J, Kaiser M, Brun R, Saf R, Weis R.
Abstract : Several 4-aminobicyclo[2.2.2]octyl esters of omega-dialkylamino acids were prepared. Their activities against the multidrug-resistant K(1) strain of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900) were determined using microplate assays and compared to those of formerly prepared analogues. The biological activity was influenced by the relative configuration in ring position 2, by the chain length of the acid moiety and by the amino substitution. The most active antiplasmodial ester was as active as chloroquine. One of the new compounds exhibited the highest antitrypanosomal activity and selectivity of all bicyclo-octane derivatives prepared so far.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity study of pentamidine analogues as antiprotozoal agents.
Year : 2009
Volume : 52
Issue : 7
First Page : 2016
Last Page : 2035
Authors : Bakunova SM, Bakunov SA, Patrick DA, Kumar EV, Ohemeng KA, Bridges AS, Wenzler T, Barszcz T, Jones SK, Werbovetz KA, Brun R, Tidwell RR.
Abstract : Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC(50) = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC(50) = 1.8 microM). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense bloodstream trypomastigotes
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase.
Year : 2009
Volume : 19
Issue : 11
First Page : 3031
Last Page : 3035
Authors : Cavalli A, Lizzi F, Bongarzone S, Brun R, Luise Krauth-Siegel R, Bolognesi ML.
Abstract : Novel quinazoline-type compounds were designed as inhibitors of the parasite specific enzyme trypanothione reductase (TR), and their biological activities were evaluated. Some of our compounds inhibited TR, showed selectivity for TR over human glutathione reductase, and inhibited parasite growth in vitro. We propose that the quinazoline framework is a privileged structure that can be purposely modified to design novel TR inhibitors. Furthermore, the use of privileged motifs might emerge as an innovative approach to antiparasitic lead candidates.
|
Antitrypanosomal activity against bloodstream Trypanosoma brucei rhodesiense STIB900 after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiprotozoal activity of pyridyl analogues of pentamidine.
Year : 2009
Volume : 52
Issue : 15
First Page : 4657
Last Page : 4667
Authors : Bakunova SM, Bakunov SA, Wenzler T, Barszcz T, Werbovetz KA, Brun R, Tidwell RR.
Abstract : A series of novel pyridyl analogues 1-18 of antiprotozoal drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) has been synthesized and tested for in vitro activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Antiprotozoal properties of compounds 1-18 depended on the placement of cationic moieties on the pyridine rings as well as the nature of substituents on the amidine groups. Diamidine 6 with cationic moieties adjacent to pyridine nitrogen atoms was the most promising compound in the series showing superior in vitro activities against T. brucei rhodesiense, P. falciparum, and L. donovani compared to pentamidine. An oral prodrug of diamidine 6, diamidoxime 9, administered at 25 mg/kg daily for 4 days, exhibited excellent antitrypanosomal efficacy in vivo curing all infected animals in the STIB900 acute mouse model of trypanosomiasis.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
6.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiprotozoal activities of dicationic bis(phenoxymethyl)benzenes, bis(phenoxymethyl)naphthalenes, and bis(benzyloxy)naphthalenes.
Year : 2009
Volume : 44
Issue : 9
First Page : 3543
Last Page : 3551
Authors : Patrick DA, Bakunov SA, Bakunova SM, Kumar EV, Chen H, Jones SK, Wenzler T, Barzcz T, Werbovetz KA, Brun R, Tidwell RR.
Abstract : A series of 37 dicationically substituted bis(phenoxymethyl)benzene bis(phenoxymethyl)naphthalene, and bis(benzyloxy)naphthalene analogues of pentamidine was prepared and evaluated for antiprotozoal activities and cytotoxicity in in vitro. 1,3-Bis(4-amidinophenoxymethyl)benzene (1) was the most active against Trypanosoma brucei rhodesiense (IC(50)=2.1 nM). 1,3-Bis[4-(N-isopropylamidino)phenoxymethyl]benzene (2) was most active against Plasmodium falciparum (IC(50)=3.6 nM) and displayed a selectivity index more than 50 times greater than that of pentamidine. Several other compounds displayed lower antiplasmodial IC(50) values and higher selectivity indices relative to pentamidine. 1,4-Bis(4-amidinophenoxymethyl)benzene (14) was the most active against Leishmania donovani (IC(50)=1.3 microM). Compound 2 displayed the greatest activity against T. b. rhodesiense in vivo, curing three of four infected mice dosed intraperitoneally at 5 mg/kg x 4 days.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by alamar blue based microplate assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of a series of N6-substituted adenosines with activity against trypanosomatid parasites.
Year : 2009
Volume : 44
Issue : 9
First Page : 3665
Last Page : 3671
Authors : Link A, Heidler P, Kaiser M, Brun R.
Abstract : The involvement of purine salvage in the accumulation of current trypanocidal drugs is important for the treatment of African sleeping sickness. The substrate specificity of essential nucleoside transporters is therefore of physiological and pharmacological interest. With the intention to contribute to the knowledge in the field, a series of 16 adenosine derivatives with substituents in N(6)-position were prepared in order to evaluate their potential to inhibit Trypanosoma brucei spp. in vitro. An unmodified ribose moiety was selected to conserve key molecular recognition motifs of the arsenal of integral membrane proteins expressed in large numbers on the protozoan plasma membrane. Two of the new compounds prepared using a polymer-assisted acylation protocol showed antitrypanosomal activities in the single digit micromolar concentration range.
|
Antimicrobial activity against Trypanosoma brucei rhodesiense STIB 900 trypomastigote forms
|
Trypanosoma brucei rhodesiense
|
4.0
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.
|
Antitrypanosomal activity against bloodstream Trypanosoma brucei rhodesiense STIB 900 after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Antitrypanosomal activity of 1,2-dihydroquinolin-6-ols and their ester derivatives.
Year : 2010
Volume : 53
Issue : 3
First Page : 966
Last Page : 982
Authors : Fotie J, Kaiser M, Delfín DA, Manley J, Reid CS, Paris JM, Wenzler T, Maes L, Mahasenan KV, Li C, Werbovetz KA.
Abstract : The current chemotherapy for second stage human African trypanosomiasis is unsatisfactory. A synthetic optimization study based on the lead antitrypanosomal compound 1,2-dihydro-2,2,4-trimethylquinolin-6-yl 3,5-dimethoxybenzoate (TDR20364, 1a) was undertaken in an attempt to discover new trypanocides with potent in vivo activity. While 6-ether derivatives were less active than the lead compound, several N1-substituted derivatives displayed nanomolar IC(50) values against T. b. rhodesiense STIB900 in vitro, with selectivity indexes up to >18000. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate (10a) displayed an IC(50) value of 0.014 microM against these parasites and a selectivity index of 1700. Intraperitoneal administration of 10a at 50 (mg/kg)/day for 4 days caused a promising prolongation of lifespan in T. b. brucei STIB795-infected mice (>14 days vs 7.75 days for untreated controls). Reactive oxygen species were produced when T. b. brucei were exposed to 10a in vitro, implicating oxidative stress in the trypanocidal mode of action of these 1,2-dihydroquinoline derivatives.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3-triazoles.
Year : 2010
Volume : 53
Issue : 1
First Page : 254
Last Page : 272
Authors : Bakunov SA, Bakunova SM, Wenzler T, Ghebru M, Werbovetz KA, Brun R, Tidwell RR.
Abstract : Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of aromatic substituents influenced in vitro antiprotozoal activities of compounds 1-60 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and their cytotoxicity for mammalian cells. Eight congeners displayed antitrypanosomal IC(50) values below 10 nM. Thirty-nine dications were more potent against P. falciparum than pentamidine (IC(50) = 58 nM), and eight analogues were more active than artemisinin (IC(50) = 6 nM). Diimidazoline 60 exhibited antiplasmodial IC(50) value of 0.6 nM. Seven congeners administered at 4 x 5 mg/kg by the intraperitoneal route cured at least three out of four animals in the acute mouse model of African trypanosomiasis. At 4 x 1 mg/kg, diamidine 46 displayed better antitrypanosomal efficacy than melarsoprol, curing all infected mice.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues.
Year : 2009
Volume : 17
Issue : 20
First Page : 7209
Last Page : 7217
Authors : Van Baelen G, Hostyn S, Dhooghe L, Tapolcsányi P, Mátyus P, Lemière G, Dommisse R, Kaiser M, Brun R, Cos P, Maes L, Hajós G, Riedl Z, Nagy I, Maes BU, Pieters L.
Abstract : Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense infected in rat L6 cells
|
Trypanosoma brucei rhodesiense
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, stereoelectronic characterization and antiparasitic activity of new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinolines.
Year : 2010
Volume : 18
Issue : 1
First Page : 142
Last Page : 150
Authors : Pagliero RJ, Lusvarghi S, Pierini AB, Brun R, Mazzieri MR.
Abstract : The synthesis and full 3D structural characterization of nine new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinoline derivatives are reported. These belong to a library whose rationale for the design was the previous knowledge of the biological relevant properties of both structural moieties. From protozoan antiparasitic screening, compounds 3 demonstrated interesting activity against Trypanozoma cruzi with low cytotoxicity. Besides, most compounds were moderately active against Plasmodium falciparum. Of these, 3 and 9 can be considered as lead scaffolds for further optimization. The substituent on BS did not influence the 3D structure properties and the (1)H NMR spectra revealed the existence of an intramolecular weak hydrogen bond, C-Hcdots, three dots, centeredOS. Molecular modeling and X-ray crystallography also confirmed this finding, which is relevant to compound conformational preference.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900 bloodstream form
|
Trypanosoma brucei rhodesiense
|
17.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi.
Year : 2010
Volume : 20
Issue : 6
First Page : 1816
Last Page : 1818
Authors : Holloway GA, Parisot JP, Novello PM, Watson KG, Armstrong T, Thompson RC, Street IP, Baell JB.
Abstract : A benzhydryl tropinone oxime that is potently toxic to Trypanosoma cruzi has been previously identified. An SAR investigation determined that no part of the original compound was superfluous and all early SAR probes led to significant drops in activity. The only alteration that could be achieved without loss of activity was replacement of the aryl chloride substituent with chloro homologues. This led to the discovery of a trifluoromethyl-containing analogue with an EC(50) against T. cruzi of 30 nM and a cytotoxicity selectivity index of over 1000 relative to rat skeletal myoblast L-6 cells.
|
Antitrypanosomal activity against Trypanosoma brucei brucei 427-221a after 40 hrs by bioluminescence assay
|
Trypanosoma brucei brucei
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Assessing the trypanocidal potential of natural and semi-synthetic diketopiperazines from two deep water marine-derived fungi.
Year : 2010
Volume : 18
Issue : 7
First Page : 2566
Last Page : 2574
Authors : Watts KR, Ratnam J, Ang KH, Tenney K, Compton JE, McKerrow J, Crews P.
Abstract : Human African trypanosomiasis (HAT, commonly known as African sleeping sickness) is categorized as a neglected disease, as it afflicts >50,000 people annually in sub-saharan Africa, and there are few formal programs in the world focused on drug discovery approaches for this disease. In this study, we examined the crude extracts of two fungal strains (Aspergillus fumigatus and Nectria inventa) isolated from deep water sediment which provided >99% growth inhibition at 1microg/mL of Trypanosoma brucei, the causative parasite of HAT. A collection of fifteen natural products was supplemented with six semi-synthetic derivatives and one commercially available compound. Twelve of the compounds, each containing a diketopiperazine core, showed excellent activity against T. brucei (IC(50)=0.002-40microM), with selectivity over mammalian cells as great as 20-fold. The trypanocidal diketopiperazines were also tested against two cysteine protease targets Rhodesain and TbCatB, where five compounds showed inhibition activity at concentrations less than 20microM. A preliminary activity pattern is described and analyzed.
|
Inhibition of Trypanosoma brucei rhodesiense recombinant rhodesain at 100 uM
|
Trypanosoma brucei rhodesiense
|
94.0
%
|
|
Journal : J. Med. Chem.
Title : On-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences.
Year : 2009
Volume : 52
Issue : 18
First Page : 5662
Last Page : 5672
Authors : Machon U, Büchold C, Stempka M, Schirmeister T, Gelhaus C, Leippe M, Gut J, Rosenthal PJ, Kisker C, Leyh M, Schmuck C.
Abstract : A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. K(i) values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.
|
Antitrypanosomal activity against Trypanosoma brucei brucei
|
Trypanosoma brucei brucei
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : On-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences.
Year : 2009
Volume : 52
Issue : 18
First Page : 5662
Last Page : 5672
Authors : Machon U, Büchold C, Stempka M, Schirmeister T, Gelhaus C, Leippe M, Gut J, Rosenthal PJ, Kisker C, Leyh M, Schmuck C.
Abstract : A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. K(i) values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.
|
Trypanocidal activity against Trypanosoma brucei rhodesiense STIB 900 after 72 hrs
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antiprotozoal steroidal saponins from the marine sponge Pandaros acanthifolium.
Year : 2010
Volume : 73
Issue : 8
First Page : 1404
Last Page : 1410
Authors : Regalado EL, Tasdemir D, Kaiser M, Cachet N, Amade P, Thomas OP.
Abstract : The chemical composition of the Caribbean sponge Pandaros acanthifolium was reinvestigated and led to the isolation of 12 new steroidal glycosides, namely, pandarosides E-J (1-6) and their methyl esters (7-12). Their structures were determined on the basis of extensive spectroscopic analyses, including two-dimensional NMR and HRESIMS data. Like the previously isolated pandarosides A-D (13-16), the new compounds 1-12 share an unusual oxidized D-ring and a cis C/D ring junction. The absolute configurations of the aglycones were assigned by interpretation of CD spectra, whereas the absolute configurations of the monosaccharide units were determined by chiral GC analyses of the acid methanolysates. The majority of the metabolites showed in vitro activity against three or four parasitic protozoa. Particularly active were the compounds 3 (pandaroside G) and its methyl ester (9), which potently inhibited the growth of Trypanosoma brucei rhodesiense (IC(50) values 0.78 and 0.038 microM, respectively) and Leishmania donovani (IC(50)'s 1.3 and 0.051 microM, respectively).
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 at 4.8 ug/mL by microplate alamar blue assay
|
Trypanosoma brucei rhodesiense
|
98.2
%
|
|
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 bloodstream form of Trypanosoma brucei rhodesiense STIB 900 after 72 hrs
|
Trypanosoma brucei rhodesiense
|
0.003
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 Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
7.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids.
Year : 2010
Volume : 45
Issue : 11
First Page : 5370
Last Page : 5383
Authors : Bringmann G, Bischof SK, Müller S, Gulder T, Winter C, Stich A, Moll H, Kaiser M, Brun R, Dreher J, Baumann K.
Abstract : Naphthylisoquinoline alkaloids have attracted considerable interest because of their intriguing structure, their unique biosynthetic origin, and their biological activities against several pathogens causing tropical diseases. Their promising pharmacologic properties make them suitable lead structures for new agents, in particular against malaria. Since these natural products are not easy to isolate in sufficient quantities or to synthesize stereoselectively, quantitative structure-activity relationship studies were accomplished to find new antiplasmodial analogs that are structurally related to the naturally occurring naphthylisoquinoline alkaloids, but more easily accessible, more active against Plasmodium falciparum, and, last but not least, less toxic. We report on the synthesis of several simplified compounds by a Suzuki coupling between the naphthalene and the isoquinoline moieties and on their activities against different pathogens causing infectious diseases. Some structures were found to exhibit excellent--and selective--activities against P. falciparum in vitro.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
9.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and antitrypanosomal evaluation of derivatives of N-benzyl-1,2-dihydroquinolin-6-ols: Effect of core substitutions and salt formation.
Year : 2011
Volume : 19
Issue : 1
First Page : 513
Last Page : 523
Authors : Reid CS, Patrick DA, He S, Fotie J, Premalatha K, Tidwell RR, Wang MZ, Liu Q, Gershkovich P, Wasan KM, Wenzler T, Brun R, Werbovetz KA.
Abstract : Analogs of the trypanocidal lead compound 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were prepared to extend the structure-activity relationship in this series of molecules, improve the in vivo antitrypanosomal activity of the lead, and determine whether ester prodrugs are needed to overcome the instability of the dihydroquinolin-6-ols. Two of the most active compounds identified in this study were 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxy)benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride. These stable solids possessed low nanomolar IC(50) values against Trypanosoma brucei rhodesiense STIB900 in vitro and provided cures in an early treatment acute mouse model of African trypanosomiasis when given ip at 50mg/kg/day for four consecutive days.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms
|
Trypanosoma brucei rhodesiense
|
17.0
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 wild-type Trypanosoma brucei rhodesiense STIB900 by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.0014
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against pentamidine-resistant Trypanosoma brucei rhodesiense STIB900 by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.0282
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against melasoprol-resistant Trypanosoma brucei rhodesiense STIB900 by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.0567
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against Trypanosoma brucei gambiense K03048 by Alamar blue assay
|
Trypanosoma brucei gambiense
|
0.0031
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against Trypanosoma brucei gambiense ITMAP141267 by Alamar blue assay
|
Trypanosoma brucei gambiense
|
0.0027
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against Trypanosoma brucei gambiense STIB930 by Alamar blue assay
|
Trypanosoma brucei gambiense
|
0.0053
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against Trypanosoma brucei brucei BS221 by Alamar blue assay
|
Trypanosoma brucei brucei
|
0.0036
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against Trypanosoma brucei brucei AT1KO by Alamar blue assay
|
Trypanosoma brucei brucei
|
0.0187
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289.
Year : 2009
Volume : 53
Issue : 10
First Page : 4185
Last Page : 4192
Authors : Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.
Abstract : African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense ST1B900 trypomastigote infected in NMR1 mouse assessed as inhibition of parasitemia at 50 mg/kg, ip administered on day 3 post infection for 4 days
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antiprotozoal activity of 1-phenethyl-4-aminopiperidine derivatives.
Year : 2009
Volume : 53
Issue : 9
First Page : 3815
Last Page : 3821
Authors : Dardonville C, Fernández-Fernández C, Gibbons SL, Jagerovic N, Nieto L, Ryan G, Kaiser M, Brun R.
Abstract : A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC50) ranging from 0.12 to 10 microM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC50 range, 0.17 to 5 microM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC50, 1.97 microM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.
|
Antiparasitic activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by microplate reader assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Didemnidines A and B, indole spermidine alkaloids from the New Zealand ascidian Didemnum sp.
Year : 2011
Volume : 74
Issue : 4
First Page : 888
Last Page : 892
Authors : Finlayson R, Pearce AN, Page MJ, Kaiser M, Bourguet-Kondracki ML, Harper JL, Webb VL, Copp BR.
Abstract : Two new indole spermidine alkaloids, didemnidines A (1) and B (2), have been isolated from the New Zealand ascidian Didemnum sp. The structures of the metabolites, determined by analysis of 2D NMR spectra and confirmed via synthesis, embody an indole-3-glyoxylamide moiety linked to the N(1) position of spermidine, the latter motif being particularly rare among marine natural products. Didemnidine B and a synthetic precursor exhibited mild in vitro growth inhibition of Plasmodium falciparum with IC(50)'s of 15 and 8.4 μM, respectively.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB 900 trypomastigotes
|
Trypanosoma brucei rhodesiense
|
12.0
nM
|
|
Journal : J. Nat. Prod.
Title : Marinoquinolines A-F, pyrroloquinolines from Ohtaekwangia kribbensis (Bacteroidetes).
Year : 2011
Volume : 74
Issue : 4
First Page : 603
Last Page : 608
Authors : Okanya PW, Mohr KI, Gerth K, Jansen R, Müller R.
Abstract : Marinoquinoline A (1) was isolated from the gliding bacterium Ohtaekwangia kribbensis together with the novel marinoquinolines B-F (2-6). Their structures were elucidated from NMR and HRESIMS data. The pyrroloquinolines showed weak antibacterial and antifungal activities and moderate cytotoxicity against four growing mammalian cell lines with IC(50) values ranging from 0.3 to 8.0 μg/mL. In a screening against tropical parasites marinoquinolines A-F (1-6) showed activity against Plasmodium falciparum K1 with IC(50) values between 1.7 and 15 μM.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB 900 bloodstream form after 72 hrs by microplate fluorimetry
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antiparasitic compounds from Cupania cinerea with activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense.
Year : 2011
Volume : 74
Issue : 4
First Page : 559
Last Page : 566
Authors : Gachet MS, Kunert O, Kaiser M, Brun R, Zehl M, Keller W, Muñoz RA, Bauer R, Schuehly W.
Abstract : In a survey of plants from Ecuador with antiprotozoal activity, Cupania cinerea was found to show significant in vitro activity against the Plasmodium falciparum K1 strain and Trypanosoma brucei rhodesiense. Subsequently, activity-guided isolation of the n-hexane and dichloromethane extracts from the bark of C. cinerea afforded two diterpene glycosides (1 and 2), named cupacinoside and 6'-de-O-acetylcupacinoside, and a lactonized triterpene bearing an oxepin moiety named cupacinoxepin (3), together with the known compounds scopoletin (4), caryophyllene oxide (5), two bisabolane sesquiterpenes (6 and 7), lichexanthone (8), gustastatin (9), lupenone (10), betulone (11), 17β,21β-epoxyhopan-3-one (12), taraxerol (13), and taraxerone (14). For compound 3, X-ray crystallography was employed to elucidate the relative configuration. For cupacinosides (1) and (2) and cupacinoxepin (3), in vitro activities against the P. falciparum K1 strain (IC(50)1, 1.3; 2, 1.8; and 3, 8.7 μM) and T. b. rhodesiense (IC(50)1, 4.5; 2, 15.8; and 3, 71.6 μM) were found. Cytotoxicity toward L-6 cells is discussed for all the compounds isolated.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB 900 trypomastigotes stage forms incubated for 72 hrs by Alamar blue staining based fluorometric assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antimalarial β-carbolines from the New Zealand ascidian Pseudodistoma opacum.
Year : 2011
Volume : 74
Issue : 9
First Page : 1972
Last Page : 1979
Authors : Chan ST, Pearce AN, Page MJ, Kaiser M, Copp BR.
Abstract : One tetrahydro-β-carboline, (-)-7-bromohomotrypargine (1), and three alkylguanidine-substituted β-carbolines, opacalines A, B, and C (2-4), have been isolated from the New Zealand ascidian Pseudodistoma opacum. The structures of the metabolites were determined by analysis of mass spectrometric and 2D NMR spectroscopic data. Natural products 2 and 3, synthetic debromo analogues 8 and 9, and intermediate 16 exhibited moderate antimalarial activity toward a chloroquine-resistant strain of Plasmodium falciparum, with an IC50 range of 2.5-14 μM. The biosynthesis of 1-4 is proposed to proceed via a Pictet-Spengler condensation of 6-bromotryptamine and the α-keto acid transamination product of either arginine or homoarginine. Cell separation and 1H NMR analysis of P. opacum identified tetrahydro-β-carboline 1 to be principally located in the zooids, while fully aromatized analogues 2-4 were localized to the test.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 at pH 7.4 by microplate assay
|
Trypanosoma brucei rhodesiense
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antiprotozoal activities of 5-phenyliminobenzo[a]phenoxazine derivatives.
Year : 2011
Volume : 21
Issue : 19
First Page : 5804
Last Page : 5807
Authors : Shi XL, Ge JF, Liu BQ, Kaiser M, Wittlin S, Brun R, Ihara M.
Abstract : A series of 5-phenyliminobenzo[a]phenoxazine derivatives were synthesized. The in vitro antiprotozoal activities were evaluated against Plasmodium falciparum K1, Trypanosoma cruzi, Leishmania donovani and Trypanosoma brucei rhodesiense. N,N-Diethyl-5-((4-methoxyphenyl)imino)-5H-benzo[a]phenoxazin-9-amine shows IC(50)=0.040 μmol L(-1) with a selective index of 1425 against Plasmodium falciparum K1.
|
Antiparasitic activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 infected in rat L6 cells after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biological evaluation of glycosyl-isoindigo derivatives against the pathogenic agents of tropical diseases (malaria, Chagas disease, leishmaniasis and human African trypanosomiasis).
Year : 2011
Volume : 21
Issue : 21
First Page : 6319
Last Page : 6321
Authors : Bouchikhi F, Anizon F, Brun R, Moreau P.
Abstract : The biological activities of diversely substituted glycosyl-isoindigo derivatives against the causative agents of tropical diseases (malaria, Chagas disease, leishmaniasis and human African trypanosomiasis) are reported. Some of the compounds tested showed interesting activities with good selectivity indices, particularly against Trypanosoma brucei rhodesiense. These results suggested, for the first time, that glycosyl-isoindigo derivatives could be of interest for the discovery of new lead compounds to treat tropical diseases.
|
Antitrypanosomal activity against blood stream form of Trypanosoma brucei rhodesiense STIB 900 infected in rat L6 cells after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based aliphatic and aromatic amines as anti-chagasic agents.
Year : 2011
Volume : 54
Issue : 23
First Page : 8214
Last Page : 8223
Authors : Papadopoulou MV, Trunz BB, Bloomer WD, McKenzie C, Wilkinson SR, Prasittichai C, Brun R, Kaiser M, Torreele E.
Abstract : A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF) T. b. rhodesiense trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms after 72 hrs by serial dilution Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
9.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New N-methylpiperazinyl derivatives of bicyclic antiprotozoal compounds.
Year : 2012
Volume : 47
First Page : 510
Last Page : 519
Authors : Faist J, Seebacher W, Saf R, Brun R, Kaiser M, Weis R.
Abstract : The 4-methylpiperazinyl group was inserted as substituent at the bridgehead of bicyclic compounds or as terminal group of their aminoacyl and aminoalkyl side chains. The new compounds were tested in vitro for their activities against the multidrug-resistant K(1) strain of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900). The results were compared to those of formerly prepared analogues and of drugs in use. A couple of bicyclo-octyl ω-(4-piperazin-1-yl)alkanoates showed high antitrypanosomal (IC(50)≤0.087μM) and antiplasmodial activity (IC(50)≤0.06μM). The most active ω-(4-methylpiperazin-1-yl)alkyl-2-azabicyclo-nonane possessed higher antiplasmodial activity (IC(50)≤0.023μM) and selectivity (S.I.=IC(50) (Cytotox.)/IC(50) (P. falciparum)=2188) than the antimalarial drug chloroquine (IC(50)=0.15μM, S.I.=1257).
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 after 70 hrs by resazurin-based spectrophotometric assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Bis(oxyphenylene)benzimidazoles: a novel class of anti-Plasmodium falciparum agents.
Year : 2011
Volume : 19
Issue : 24
First Page : 7493
Last Page : 7500
Authors : Mayence A, Vanden Eynde JJ, Kaiser M, Brun R, Yarlett N, Huang TL.
Abstract : A small library of 26 2,2'-[alkane-α,ω-diylbis(oxyphenylene)]bis-1H-benzimidazoles has been prepared and evaluated against Giardia intestinalis, Entamoeba histolytica, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. Among the tested compounds, eight derivatives (17, 19, 20, 24, 27, 30, 32 and 35) exhibited an anti-Plasmodium falciparum activity characterized by IC(50) values in the range of 180-410 nM (0.11-0.21 μg/mL) and selectivity indexes (IC(50) rat skeletal myoblasts L6 cells vs IC(50)P. falciparum K1 strain) varying between 92 and more than 450. Two of the eight novel drug leads, namely compounds 19 and 32, were also active against G. intestinalis and L. donovani with selectivity indexes of 122 and >164 respectively.
|
Trypanocidal activity against Trypanosoma brucei rhodesiense STIB 900 bloodstream forms after 72 hrs by resazurin assay
|
Trypanosoma brucei rhodesiense
|
0.005
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 blood stream form of Trypanosoma brucei after 69 hrs by resazurin-based fluorescence assay
|
Trypanosoma brucei
|
33.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Quinol derivatives as potential trypanocidal agents.
Year : 2012
Volume : 20
Issue : 4
First Page : 1607
Last Page : 1615
Authors : Capes A, Patterson S, Wyllie S, Hallyburton I, Collie IT, McCarroll AJ, Stevens MF, Frearson JA, Wyatt PG, Fairlamb AH, Gilbert IH.
Abstract : Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photo-dimers.
Year : 2012
Volume : 20
Issue : 4
First Page : 1482
Last Page : 1493
Authors : McCracken ST, Kaiser M, Boshoff HI, Boyd PD, Copp BR.
Abstract : Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of Mycobacterium tuberculosis and a range of tropical diseases including Plasmodium falciparum and Leishmania donovani. In an effort to expand the structure-activity relationship of this compound class towards infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesized. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense and Trypanosoma cruzi. Of the styryl-pyranones, natural product 3 and non-natural styrene and naphthalene substituted examples 13, 18, 21, 22 and 23 exhibited antimalarial activity (IC(50) <10 μM) with selectivity indices (SI) >10. Δ(7) Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers 5 and 34 exhibited moderate IC(50)s of 2.3 to 17 μM towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers 31 and 33 were identified as being moderately active towards P. falciparum (IC(50) 1.5 and 1.7 μM) with good selectivity (SI ~80). The 4-tert-butyl aniba-dimer A analogue 33 also exhibited activity towards L. donovani (IC(50) 4.5 μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis.
|
Antitrypanosomal activity against Trypanosoma brucei brucei TC221 infected in mouse J774.1 cells after 48 hrs by alamar blue assay
|
Trypanosoma brucei brucei
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei.
Year : 2012
Volume : 55
Issue : 6
First Page : 2538
Last Page : 2548
Authors : Hiltensperger G, Jones NG, Niedermeier S, Stich A, Kaiser M, Jung J, Puhl S, Damme A, Braunschweig H, Meinel L, Engstler M, Holzgrabe U.
Abstract : Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei , Trypanosoma brucei gambiense , and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC(50) = 47 nM) and T. b. rhodesiense (IC(50) = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.
|
Antitrypanosomal activity against trypomastigotes of Trypanosoma brucei rhodesiense STIB 900 infected in rat L6 cells after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.005
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 brucei rhodesiense STIB900 infected in rat L6 cells after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes.
Year : 2012
Volume : 55
Issue : 6
First Page : 2606
Last Page : 2622
Authors : Taladriz A, Healy A, Flores Pérez EJ, Herrero García V, Ríos Martínez C, Alkhaldi AA, Eze AA, Kaiser M, de Koning HP, Chana A, Dardonville C.
Abstract : A series of 73 bisphosphonium salts and 10 monophosphonium salt derivatives were synthesized and tested in vitro against several wild type and resistant lines of Trypanosoma brucei (T. b. rhodesiense STIB900, T. b. brucei strain 427, TbAT1-KO, and TbB48). More than half of the compounds tested showed a submicromolar EC(50) against these parasites. The compounds did not display any cross-resistance to existing diamidine therapies, such as pentamidine. In most cases, the compounds displayed a good selectivity index versus human cell lines. None of the known T. b. brucei drug transporters were required for trypanocidal activity, although some of the bisphosphonium compounds inhibited the low affinity pentamidine transporter. It was found that phosphonium drugs act slowly to clear a trypanosome population but that only a short exposure time is needed for irreversible damage to the cells. A comparative molecular field analysis model (CoMFA) was generated to gain insights into the SAR of this class of compounds, identifying key features for trypanocidal activity.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 by Alamar blue growth inhibition assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of nitroheterocycles active against African trypanosomes. In vitro screening and preliminary SAR studies.
Year : 2012
Volume : 22
Issue : 14
First Page : 4506
Last Page : 4516
Authors : Arán VJ, Kaiser M, Dardonville C.
Abstract : A selection of 76 nitroheterocycles and related compounds from our in-house compound library was screened in vitro against the parasite Trypanosoma brucei rhodesiense, causative agent of human African trypanosomiasis (HAT). The unspecific cytotoxicity of the compounds was also evaluated against rat myoblast L6-cells to measure the selectivity of the compounds towards the parasite. This screening revealed some preliminary structure-activity relationships (SAR) among the series, and six hit compounds showing interesting activity (IC(50)≤10μM) and fair selectivity (SI>17). The 7-nitroquinoxalin-2-one and 5-nitroindazole scaffold derivatives 58 and 35, respectively, are particularly interesting because of their established oral bioavailability in mice. These hits represent interesting starting points for a medicinal project aimed at identifying the SAR behind this class of compounds.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 trypomastigotes
|
Trypanosoma brucei rhodesiense
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents.
Year : 2012
Volume : 55
Issue : 11
First Page : 5554
Last Page : 5565
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Chatelain E, Kaiser M, Wilkinson SR, McKenzie C, Ioset JR.
Abstract : A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against Trypanosoma cruzi intracellular amastigotes (IC(50) ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≤ IC(50) < 6.0 μM) against Trypanosoma brucei rhodesiense trypomastigotes were 5-31-fold more active against bloodstream-form Trypanosoma brucei brucei trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani . Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei brucei Lister 427 clone 221a overexpressing tet-inducible NTR in presence of tetracycline after 3 days
|
Trypanosoma brucei brucei
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents.
Year : 2012
Volume : 55
Issue : 11
First Page : 5554
Last Page : 5565
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Chatelain E, Kaiser M, Wilkinson SR, McKenzie C, Ioset JR.
Abstract : A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against Trypanosoma cruzi intracellular amastigotes (IC(50) ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≤ IC(50) < 6.0 μM) against Trypanosoma brucei rhodesiense trypomastigotes were 5-31-fold more active against bloodstream-form Trypanosoma brucei brucei trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani . Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei brucei Lister 427 clone 221a overexpressing tet-inducible NTR in absence of tetracycline after 3 days
|
Trypanosoma brucei brucei
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents.
Year : 2012
Volume : 55
Issue : 11
First Page : 5554
Last Page : 5565
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Chatelain E, Kaiser M, Wilkinson SR, McKenzie C, Ioset JR.
Abstract : A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against Trypanosoma cruzi intracellular amastigotes (IC(50) ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≤ IC(50) < 6.0 μM) against Trypanosoma brucei rhodesiense trypomastigotes were 5-31-fold more active against bloodstream-form Trypanosoma brucei brucei trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani . Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense bloodstream forms
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Alkynoic fatty acids inhibit topoisomerase IB from Leishmania donovani.
Year : 2012
Volume : 22
Issue : 19
First Page : 6185
Last Page : 6189
Authors : Carballeira NM, Cartagena M, Sanabria D, Tasdemir D, Prada CF, Reguera RM, Balaña-Fouce R.
Abstract : 2-Alkynoic fatty acids display antimycobacterial, antifungal, and pesticidal activities but their antiprotozoal activity has received little attention. In this work we synthesized the 2-octadecynoic acid (2-ODA), 2-hexadecynoic acid (2-HDA), and 2-tetradecynoic acid (2-TDA) and show that 2-ODA is the best inhibitor of the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) with an EC(50)=5.3±0.7μM. The potency of LdTopIB inhibition follows the trend 2-ODA>2-HDA>2-TDA, indicating that the effectiveness of inhibition depends on the fatty acid carbon chain length. All of the studied 2-alkynoic fatty acids were less potent inhibitors of the human topoisomerase IB enzyme (hTopIB) as compared to LdTopIB. 2-ODA also displayed in vitro activity against Leishmania donovani (IC(50)=11.0μM), but it was less effective against other protozoa, Trypanosoma cruzi (IC(50)=48.1μM) and Trypanosoma brucei rhodesiense (IC(50)=64.5μM). The antiprotozoal activity of the 2-alkynoic fatty acids, in general, followed the trend 2-ODA>2-HDA>2-TDA. The experimental information gathered so far indicates that 2-ODA is a promising antileishmanial compound.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms assessed as reduction in cell viability after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
9.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis.
Year : 2011
Volume : 46
Issue : 5
First Page : 1524
Last Page : 1535
Authors : Trunz BB, Jędrysiak R, Tweats D, Brun R, Kaiser M, Suwiński J, Torreele E.
Abstract : Nitroimidazoles are a well-known class of antibacterial and antiprotozoal drugs but in spite of the widespread clinical and veterinary use of these drugs, this family has been stigmatized in part due to associated genotoxicity problems. Here we report the synthesis, the anti-trypanosomal activity and a structure-activity relationship (SAR) study of a series of about fifty 1-aryl-4-nitro-1H-imidazoles, with an emphasis on selected in vivo active molecules. Compounds 4-nitro-1-{4-(trifluoromethoxy)phenyl}-1H-imidazole and 1-(3,4-dichlorophenyl)-4-nitro-1H-imidazole are curative in mouse models of both acute and chronic African trypanosomiasis when given orally at doses of 25-50 mg/kg for 4 days for the acute infection, and 50-100 mg/kg (bid) for 5 days in the chronic model. While both compounds are bacterial mutagens, activity is lost in strains lacking bacterial specific nitro-reductases. Mammalian nitro-reductases do not reduce nitroaromatic compounds with low redox potentials with same avidity as their bacterial counterparts and these compounds were shown to be devoid of genotoxicity in mammalian cells. Both compounds are promising leads for the treatment of human African trypanosomiasis (HAT or sleeping sickness), including the fatal stage 2 of the disease, for which new treatments are urgently needed.
|
Cytotoxicity against in rat L6 cells assessed as reduction in cell viability after 70 hrs by alamar blue assay
|
Rattus norvegicus
|
1.3
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : 1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis.
Year : 2011
Volume : 46
Issue : 5
First Page : 1524
Last Page : 1535
Authors : Trunz BB, Jędrysiak R, Tweats D, Brun R, Kaiser M, Suwiński J, Torreele E.
Abstract : Nitroimidazoles are a well-known class of antibacterial and antiprotozoal drugs but in spite of the widespread clinical and veterinary use of these drugs, this family has been stigmatized in part due to associated genotoxicity problems. Here we report the synthesis, the anti-trypanosomal activity and a structure-activity relationship (SAR) study of a series of about fifty 1-aryl-4-nitro-1H-imidazoles, with an emphasis on selected in vivo active molecules. Compounds 4-nitro-1-{4-(trifluoromethoxy)phenyl}-1H-imidazole and 1-(3,4-dichlorophenyl)-4-nitro-1H-imidazole are curative in mouse models of both acute and chronic African trypanosomiasis when given orally at doses of 25-50 mg/kg for 4 days for the acute infection, and 50-100 mg/kg (bid) for 5 days in the chronic model. While both compounds are bacterial mutagens, activity is lost in strains lacking bacterial specific nitro-reductases. Mammalian nitro-reductases do not reduce nitroaromatic compounds with low redox potentials with same avidity as their bacterial counterparts and these compounds were shown to be devoid of genotoxicity in mammalian cells. Both compounds are promising leads for the treatment of human African trypanosomiasis (HAT or sleeping sickness), including the fatal stage 2 of the disease, for which new treatments are urgently needed.
|
Antitrypanosomal activity against trypomastigote form of Trypanosoma brucei rhodesiense STIB 900 assessed as growth inhibition after 72 hrs by microplate fluorometry
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Conjugation of quinones with natural polyamines: toward an expanded antitrypanosomatid profile.
Year : 2012
Volume : 55
Issue : 23
First Page : 10490
Last Page : 10500
Authors : Lizzi F, Veronesi G, Belluti F, Bergamini C, López-Sánchez A, Kaiser M, Brun R, Krauth-Siegel RL, Hall DG, Rivas L, Bolognesi ML.
Abstract : A combinatorial library of quinone-polyamine conjugates designed to optimize the antitrypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid-phase approach. The conjugates were evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and several showed promising activity. A subset also inhibited trypanothione reductase in vitro and induced oxidase activity of the enzyme. A highly potent analogue (7) was identified with activity against T. brucei as low as 70 nM and a selectivity index of 72. Interestingly, the presence of a cadaverine tail confers to 7 the ability to target mitochondrial function in Leishmania. In fact, in L. donovani promastigotes, we verified for 7 a decrease of cytoplasmic ATP and mitochondrial potential. Therefore, the current results support the suitability of the conjugation approach for the development of novel polyamine conjugates with enhanced therapeutic potential.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 after 70 hrs by resazurin reduction assay
|
Trypanosoma brucei rhodesiense
|
5.5
nM
|
|
Journal : J. Med. Chem.
Title : Aminoalkyl derivatives of guanidine diaromatic minor groove binders with antiprotozoal activity.
Year : 2013
Volume : 56
Issue : 3
First Page : 700
Last Page : 711
Authors : McKeever C, Kaiser M, Rozas I.
Abstract : Considering the strong DNA minor groove binding observed for our previous series of diaromatic symmetric and asymmetric guanidinium and 2-aminoimidazolinium derivatives, we report now the synthesis of new aminoalkyl derivatives of diaromatic guanidines with potential as DNA minor groove binders and antiprotozoal activity. The preparation of these aminoalkyl derivatives (12a-e, 13a-e, 14a-c,e, 15a-e, 16a-e) is presented as well as their affinity for DNA which was evaluated by means of DNA thermal denaturation experiments. Finally, the antiprotozoal activity of most of these aminoalkyl minor groove binders was evaluated in vitro against Trypanosoma brucei rhodesiense (8 compounds) and Plasmodium falciparum (18 compounds). The O-linked derivatives 13c and 14c showed 100 nM activities against P. falciparum, whereas for T. b. rhodesiense all compounds tested showed micromolar activity. Some of the derivatives prepared seem to exert the antimalarial activity by binding to the DNA minor groove whereas other sets of compounds could exert this antimalarial activity by inhibiting the parasite dihydrofolate reductase, for example.
|
Trypanocidal activity against Trypanosoma brucei rhodesiense Z310 after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
7.8
nM
|
|
Journal : J. Med. Chem.
Title : A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro.
Year : 2013
Volume : 56
Issue : 3
First Page : 796
Last Page : 806
Authors : Zhou L, Stewart G, Rideau E, Westwood NJ, Smith TK.
Abstract : Recently, the World Health Organization approved the nifurtimox-eflornithine combination therapy for the treatment of human African trypanosomiasis, renewing interest in nitroheterocycle therapies for this and associated diseases. In this study, we have synthesized a series of novel 5-nitro-2-furancarboxylamides that show potent trypanocidal activity, ∼1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human HeLa cells. More importantly, the most potent analogue showed very limited cross-resistance to nifurtimox-resistant cells and vice versa. This implies that our novel, relatively easy to synthesize and therefore cheap, 5-nitro-2-furancarboxylamides are targeting a different, but still essential, biochemical process to those targeted by nifurtimox or its metabolites in the parasites. The significant increase in potency (smaller dose probably required) has the potential for greatly reducing unwanted side effects and also reducing the likelihood of drug resistance. Collectively, these findings have important implications for the future therapeutic treatment of African sleeping sickness.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and preliminary structure-activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds.
Year : 2013
Volume : 23
Issue : 2
First Page : 452
Last Page : 454
Authors : Liew LP, Kaiser M, Copp BR.
Abstract : Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC(50) 0.89 μM). Preliminary structure-activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC(50) 8.6 nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms incubated for 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro antimalarial testing of neocryptolepines: SAR study for improved activity by introduction and modifications of side chains at C2 and C11 on indolo[2,3-b]quinolines.
Year : 2013
Volume : 56
Issue : 4
First Page : 1431
Last Page : 1442
Authors : Mei ZW, Wang L, Lu WJ, Pang CQ, Maeda T, Peng W, Kaiser M, El Sayed I, Inokuchi T.
Abstract : To obtain a high antimalarial activity with neocryptolepine derivatives, modifying and changing the side chains at the C11 position with varying the substituents of an electron-withdrawing or electron-donating nature at the C2 position for a SAR study were executed. Installation of alkylamino and ω-aminoalkylamino groups at the C11 position of the neocryptolepine core was successful. For further variation, the aminoalkylamino substituents were transformed into the corresponding acyclic or cyclic carbamides or thiocarbamides. These side chain modified neocryptolepine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro and for cytotoxicity toward mammalian L6 cells. Among the tested compounds, the compound 17f showed an IC50 of 2.2 nM for CQS (NF54) and a selectivity index of 1400, and 17i showed an IC50 of 2.2 nM for CQR (K1), a selectivity index of 1243, and a resistance index of 0.5.
|
Antitrypanosomal activity against Trypanosoma brucei gambiense KO48 after 70 hrs by Alamar Blue assay
|
Trypanosoma brucei gambiense
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2013
Volume : 56
Issue : 7
First Page : 2850
Last Page : 2860
Authors : Hwang JY, Smithson D, Zhu F, Holbrook G, Connelly MC, Kaiser M, Brun R, Guy RK.
Abstract : We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei . Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense ) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.
|
Antitrypanosomal activity against Trypanosoma brucei gambiense DAL 898R after 70 hrs by Alamar Blue assay
|
Trypanosoma brucei gambiense
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2013
Volume : 56
Issue : 7
First Page : 2850
Last Page : 2860
Authors : Hwang JY, Smithson D, Zhu F, Holbrook G, Connelly MC, Kaiser M, Brun R, Guy RK.
Abstract : We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei . Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense ) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.
|
Antitrypanosomal activity against Trypanosoma brucei gambiense STIB930 after 70 hrs by Alamar Blue assay
|
Trypanosoma brucei gambiense
|
6.7
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2013
Volume : 56
Issue : 7
First Page : 2850
Last Page : 2860
Authors : Hwang JY, Smithson D, Zhu F, Holbrook G, Connelly MC, Kaiser M, Brun R, Guy RK.
Abstract : We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei . Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense ) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.
|
Antitrypanosomal activity against bloodstream forms of wild type Trypanosoma brucei rhodesiense STIB900 after 70 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
7.2
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2013
Volume : 56
Issue : 7
First Page : 2850
Last Page : 2860
Authors : Hwang JY, Smithson D, Zhu F, Holbrook G, Connelly MC, Kaiser M, Brun R, Guy RK.
Abstract : We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei . Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense ) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.
|
Antiparasitic activity against Trypanosoma brucei assessed as growth inhibition
|
Trypanosoma brucei
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Examination of the mode of action of the almiramide family of natural products against the kinetoplastid parasite Trypanosoma brucei.
Year : 2013
Volume : 76
Issue : 4
First Page : 630
Last Page : 641
Authors : Sanchez LM, Knudsen GM, Helbig C, De Muylder G, Mascuch SM, Mackey ZB, Gerwick L, Clayton C, McKerrow JH, Linington RG.
Abstract : Almiramide C is a marine natural product with low micromolar activity against Leishmania donovani, the causative agent of leishmaniasis. We have now shown that almiramide C is also active against the related parasite Trypanosoma brucei, the causative agent of human African trypanosomiasis. A series of activity-based probes have been synthesized to explore both the molecular target of this compound series in T. brucei lysates and site localization through epifluorescence microscopy. These target identification studies indicate that the almiramides likely perturb glycosomal function through disruption of membrane assembly machinery. Glycosomes, which are organelles specific to kinetoplastid parasites, house the first seven steps of glycolysis and have been shown to be essential for parasite survival in the bloodstream stage. There are currently no reported small-molecule disruptors of glycosome function, making the almiramides unique molecular probes for this understudied parasite-specific organelle. Additionally, examination of toxicity in an in vivo zebrafish model has shown that these compounds have little effect on organism development, even at high concentrations, and has uncovered a potential side effect through localization of fluorescent derivatives to zebrafish neuromast cells. Combined, these results further our understanding of the potential value of this lead series as development candidates against T. brucei.
|
Antitrypanosomal activity against bloodstream form Trypanosoma brucei brucei Lister 427 after 48 hrs by hemocytometer
|
Trypanosoma brucei brucei
|
6.3
nM
|
|
Journal : J. Med. Chem.
Title : Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis.
Year : 2013
Volume : 56
Issue : 10
First Page : 3820
Last Page : 3832
Authors : Patel G, Karver CE, Behera R, Guyett PJ, Sullenberger C, Edwards P, Roncal NE, Mensa-Wilmot K, Pollastri MP.
Abstract : Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 trypomastigotes after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : New Promising Compounds with in Vitro Nanomolar Activity against Trypanosoma cruzi.
Year : 2013
Volume : 4
Issue : 6
First Page : 538
Last Page : 541
Authors : Friggeri L, Scipione L, Costi R, Kaiser M, Moraca F, Zamperini C, Botta B, Di Santo R, De Vita D, Brun R, Tortorella S.
Abstract : The antiparasitic activity of azole and new 4-aminopyridine derivatives has been investigated. The imidazoles 1 and 3-5 showed a potent in vitro antichagasic activity with IC50 values in the low nanomolar concentration range. The (S)-1, (S)-3, and (S)-5 enantiomers showed (up to) a thousand-fold higher activity than the reference drug benznidazole and furthermore low cytotoxicity on rat myogenic L6 cells.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiprotozoal activity of dicationic m-terphenyl and 1,3-dipyridylbenzene derivatives.
Year : 2013
Volume : 56
Issue : 13
First Page : 5473
Last Page : 5494
Authors : Patrick DA, Ismail MA, Arafa RK, Wenzler T, Zhu X, Pandharkar T, Jones SK, Werbovetz KA, Brun R, Boykin DW, Tidwell RR.
Abstract : 4,4″-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of ≤ 3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of ≤ 10 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 bloodstream form after 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis.
Year : 2013
Volume : 66
First Page : 450
Last Page : 465
Authors : Ferrins L, Rahmani R, Sykes ML, Jones AJ, Avery VM, Teston E, Almohaywi B, Yin J, Smith J, Hyland C, White KL, Ryan E, Campbell M, Charman SA, Kaiser M, Baell JB.
Abstract : A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC₅₀ of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.
|
Antiprotozoal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by microplate fluorometry
|
Trypanosoma brucei rhodesiense
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiprotozoal activity of bicyclic diamines with a N-methylpiperazinyl group at the bridgehead atom.
Year : 2013
Volume : 21
Issue : 17
First Page : 4988
Last Page : 4996
Authors : Faist J, Seebacher W, Kaiser M, Brun R, Saf R, Weis R.
Abstract : ω-Aminoacyl and -alkyl derivatives of 4-(4-methylpiperazin-1-yl)bicyclo[2.2.2]octan-2-amines and of 5-(4-methylpiperazin-1-yl)-2-azabicyclo[3.2.2]nonanes were prepared and their activities were examined in vitro against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). Some of the newly synthesized compounds showed very promising antiprotozoal activity and selectivity. A few of the alkylamino-2-azabicyclo[3.2.2]nonanes exhibited high antiplasmodial activity, whereas a single bicyclo[2.2.2]octane derivative was the most potent antitrypanosomal compound. The results of the newly synthesized compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure-activity relationships were discussed.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
6.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiprotozoal activities of benzyl phenyl ether diamidine derivatives.
Year : 2013
Volume : 67
First Page : 310
Last Page : 324
Authors : Patrick DA, Bakunov SA, Bakunova SM, Jones SK, Wenzler T, Barszcz T, Kumar A, Boykin DW, Werbovetz KA, Brun R, Tidwell RR.
Abstract : Sixty-two cationic benzyl phenyl ether derivatives (36 amidines and 26 prodrugs) were prepared and assayed for activities in vitro and in vivo against Trypanosoma brucei rhodesiense (STIB900), and in vitro against Plasmodium falciparum (K1) and Leishmania donovani axenic amastigotes. 3-Amidinobenzyl 4-amidino-2-iodo-6-methoxyphenyl ether dihydrochloride (55, IC50 = 3.0 nM) and seven other compounds exhibited IC50 values below 10 nM against T. b. rhodesiense in vitro. The 2-bromo-4,4'-diamidino analogue 19 (IC50 = 4.0 nM) and 12 other analogues were more potent than pentamidine (IC50 = 46 nM) against P. falciparum. The 3',4-diamidino-2,6-diiodo analogue 49 (IC50 = 1.4 μM) and two other compounds were more effective than pentamidine (IC50 = 1.8 μM) against L. donovani. A prodrug, 3',4-bis(N″-methoxy)amidino-2-bromo derivative 38, was the most efficacious against trypanosome infected mice, attaining 4/4 cures in four daily 25 mg/kg oral doses, and the 2-chloro-4,4'-diamidine 18 cured 3/4 mice in four daily 5 mg/kg intraperitoneal doses.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antitrypanosomal triterpenoid with an ε-lactone E-ring from Salvia urmiensis.
Year : 2013
Volume : 76
Issue : 9
First Page : 1806
Last Page : 1809
Authors : Moridi Farimani M, Nejad Ebrahimi S, Salehi P, Bahadori MB, Sonboli A, Khavasi HR, Zimmermann S, Kaiser M, Hamburger M.
Abstract : A new triterpenoid, urmiensolide (1), was isolated from Salvia urmiensis. The structure was elucidated by a combination of 1D and 2D NMR, HRESIMS, and X-ray crystallographic analyses. The absolute configuration was established by comparison of experimental and simulated ECD spectra. Urmiensolide is the first pentacyclic triterpenoid bearing a ε-lactone E-ring. The compound showed in vitro antitrypanosoal activity with an IC₅₀ value of 5.6 μM against the Trypanosoma brucei rhodesiense STIB 900 strain and a selectivity index of 33. A possible biosynthetic pathway of 1 from α-amyrin is proposed.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense assessed as parasite growth inhibition
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Natural product derived antiprotozoal agents: synthesis, biological evaluation, and structure-activity relationships of novel chromene and chromane derivatives.
Year : 2013
Volume : 56
Issue : 18
First Page : 7442
Last Page : 7448
Authors : Harel D, Schepmann D, Prinz H, Brun R, Schmidt TJ, Wünsch B.
Abstract : Various natural products with the chromane and chromene scaffold exhibit high antiprotozoal activity. The natural product encecalin (7) served as key intermediate for the synthesis of different ethers 9, amides 11, and amines 12. The chromane analogues 14 and the phenols 15 were obtained by reductive amination of ketones 13 and 6, respectively. Angelate 3, ethers 9, and amides 11 did not show considerable antiprotozoal activity. However, the chromene and chromane derived amines 12, 14, and 15 revealed promising antiprotozoal activity and represent novel lead compounds. Whereas benzylamine 12a and α-methylbenzylamine 12g were active against P. falciparum with IC50 values in the range of chloroquine, the analogous phenols 15a and 15b were unexpectedly 10- to 25-fold more potent than chloroquine with selectivity indexes of 6760 and 1818, respectively. The phenylbutylamine 14d based on the chromane scaffold has promising activity against T. brucei rhodesiense and L. donovani.
|
Antimicrobial activity against blood stream form of Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based piperazines and 2-amino-1,3-benzothiazoles as antichagasic agents.
Year : 2013
Volume : 21
Issue : 21
First Page : 6600
Last Page : 6607
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Kaiser M, Chatelain E, Ioset JR.
Abstract : We have previously shown that 3-nitro-1H-1,2,4-triazole-based amines demonstrate significant trypanocidal activity, in particular against Trypanosoma cruzi, the causative parasite of Chagas disease. In the present work we further expanded our research by evaluating in vitro the trypanocidal activity of nitrotriazole-based piperazines and nitrotriazole-based 2-amino-1,3-benzothiazoles to establish additional SARs. All nitrotriazole-based derivatives were active or moderately active against T. cruzi; however two of them did not fulfill the selectivity criteria. Five derivatives were active or moderately active against Trypanosoma brucei rhodesiense while one derivative was moderately active against Leishmania donovani. Active compounds against T. cruzi demonstrated selectivity indexes (toxicity to host cells/toxicity to T. cruzi amastigotes) from 117 to 1725 and 12 of 13 compounds were up to 39-fold more potent than the reference compound benznidazole. Detailed SARs are discussed.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 assessed as growth inhibition after 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiprotozoal activity of dicationic 3,5-diphenylisoxazoles, their prodrugs and aza-analogues.
Year : 2014
Volume : 22
Issue : 1
First Page : 559
Last Page : 576
Authors : Patrick DA, Bakunov SA, Bakunova SM, Wenzler T, Brun R, Tidwell RR.
Abstract : Fifty novel prodrugs and aza-analogues of 3,5-bis(4-amidinophenyl)isoxazole and its derivatives were prepared. Eighteen of the 24 aza-analogues exhibited IC₅₀ values below 25 nM against Trypanosoma brucei rhodesiense or Plasmodium falciparum. Six compounds had antitrypanosomal IC₅₀ values below 10 nM. Twelve analogues showed similar antiplasmodial activities, including three with sub-nanomolar potencies. Forty-four diamidines (including 16 aza-analogues) and the 26 prodrugs were evaluated for efficacy in mice infected with T. b. rhodesiense STIB900. Six diamidines cured 4/4 mice at daily 5 mg/kg intraperitoneal doses for 4 days, giving results far superior to pentamidine and furamidine. One prodrug attained 3/4 cures at daily 25 mg/kg oral doses for 4 days.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 assessed as parasite growth inhibition after 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
3.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Activity of diimidazoline amides against African trypanosomiasis.
Year : 2014
Volume : 24
Issue : 3
First Page : 944
Last Page : 948
Authors : Dong Y, Wang X, Cal M, Kaiser M, Vennerstrom JL.
Abstract : We identified several diimidazoline mono- and diamides that were as potent as pentamidine against Trypanosoma brucei rhodesiense in vitro. All of these were also less cytotoxic than pentamidine, but none was as effective as the latter in a T. brucei rhodesiense-infected mouse model. A single imidazoline may be sufficient for high antitrypanosomal activity provided that a second weak base functional group is present.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
6.0
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 bloodstream forms of Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antiparasitic chaiyaphumines from entomopathogenic Xenorhabdus sp. PB61.4.
Year : 2014
Volume : 77
Issue : 4
First Page : 779
Last Page : 783
Authors : Grundmann F, Kaiser M, Schiell M, Batzer A, Kurz M, Thanwisai A, Chantratita N, Bode HB.
Abstract : A new class of four depsipentapeptides called chaiyaphumines A-D (1-4) was isolated from Xenorhabdus sp. PB61.4. Their structures were elucidated by detailed 1D and 2D NMR experiments and by a Marfey's analysis following flash hydrolysis of the peptide. Verification of the structure was achieved by three-dimensional modeling using NOE-derived distance constraints, molecular dynamics, and energy minimization. Chaiyaphumine A (1) showed good activity against Plasmodium falciparum (IC50 of 0.61 μM), the causative agent of malaria, and was active against other protozoal tropical disease causing agents.
|
Antimicrobial activity against trypomastigote stage of Trypanosoma brucei rhodesiense STIB900 infected in rat L6 cells after 96 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
8.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines.
Year : 2014
Volume : 81
First Page : 481
Last Page : 491
Authors : Ríos Martínez CH, Lagartera L, Kaiser M, Dardonville C.
Abstract : Two series of N-alkyl, N-alkoxy, and N-hydroxy bisguanidines derived from the N-phenylbenzamide and 1,3-diphenylurea scaffolds were synthesised in three steps from the corresponding 4-amino-N-(4-aminophenyl)benzamide and 1,3-bis(4-aminophenyl)urea, respectively. All of the new compounds were evaluated in vitro against T. b. rhodesiense (STIB900) trypomastigotes and Plasmodium falciparum NF54 parasites (erythrocytic stage). N-alkoxy and N-hydroxy derivatives showed weak micromolar range IC50 values against T. b. rhodesiense and P. falciparum whereas the N-alkyl analogues displayed submicromolar and low nanomolar IC50 values against P. falciparum and Trypanosoma brucei, respectively. Two compounds, 4-(2-ethylguanidino)-N-(4-(2-ethylguanidino)phenyl)benzamide dihydrochloride (7b) and 4-(2-isopropylguanidino)-N-(4-(2-isopropylguanidino)phenyl)benzamide dihydrochloride (7c), which showed favourable drug-like properties and in vivo efficacy (100% cures) in the STIB900 mouse model of acute human African trypanosomiasis represent interesting leads for further in vivo studies. The binding of these compounds to AT-rich DNA was confirmed by surface plasmon resonance (SPR) biosensor experiments.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes after 3 days by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antiparasitic activity of new bis-arylimidamides: DB766 analogs modified in the terminal groups.
Year : 2014
Volume : 83
First Page : 167
Last Page : 173
Authors : Liu ZY, Wenzler T, Brun R, Zhu X, Boykin DW.
Abstract : Fifteen novel bis-arylimidamide derivatives with various 6-membered (7a-c) and 5-membered (7d-o) heterocyclic rings replacing the terminal pyridyl rings of the lead compound DB766{(2,5-bis[2-i-propoxy-4-(2-pyridylimino)aminophenylfuran]}, were prepared and evaluated versus Trypanosoma cruzi, Leishmania amazonensis, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Compound 7a with pyrimidine replacing the pyridine rings showed good activity versus T. cruzi, T. brucei rhodesiense and P. falciparum (IC50 = 200 nM, 32 nM and 8.5 nM, respectively). Three compounds (7g, 7i, 7j) with thiazole replacing the pyridine rings gave low micromolar (0.17-0.3 μM) IC50 values versus L. amazonensis, however only 7g exhibited an acceptable selectivity index (SI = 27). Compounds 7a, 7j and 7m exhibited potent activity against T. brucei rhodesiense (IC50 = 12-60 nM). Ten of the 15 compounds with pyrimidine, pyrrole, thiazole and imidazole terminal units were highly active against P. falciparum (IC50 = 9-87 nM). Both pyrimidine and pyridine terminal groups are advantageous for anti-T. cruzi activity and several different heterocyclic terminal units are effective versus P. falciparum, both findings merit further investigation.
|
Antitrypanocidal activity against suramin-sensitive Trypanosoma brucei brucei Squib427 assessed as reduction in parasite growth after 72 hrs
|
Trypanosoma brucei brucei
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds.
Year : 2014
Volume : 22
Issue : 19
First Page : 5241
Last Page : 5248
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Dirié B, Lyssens S, Michiels J, Cos P, Lewi PJ, Vanham G, Maes L, Van der Veken P, Augustyns K.
Abstract : The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antitrypanocidal activity against suramin-sensitive Trypanosoma brucei rhodesiense STIB-900 assessed as reduction in parasite growth after 72 hrs
|
Trypanosoma brucei rhodesiense
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds.
Year : 2014
Volume : 22
Issue : 19
First Page : 5241
Last Page : 5248
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Dirié B, Lyssens S, Michiels J, Cos P, Lewi PJ, Vanham G, Maes L, Van der Veken P, Augustyns K.
Abstract : The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.
|
Trypanocidal activity against wild type bloodstream forms of Trypanosoma brucei brucei Lister 427 clone 221a assessed as inhibition of proliferation after 3 days by resazurin assay
|
Trypanosoma brucei brucei
|
6.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides as potential antitrypanosomal agents.
Year : 2014
Volume : 87
First Page : 79
Last Page : 88
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Kaiser M.
Abstract : We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.
|
Trypanocidal activity against bloodstream forms of Trypanosoma brucei brucei Lister 427 clone 221a overexpressing type I nitroreductase assessed as inhibition of proliferation after 3 days by resazurin assay in absence of tetracycline
|
Trypanosoma brucei brucei
|
3.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides as potential antitrypanosomal agents.
Year : 2014
Volume : 87
First Page : 79
Last Page : 88
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Kaiser M.
Abstract : We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.
|
Trypanocidal activity against bloodstream forms of Trypanosoma brucei brucei Lister 427 clone 221a overexpressing type I nitroreductase assessed as inhibition of proliferation after 3 days by resazurin assay in presence of tetracycline
|
Trypanosoma brucei brucei
|
3.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides as potential antitrypanosomal agents.
Year : 2014
Volume : 87
First Page : 79
Last Page : 88
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Kaiser M.
Abstract : We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigote forms
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antitrypanosomal quinoline alkaloids from the roots of Waltheria indica.
Year : 2014
Volume : 77
Issue : 10
First Page : 2304
Last Page : 2311
Authors : Cretton S, Breant L, Pourrez L, Ambuehl C, Marcourt L, Ebrahimi SN, Hamburger M, Perozzo R, Karimou S, Kaiser M, Cuendet M, Christen P.
Abstract : Chemical investigation of the dichloromethane root extract of Waltheria indica led to the isolation and characterization of 10 quinoline alkaloids, namely, 8-deoxoantidesmone (1), waltheriones E-L (2-9), and antidesmone (10). Among these, compounds 2-9 have not yet been described in the literature. Their chemical structures were established by means of spectroscopic data interpretation including (1)H and (13)C NMR, HSQC, HMBC, COSY, and NOESY experiments and UV, IR, and HRESIMS. The absolute configurations of the compounds were established by comparison of experimental and TDDFT-calculated ECD spectra. In addition, the isolated constituents were evaluated for their in vitro antitrypanosomal activity. Compounds 4, 5, and 8 showed potent and selective growth inhibition toward Trypanosoma cruzi with IC50 values between 0.02 and 0.04 μM. Cytotoxicity for mouse skeletal L-6 cells was also determined for these compounds.
|
Antiplasmodial activity against Trypanosoma brucei rhodesiense assessed as growth inhibition
|
Trypanosoma brucei rhodesiense
|
3.0
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.
|
Antiprotozoan activity against Trypanosoma brucei rhodesiense STIB 900 trypomastigotes
|
Trypanosoma brucei rhodesiense
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hydroxamic acid based histone deacetylase inhibitors with confirmed activity against the malaria parasite.
Year : 2015
Volume : 25
Issue : 3
First Page : 459
Last Page : 461
Authors : Giannini G, Battistuzzi G, Vignola D.
Abstract : Recent studies have highlighted a key role in regulating gene transcription, in both eukaryotes and prokaryotes, by enzymes that control the acetylation and deacetylation of histones. In particular, inhibitors of histone deacetylases (HDAC-Is) have been shown effective in controlling the development of many parasites, such as the plasmodium of malaria. Here we report the results of a study aimed at evaluating antiparasitic effect of two classes of HDAC-Is bearing different zinc binding group (hydroxamic acid vs thiol). The study showed that only the hydroxamic acid based HDAC inhibitors were active, with Plasmodium falciparum being the most sensitive parasite, having from low double-digit to single-digit nanomolar range in vitro activities. Among three derivatives evaluated also in vivo, ST8086AA1 (8) effectively inhibited 88% of the development of Plasmodium falciparum.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Xenortide Biosynthesis by Entomopathogenic Xenorhabdus nematophila.
Year : 2014
Volume : 77
Issue : 8
First Page : 1976
Last Page : 1980
Authors : Reimer D, Nollmann FI, Schultz K, Kaiser M, Bode HB.
Abstract : The biosynthesis gene cluster of the xenortides and a new derivative, xenortide D, which is produced in only trace amounts, was identified in Xenorhabdus nematophila. The structure of xenortide D was elucidated using a combination of labeling experiments followed by MS analysis and was confirmed by synthesis. Bioactivity tests revealed a weak activity of tryptamine-carrying xenortides against Plasmodium falciparum and Trypanosoma brucei.
|
Antimicrobial activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
0.002
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.
|
Antiprotozoal activity against bloodstream forms of Trypanosoma brucei rhodesiense STIB 900 after 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-trypanosomal cadinanes synthesized by transannular cyclization of the natural sesquiterpene lactone nobilin.
Year : 2015
Volume : 23
Issue : 7
First Page : 1521
Last Page : 1529
Authors : De Mieri M, Kaiser M, Brun R, Thormann U, Imanidis G, Hamburger M.
Abstract : Acid-catalyzed transannular cyclization of the germacrene-type sesquiterpene lactone nobilin 1 was investigated with the aim of obtaining new anti-trypanosomal cadinane derivatives. The reaction was regiospecific in all tested reaction conditions. Compounds were fully characterized by spectroscopic and computational methods, and the anti-trypanosomal activity was evaluated and compared to nobilin (IC50 3.19±1.69μM). The tricyclic derivative 11 showed most potent in vitro activity against Trypanosoma brucei rhodesiense bloodstream forms (IC50 0.46±0.01μM). Acid-catalyzed transannular cyclization of natural cyclodecadienes is an efficient strategy to generate new natural product derivatives with anti-protozoal activity.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities.
Year : 2015
Volume : 25
Issue : 7
First Page : 1390
Last Page : 1393
Authors : Seebacher W, Wolkinger V, Faist J, Kaiser M, Brun R, Saf R, Bucar F, Gröblacher B, Brantner A, Merino V, Kalia Y, Scapozza L, Perozzo R, Weis R.
Abstract : Several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. The new compounds were tested for their activities against one strain of the causative organism of Malaria tropica, Plasmodium falciparum K1, which is resistant against chloroquine and pyrimethamine. In addition, their cytotoxicity and their activity against the pathogen of the East African form of sleeping sickness, Trypanosoma brucei rhodesiense, were investigated. Structure-activity relationships are discussed considering data of readily prepared compounds. For the first time, a distinct in vivo activity was observed against Plasmodium berghei in a mouse model. The active compound was further investigated.
|
Antitrypanosomal activity against trypomastigote stage of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents.
Year : 2015
Volume : 58
Issue : 3
First Page : 1307
Last Page : 1319
Authors : Papadopoulou MV, Bloomer WD, Lepesheva GI, Rosenzweig HS, Kaiser M, Aguilera-Venegas B, Wilkinson SR, Chatelain E, Ioset JR.
Abstract : 3-Nitro-1H-1,2,4-triazole-based amides with a linear, rigid core and 3-nitrotriazole-based fluconazole analogues were synthesized as dual functioning antitrypanosomal agents. Such compounds are excellent substrates for type I nitroreductase (NTR) located in the mitochondrion of trypanosomatids and, at the same time, act as inhibitors of the sterol 14α-demethylase (T. cruzi CYP51) enzyme. Because combination treatments against parasites are often superior to monotherapy, we believe that this emerging class of bifunctional compounds may introduce a new generation of antitrypanosomal drugs. In the present work, the synthesis and in vitro and in vivo evaluation of such compounds is discussed.
|
Antiprotozoal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 trypomastigote by alamar-blue assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Antiprotozoal activity and DNA binding of dicationic acridones.
Year : 2015
Volume : 58
Issue : 4
First Page : 1940
Last Page : 1949
Authors : Montalvo-Quirós S, Taladriz-Sender A, Kaiser M, Dardonville C.
Abstract : Dicationic acridone derivatives were synthesized and their antiparasitic activity was evaluated. Acridones displayed in vitro nanomolar IC50 values against Trypanosoma brucei rhodesiense STIB900 with selectivity indices >1000. Compounds 1b, 3a, and 3b were as potent as the reference drug melarsoprol in this assay. Submicromolar-range activities were observed against wild-type (NF54) and resistant (K1) strains of Plasmodium falciparum, whereas no significant activity was detected against Trypanosoma cruzi or Leishmania donovani. Compounds 1a and 1b were curative in the STIB900 mouse model for human African trypanosomiasis. UV spectrophotometric titrations and circular dichroism (CD) experiments with fish sperm (FS) DNA showed that these compounds form complexes with DNA with binding affinities in the 10(4) M(-1) range. Biological and biophysical data show that antiparasitic activity, toxicity, and DNA binding of this series of acridones are dependent on the relative position of both imidazolinium cations on the heterocyclic scaffold.
|
Antitrypanosomal activity against bloodstream forms of Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile.
Year : 2015
Volume : 58
Issue : 16
First Page : 6422
Last Page : 6434
Authors : Prati F, Bergamini C, Molina MT, Falchi F, Cavalli A, Kaiser M, Brun R, Fato R, Bolognesi ML.
Abstract : A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases.
|
Antiparasitic activity against trypomastigote stage of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation.
Year : 2015
Volume : 23
Issue : 19
First Page : 6467
Last Page : 6476
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, O'Shea IP, Wilkinson SR, Kaiser M, Chatelain E, Ioset JR.
Abstract : 3-Nitro-1H-1,2,4-triazole- and 2-nitro-1H-imidazole-based amides with an aryloxy-phenyl core were synthesized and evaluated as antitrypanosomal agents. All 3-nitrotriazole-based derivatives were extremely potent anti-Trypanosoma cruzi agents at sub nM concentrations and exhibited a high degree of selectivity for the parasite. The 2-nitroimidazole analogs were only moderately active against T. cruzi amastigotes and exhibited low selectivity. Both types of compound were active against Leishmania donovani axenic amastigotes with excellent selectivity for the parasite, whereas three 2-nitroimidazole-based analogs were also moderately active against infected macrophages. However, no compound demonstrated selective activity against Trypanosoma brucei rhodesiense. The most potent in vitro anti-T. cruzi compounds were tested in an acute murine model and reduced the parasites to an undetectable level after five days of treatment at 13 mg/kg/day. Such compounds are potential inhibitors of T. cruzi CYP51 and, being excellent substrates for the type I nitroreductase (NTR) which is specific to trypanosomatids, work as prodrugs and constitute a new generation of effective and more affordable antitrypanosomal agents.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 assessed as growth inhibition after 70 hrs by resazurin dye-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : MedChemComm
Title : Synthesis and evaluation of phenoxymethylbenzamide analogues as anti-trypanosomal agents
Year : 2015
Volume : 6
Issue : 3
First Page : 403
Last Page : 406
Authors : Manos-Turvey A, Watson EE, Sykes ML, Jones AJ, Baell JB, Kaiser M, Avery VM, Payne RJ
|
Antitrypanosomal activity against bloodstream trypomastigote forms of Trypanosoma brucei rhodesiense STIB 900 assessed as inhibition of growth
|
Trypanosoma brucei rhodesiense
|
9.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents.
Year : 2015
Volume : 103
First Page : 325
Last Page : 334
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, O'Shea IP, Wilkinson SR, Kaiser M.
Abstract : Novel linear 3-nitro-1H-1,2,4-triazole-based piperazides were synthesized and evaluated as antitrypanosomal agents. In addition, some bisarylpiperazine-ethanones which were formed as by-products were also screened for antiparasitic activity. Most 3-nitrotriazole-based derivatives were potent and selective against Trypanosoma cruzi parasites, but only one displayed these desired properties against Trypanosoma brucei rhodesiense. Moreover, two 3-nitrotriazole-based chlorophenylpiperazides were moderately and selectively active against Leishmania donovani. Although the bisarylpiperazine-ethanones were active or moderately active against T. cruzi, none of them demonstrated an acceptable selectivity. In general, 3-nitrotriazole-based piperazides were less toxic to host L6 cells than the previously evaluated 3-nitrotriazole-based piperazines and seven of 13 were 1.54- to 31.2-fold more potent antichagasic agents than the reference drug benznidazole. Selected compounds showed good ADMET characteristics. One potent in vitro antichagasic compound (3) was tested in an acute murine model and demonstrated antichagasic activity after a 10-day treatment of 15 mg/kg/day. However, neither compound 3 nor benznidazole showed a statistically significant P value compared to control due to high variability in parasite burden among the untreated animals. Working as prodrugs, 3-nitrotriazole-based piperazides were excellent substrates of trypanosomal type I nitroreductases and constitute a novel class of potentially effective and more affordable antitrypanosomal agents.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
51.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes.
Year : 2016
Volume : 108
First Page : 347
Last Page : 353
Authors : Bhambra AS, Edgar M, Elsegood MR, Li Y, Weaver GW, Arroo RR, Yardley V, Burrell-Saward H, Krystof V.
Abstract : Current treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 < 1 μM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 trypomastigotes assessed as inhibition of parasite growth after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
9.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds.
Year : 2016
Volume : 117
First Page : 179
Last Page : 186
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Szular J, Kaiser M.
Abstract : A small series of 5-nitro-2-aminothiazole-based amides containing arylpiperazine-, biphenyl- or aryloxyphenyl groups in their core were synthesized and evaluated as antitrypanosomatid agents. All tested compounds were active or moderately active against Trypanosoma cruzi amastigotes in infected L6 cells and Trypanosoma brucei brucei, four of eleven compounds were moderately active against Leishmania donovani axenic parasites while none were deemed active against T. brucei rhodesiense. For the most active/moderately active compounds a moderate selectivity against each parasite was observed. There was good correlation between lipophilicity (clogP value) and antileishmanial activity or toxicity against L6 cells. Similarly, good correlation existed between clogP values and IC50 values against T. cruzi in structurally related subgroups of compounds. Three compounds were more potent as antichagasic agents than benznidazole but were not activated by the type I nitrorectusase (NTR).
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 bloodstream forms after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiprotozoal activity of bicycles featuring a dimethylamino group at their bridgehead.
Year : 2016
Volume : 24
Issue : 16
First Page : 3781
Last Page : 3789
Authors : Faist J, Seebacher W, Saf R, Brun R, Kaiser M, Weis R.
Abstract : Several dimethylamino-derivatives of the new compound-class 3-azabicyclo[3.2.2]nonanes were prepared. For better comparison of activity also a few analogues of bicyclo[2.2.2]octanes and 2-azabicyclo[3.2.2]nonanes were synthesized. Their activities were examined in vitro against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). A couple of the newly synthesized compounds showed promising antiprotozoal activity and selectivity. The results of the biological tests of the novel compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure-activity relationships were discussed.
|
Antiparasitic activity against bloodstream forms of Trypanosoma brucei rhodesiense STIB 900 assessed as growth inhibition after 72 hrs by resazurin assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and potent antiprotozoal activity of mono/di amidino 2-anilinobenzimidazoles versus Plasmodium falciparum and Trypanosoma brucei rhodesiense.
Year : 2016
Volume : 24
Issue : 18
First Page : 4038
Last Page : 4044
Authors : Karaaslan C, Kaiser M, Brun R, Göker H.
Abstract : A series of mono and dicationic new 2-anilinobenzimidazole carboxamidines were prepared in a four step process starting from 4-amino-3-nitrobenzonitrile and corresponding o-phenylenediamines. Their antiparasitic activity against Plasmodium falciparum (P. falciparum) and Trypanosoma brucei rhodesiense (T.b. rhodesiense) were evaluated in vitro. Some of the dicationic compounds (10,12,14) showed equal or very close activity against T.b. rhodesiense with melarsoprol and also showed promising activity against P. falciparum as compared to chloroquine. Among the monocationic derivatives compound 21 exhibited best inhibitory activity against P. falciparum.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms isolated from patient after 70 hrs by microplate alamar blue assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Bioorg Med Chem
Title : New derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity.
Year : 2017
Volume : 25
Issue : 3
First Page : 941
Last Page : 948
Authors : Faist J, Hinteregger C, Seebacher W, Saf R, Mäser P, Kaiser M, Weis R.
Abstract : Novel ω-aminoacyl and -alkyl derivatives of 7-chloroquinolin-4-amine were prepared and their structures confirmed by NMR spectroscopy. Their antiprotozoal activities were examined in vitro against the sensitive NF54 strain as well as against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results were compared with the activities of clinically used drugs. Their antitrypanosomal activities were only moderate whereas their antiplasmodial activities looked very promising. Some were equal or slightly more active than chloroquine against the sensitive strain. However, in comparison to chloroquine, the activity of the new compounds was decreased much less in the resistant strain. Several possessed activity against both strains in low nanomolar concentration.
|
Antitrypanosomal activity against bloodstream forms of Trypanosoma brucei rhodesiense STIB900 trypomastigotes after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and activity of nucleoside-based antiprotozoan compounds.
Year : 2017
Volume : 25
Issue : 7
First Page : 2091
Last Page : 2104
Authors : Tran HA, Zheng Z, Wen X, Manivannan S, Pastor A, Kaiser M, Brun R, Snyder FF, Back TG.
Abstract : Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas' disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50=110nM and SI=1010, while a modified guanosine displayed potent activities against L. donovani (IC50=60nM, SI=2720) and T. brucei (IC50=130nM, SI=1250), as well as moderate activity against T. cruzi (IC50=3.4µM, SI=48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and antitrypanosomal activities of novel pyridylchalcones.
Year : 2017
Volume : 128
First Page : 213
Last Page : 218
Authors : Bhambra AS, Ruparelia KC, Tan HL, Tasdemir D, Burrell-Saward H, Yardley V, Beresford KJM, Arroo RRJ.
Abstract : A library of novel pyridylchalcones were synthesised and screened against Trypanosoma brucei rhodesiense. Eight were shown to have good activity with the most potent 8 having an IC50 value of 0.29 μM. Cytotoxicity testing with human KB cells showed a good selectivity profile for this compound with a selectivity index of 47. Little activity was seen when the library was tested against Leishmania donovani. In conclusion, pyridylchalcones are promising leads in the development of novel compounds for the treatment of human African trypanosomiasis (HAT).
|
Antiprotozoal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J Nat Prod
Title : Antiprotozoal Activity-Based Profiling of a Dichloromethane Extract from Anthemis nobilis Flowers.
Year : 2017
Volume : 80
Issue : 2
First Page : 459
Last Page : 470
Authors : De Mieri M, Monteleone G, Ismajili I, Kaiser M, Hamburger M.
Abstract : A dichlomethane extract of Anthemis nobilis flower cones showed promising in vitro antiprotozoal activity against Trypanosoma brucei rhodesiense and Leishmania donovani, with IC50 values of 1.43 ± 0.50 and 1.40 ± 0.07 μg/mL, respectively. A comprehensive profiling of the most active fractions afforded 19 sesquiterpene lactones, including 15 germacranolides, two seco-sesquiterpenes, one guaianolide sesquiterpene lactone, and one cadinane acid. Of these, 13 compounds were found to be new natural products. The compounds were characterized by extensive spectroscopic data analysis (1D and 2D NMR, HRMS, circular dichroism) and computational methods, and their in vitro antiprotozoal activity was evaluated. The furanoheliangolide derivative 15 showed high potency and selectivity in vitro against T. b. rhodesiense bloodstream forms (IC50 0.08 ± 0.01 μM; SI 63). In silico calculations were consistent with the drug-like properties of 15.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
4.0
nM
|
|
Journal : J Med Chem
Title : 2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.
Year : 2018
Volume : 61
Issue : 8
First Page : 3370
Last Page : 3388
Authors : Giroud M, Kuhn B, Saint-Auret S, Kuratli C, Martin RE, Schuler F, Diederich F, Kaiser M, Brun R, Schirmeister T, Haap W.
Abstract : Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 2 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
180.0
nM
|
|
Journal : J Med Chem
Title : 2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.
Year : 2018
Volume : 61
Issue : 8
First Page : 3370
Last Page : 3388
Authors : Giroud M, Kuhn B, Saint-Auret S, Kuratli C, Martin RE, Schuler F, Diederich F, Kaiser M, Brun R, Schirmeister T, Haap W.
Abstract : Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 6 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
99.0
nM
|
|
Journal : J Med Chem
Title : 2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.
Year : 2018
Volume : 61
Issue : 8
First Page : 3370
Last Page : 3388
Authors : Giroud M, Kuhn B, Saint-Auret S, Kuratli C, Martin RE, Schuler F, Diederich F, Kaiser M, Brun R, Schirmeister T, Haap W.
Abstract : Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 16 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
86.0
nM
|
|
Journal : J Med Chem
Title : 2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.
Year : 2018
Volume : 61
Issue : 8
First Page : 3370
Last Page : 3388
Authors : Giroud M, Kuhn B, Saint-Auret S, Kuratli C, Martin RE, Schuler F, Diederich F, Kaiser M, Brun R, Schirmeister T, Haap W.
Abstract : Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 24 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
44.0
nM
|
|
Journal : J Med Chem
Title : 2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.
Year : 2018
Volume : 61
Issue : 8
First Page : 3370
Last Page : 3388
Authors : Giroud M, Kuhn B, Saint-Auret S, Kuratli C, Martin RE, Schuler F, Diederich F, Kaiser M, Brun R, Schirmeister T, Haap W.
Abstract : Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB 900 assessed as parasite growth inhibition after 48 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
26.0
nM
|
|
Journal : J Med Chem
Title : 2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.
Year : 2018
Volume : 61
Issue : 8
First Page : 3370
Last Page : 3388
Authors : Giroud M, Kuhn B, Saint-Auret S, Kuratli C, Martin RE, Schuler F, Diederich F, Kaiser M, Brun R, Schirmeister T, Haap W.
Abstract : Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
|
Antiprotozoal activity against patient derived Trypanosoma brucei rhodesiense STIB 900 bloodstream form after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : J Nat Prod
Title : Dioncophyllines C2, D2, and F and Related Naphthylisoquinoline Alkaloids from the Congolese Liana Ancistrocladus ileboensis with Potent Activities against Plasmodium falciparum and against Multiple Myeloma and Leukemia Cell Lines.
Year : 2017
Volume : 80
Issue : 2
First Page : 443
Last Page : 458
Authors : Li J, Seupel R, Feineis D, Mudogo V, Kaiser M, Brun R, Brünnert D, Chatterjee M, Seo EJ, Efferth T, Bringmann G.
Abstract : Dioncophylline F (1), the first 5,8'-coupled dioncophyllaceous alkaloid (i.e., lacking an oxygen function at C-6 and possessing an R-configuration at C-3), was isolated from the recently described Congolese liana Ancistrocladus ileboensis. Two further, likewise Dioncophyllaceae-type, alkaloids, the dioncophyllines C2 (2) and D2 (3), were identified, along with the Ancistrocladaceae-type compound ancistrocladisine B (4), which is oxygenated at C-6 and S-configured at C-3. The structures of the new compounds were determined by spectroscopic, chemical, and chiroptical methods. The stereostructure of 1 was further confirmed by total synthesis. As a consequence of the lack of a methyl group ortho to their biaryl axes, both dioncophylline F (1) and the 7,8'-coupled dioncophylline D2 (3) occur as pairs of configurationally semistable and, thus, slowly interconverting atropo-diastereomers, whereas dioncophylline C2 (2), with its 5,1'-linkage, is configurationally stable at the axis. Eight further known naphthylisoquinolines were isolated from A. ileboensis, among them dioncophylline A (P-10), its 4'-O-demethyl analogue P-11, and 5'-O-methyldioncophylline D (7), which were found to display strong cytotoxic activities against multiple myeloma INA-6 cells (P-10 even stronger than the standard drug melphalan) and against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant subline, CEM/ADR5000. Moreover, the dioncophyllines 1, 3, and 7 showed high-and specific-activities against the malaria parasite Plasmodium falciparum.
|
Antitrypanosomal activity against blood stream form of Trypanosoma brucei rhodesiense STIB900 trypomastigotes after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
8.0
nM
|
|
Journal : Eur J Med Chem
Title : The antitrypanosomal and antitubercular activity of some nitro(triazole/imidazole)-based aromatic amines.
Year : 2017
Volume : 138
First Page : 1106
Last Page : 1113
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Kaiser M.
Abstract : A limited number of novel 3-nitrotriazole- and 2-nitroimidazole-linked quinolines and quinazolines were synthesized and screened for in vitro antitrypanosomal and antitubercular activities as well as cytotoxicity in normal cells. All compounds were active against T. cruzi amastigotes, while all but one were active or moderately active against T. b. rhodesiense. However, only two chloroquinolines exhibited satisfactory selectivity indices (SI) against T. cruzi and only one of them demonstrated a satisfactory SI against T. b. rhodesiense. All tested compounds demonstrated a Minimum Inhibitory Concentration (MIC) ≥ 200 μM against aerobic Mtb. However, the 2-nitroimidazole-based analogs were active against hypoxic Mtb with MIC values 2.89-9.18 μM. The present data support our previous observations that 2-nitroimidazole-based aromatic amines are selectively active against nonreplicating Mtb, while 3-nitrotriazole-based aromatic amines are potent antichagasic agents.
|
Antiprotozoal activity against blood stream form of Trypanosoma brucei rhodesiense STIB900 after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
15.0
nM
|
|
Journal : J Nat Prod
Title : Antiprotozoal Linear Furanosesterterpenoids from the Marine Sponge Ircinia oros.
Year : 2017
Volume : 80
Issue : 9
First Page : 2566
Last Page : 2571
Authors : Chianese G, Silber J, Luciano P, Merten C, Erpenbeck D, Topaloglu B, Kaiser M, Tasdemir D.
Abstract : Chemical investigation of the marine sponge Ircinia oros yielded four linear furanosesterterpenoids, including the known metabolites ircinin-1 (1) and ircinin-2 (2) and two new compounds, ircinialactam E (3) and ircinialactam F (4). Their chemical structures were elucidated by using a combination of [α]D, NMR, HRMS, and FT-IR spectroscopy. The absolute configuration of C-18 in compounds 1-3 was identified as R by electronic circular dichroism (ECD) spectroscopy coupled with time-dependent density functional theory calculations. Compounds 1-4 showed moderate leishmanicidal, trypanocidal, and antiplasmodial activities (IC50 values 28-130 μM). This is the second report of rare glycinyl lactam derivatives 3 and 4 from the genus Ircinia.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense bloodstream forms after 72 hrs by alamar blue staining based fluorescence assay
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : J Nat Prod
Title : Jozilebomines A and B, Naphthylisoquinoline Dimers from the Congolese Liana Ancistrocladus ileboensis, with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line.
Year : 2017
Volume : 80
Issue : 10
First Page : 2807
Last Page : 2817
Authors : Li J, Seupel R, Bruhn T, Feineis D, Kaiser M, Brun R, Mudogo V, Awale S, Bringmann G.
Abstract : Two new naphthylisoquinoline dimers, jozilebomines A (1a) and B (1b), were isolated from the roots of the Congolese plant Ancistrocladus ileboensis, along with the known dimer jozimine A2 (2). These compounds are Dioncophyllaceae-type metabolites, i.e., lacking oxygen functions at C-6 and with an R-configuration at C-3 in their tetrahydroisoquinoline moieties. The dimers 1a and 1b consist of two 7,1'-coupled naphthylisoquinoline monomers linked through an unprecedented 3',6″-coupling in the binaphthalene core and not, as in 2, via the C-3-positions of the two naphthalene units. Thus, different from the C2-symmetric jozimine A2 (2), the new jozilebomines are constitutionally unsymmetric. The central biaryl axis of each of the three dimers is rotationally hindered, so that 1a, 1b, and 2 possess three consecutive chiral axes. The two jozilebomines have identical constitutions and the same absolute configurations at all four stereogenic centers, but differ from each other in their axial chirality. Their structural elucidation was achieved by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and calculated ECD data. They exhibited distinct and specific antiplasmodial activities. All dimers showed potent cytotoxicity against HeLa human cervical cancer cells and preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions. Furthermore, these dimers significantly inhibited the colony formation of PANC-1 cells, even when exposed to noncytotoxic concentration for a short time. Jozilebomines A (1a) and B (1b) and jozimine A2 (2) represent novel potential candidates for future drug development against pancreatic cancer.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB 900 bloodstream forms after 72 hrs by alamar blue staining based fluorescence assay
|
Trypanosoma brucei rhodesiense
|
3.0
nM
|
|
Journal : J Nat Prod
Title : Antiprotozoal Sesquiterpene Lactones and Other Constituents from Tarchonanthus camphoratus and Schkuhria pinnata.
Year : 2018
Volume : 81
Issue : 1
First Page : 124
Last Page : 130
Authors : Kimani NM, Matasyoh JC, Kaiser M, Brun R, Schmidt TJ.
Abstract : In continuation of a search for new antiprotozoal agents from plants of the family Asteraceae, Tarchonanthus camphoratus and Schkuhria pinnata have been investigated. By following the promising in vitro activity of the dichloromethane extracts from their aerial parts, bioassay-guided chromatographic isolation yielded two known sesquiterpene lactones (1 and 2) from T. camphoratus and 20 known compounds of this type from S. pinnata. From the latter, a new eudesmanolide, (1R*,5S*,6R*,7R*,8R*,10R*)-1-hydroxy-8-[5″-hydroxy-4'-(2″-hydroxyisovaleroyloxy)tigloyloxy]-3-oxoeudesma-11(13)-en-6,12-olide (3), and two new germacranolides, 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)costunolide (14) and 1(10)-epoxy-3β-hydroxy-8β-[5'-hydroxy-4'-(2″-hydroxyisovaleroyloxy)tigloyloxy]costunolide (16), were obtained. Additionally, the flavonoid pectolinarigenin (24) and 3-hydroxy-4,5-dimethoxybenzenepropanol (25) were also isolated from S. pinnata. The compounds were characterized by analysis of 1D and 2D NMR spectroscopic and HR/MS data. In vitro antitrypanosomal activity and cytotoxicity against mammalian cells (L6 cell line) were evaluated for all the compounds. Santhemoidin A (13) and 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)costunolide (14) were the most active compounds found in this study, with IC50 values of 0.10 and 0.13 μM against Trypanosoma brucei rhodesiense trypomastigotes and selectivity indices of 20.5 and 29.7, respectively.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms after 70 hrs by Alamar blue staining-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of new 1-benzyl tetrahydropyridinylidene ammonium salts and their antimicrobial and anticellular activities.
Year : 2018
Volume : 143
First Page : 97
Last Page : 106
Authors : Mohsin NU, Seebacher W, Faist J, Hochegger P, Kaiser M, Mäser P, Belaj F, Saf R, Kretschmer N, Alajlani M, Turek I, Brantner A, Bauer R, Bucar F, Weis R.
Abstract : A series of N-benzyl tetrahydropiperidinylidene pyrrolidinium salts have been synthesized and investigated for their antiplasmodial and antitrypanosomal activities as well as for their cytotoxic effects. The antibacterial, antimycobacterial and anticancer potencies of selected compounds were examined, too. Physicochemical parameters were calculated and structure-activity-relationships are discussed.
|
Antitrypanosomal activity against suramin-sensitive Trypanosoma brucei brucei Squib 427 after 72 hrs by resazurin dye-based fluorometric method
|
Trypanosoma brucei brucei
|
30.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel triazine dimers with potent antitrypanosomal activity.
Year : 2018
Volume : 143
First Page : 306
Last Page : 319
Authors : Venkatraj M, Salado IG, Heeres J, Joossens J, Lewi PJ, Caljon G, Maes L, Van der Veken P, Augustyns K.
Abstract : Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds active against these neglected tropical diseases prompted us to investigate antitrypanosomal activity of triazine dimers. Optimization of the triazine dimers resulted in 3,3'-(((ethane-1,2-diylbis(azanediyl))bis(4-(mesityloxy)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile (compound 38), a compound with very potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB-900 after 72 hrs by resazurin dye-based fluorometric method
|
Trypanosoma brucei rhodesiense
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel triazine dimers with potent antitrypanosomal activity.
Year : 2018
Volume : 143
First Page : 306
Last Page : 319
Authors : Venkatraj M, Salado IG, Heeres J, Joossens J, Lewi PJ, Caljon G, Maes L, Van der Veken P, Augustyns K.
Abstract : Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds active against these neglected tropical diseases prompted us to investigate antitrypanosomal activity of triazine dimers. Optimization of the triazine dimers resulted in 3,3'-(((ethane-1,2-diylbis(azanediyl))bis(4-(mesityloxy)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile (compound 38), a compound with very potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms after 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
10.0
nM
|
|
Journal : J Nat Prod
Title : Phytochemical Study of Salvia leriifolia Roots: Rearranged Abietane Diterpenoids with Antiprotozoal Activity.
Year : 2018
Volume : 81
Issue : 6
First Page : 1384
Last Page : 1390
Authors : Farimani MM, Khodaei B, Moradi H, Aliabadi A, Ebrahimi SN, De Mieri M, Kaiser M, Hamburger M.
Abstract : Phytochemical investigation of the lipophilic extract of the roots of Salvia leriifolia resulted in the isolation of the new rearranged abietane diterpenoids leriifoliol (1) and leriifolione (2), together with 10 known diterpenoids. Structure elucidations were performed via extensive NMR and HRESIMS data, and the absolute configurations of compounds 1 and 3-5 were established by evaluation of experimental and calculated ECD spectra. The antiplasmodial activity of the new isolates was assayed against Trypanosoma brucei rhodesiense, T. cruzi, Plasmodium falciparum, and Leishmania donovani and also toxicity against rat myoblast (L6) cells. Compound 1 displayed antimalarial and low cytotoxic activity with IC50 values of 0.4 and 33.6 μM, respectively, and a selectivity index of 84. Compound 2 displayed activity against T. brucei, T. cruzi, and L. donovani, with IC50 values of 1.0, 4.6, and 1.0 μM, respectively. Putative biosynthetic pathways toward the formation of 1, 2, and 3 are proposed. Leriifoliol (1) is the first 20- nor-9,10- seco-abietane, while 2 exhibits an uncommon 6-6-5 fused-ring system.
|
Antitrypanosomal activity against Trypanosoma brucei gambiense GUTat 3.1 after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei gambiense
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of proline derived benzenesulfonamides: A potent anti-Trypanosoma brucei gambiense agent.
Year : 2018
Volume : 154
First Page : 110
Last Page : 116
Authors : Ugwu DI, Okoro UC, Mishra NK.
Abstract : Thousands of death in Africa and other developing nations are still attributed to trypanosomiasis. Excessive sleep has been associated with increased inflammation. We report herein, the synthesis, antitrypanosomal and anti-inflammatory activities of eight new carboxamide derivatives bearing substituted benzenesulfonamides. The base promoted reactions of l-proline and L-4-hydroxyproline with substituted benzenesulfonyl chlorides gave the benzenesulfonamides (11a-h) in excellent yields. Boric acid mediated amidation of the benzenesulfonamides (11a-h) and p-aminobenzoic acid (12) gave the new carboxamides (13a-h) in excellent yields. The new carboxamides were tested for their antitrypanosomal and anti-inflammatory activities against Trypanosome brucei gambiense and inhibition of carrageenan-induced rat paw edema. Compound 13f was the most potent antitrypanosomal agent with an IC50 value of 2 nM as against 5 nM for melarsoprol; whereas compound 13a was the most potent anti-inflammatory agent with percentage inhibition of carrageenan-induced rat paw edema of 58, 60, 67 and 84% after 0.5 h, 1 h, 2 h and 3 h administration respectively. The structure-activity relationship study revealed that substitution at the para position in the benzenesulfonamide ring increased both the antitrypanosomal and anti-inflammatory activities. The 4-hydroxyprolines (13a-d) showed higher anti-inflammatory activity than the prolines (13e-h). In contrast, the prolines (13e-h) had higher antitrypanosomal activities than the 4-hydroxyprolines. The link between excessive sleep and inflammation makes the report of this class of compounds possessing both antitrypanosomal and anti-inflammatory activity worthwhile. The pharmacokinetic studies showed that the compounds would not pose oral bioavailability, transport and permeability problems.
|
Antiplasmodial activity against Trypanosoma brucei rhodesiense STIB 900 trypomastigote after 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : J Nat Prod
Title : Mbandakamine-Type Naphthylisoquinoline Dimers and Related Alkaloids from the Central African Liana Ancistrocladus ealaensis with Antiparasitic and Antileukemic Activities.
Year : 2018
Volume : 81
Issue : 4
First Page : 918
Last Page : 933
Authors : Tshitenge DT, Feineis D, Mudogo V, Kaiser M, Brun R, Seo EJ, Efferth T, Bringmann G.
Abstract : Four new dimeric naphthylisoquinoline alkaloids, michellamine A5 (2) and mbandakamines C-E (4-6), were isolated from the Congolese plant Ancistrocladus ealaensis, along with the known dimer mbandakamine A (3). They represent constitutionally unsymmetric dimers, each consisting of two 5,8'-coupled naphthylisoquinoline monomers. While the molecular halves of michellamine A5 (2) are linked via C-6' of both of the naphthalene moieties, i.e., via the least-hindered positions, so that the central biaryl axis is configurationally unstable and not an additional element of chirality, the mbandakamines 3-6 possess three consecutive stereogenic axes. Their monomeric units are linked through an unprecedented 6',1″-coupling in the binaphthalene core, leading to a high steric load, since the central axis is located in one of the peri-positions, neighboring one of the outer axes. In addition, four new 5,8'-coupled monomeric naphthylisoquinolines, viz., ancistroealaines C-F (7-10), were identified, along with four "naphthalene-devoid" tetra- and dihydroisoquinolines, named ealaines A-D (11-14). The new mbandakamines C (4) and D (5) showed pronounced activities against the malaria parasite Plasmodium falciparum, and they were likewise found to display strong cytotoxic activities against human leukemia (CCRF-CEM) and multi-drug-resistant tumor cells (CEM/ADR5000).
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigote after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
8.8
nM
|
|
Journal : Eur J Med Chem
Title : Biological evaluation and structure-activity relationships of imidazole-based compounds as antiprotozoal agents.
Year : 2018
Volume : 156
First Page : 53
Last Page : 60
Authors : Saccoliti F, Madia VN, Tudino V, De Leo A, Pescatori L, Messore A, De Vita D, Scipione L, Brun R, Kaiser M, Mäser P, Calvet CM, Jennings GK, Podust LM, Costi R, Di Santo R.
Abstract : We discovered a series of azole antifungal compounds as effective antiprotozoal agents. They displayed promising inhibitory activities within the micromolar-submicromolar range against P. falciparum, L. donovani, and T. b. rhodesiense. Moreover, most of such compounds showed excellent nanomolar IC50 against T. cruzi, showing also very low cytotoxicity. Discussion of structure-activity relationships and biological data for these compounds are provided against the different parasites. To assess the mechanism of action against T. cruzi we proved that the most potent compounds (3b, 3j-l) inhibited the T. cruzi CYP51. Moreover, the most active derivative 3j dramatically reduced parasitemia in T. cruzi mouse model without acute toxicity.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes assessed as growth inhibition after 72 hrs by Alamar Blue dye-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
7.0
nM
|
|
Journal : J Nat Prod
Title : A Near-Complete Series of Four Atropisomeric Jozimine A2-Type Naphthylisoquinoline Dimers with Antiplasmodial and Cytotoxic Activities and Related Alkaloids from Ancistrocladus abbreviatus.
Year : 2019
Volume : 82
Issue : 11
First Page : 3033
Last Page : 3046
Authors : Fayez S, Li J, Feineis D, Aké Assi L, Kaiser M, Brun R, Anany MA, Wajant H, Bringmann G.
Abstract : Three new naphthylisoquinoline dimers, jozibrevines A-C (1a-c), were isolated from the West African shrub Ancistrocladus abbreviatus, along with the known dimer jozimine A2 (1d). The two molecular moieties of 1a-d are coupled via the sterically constrained 3',3″-positions of their two naphthalene units, so that the central biaryl linkage is rotationally hindered. With the two outer axes also being chiral, 1a-d possess three consecutive stereogenic axes. The four isolated dimers all have the same constitutions and identical absolute configurations at the four stereogenic centers, but differ by their axial chirality. They belong to the extremely small class of Dioncophyllaceae-type naphthylisoquinoline dimers, i.e., being devoid of oxygen functions at C-6 and bearing the R-configuration at C-3 in their isoquinoline portions. Besides these dimers, the plant produces predominantly typical Ancistrocladaceae-type monomeric compounds, i.e., with the S-configuration at C-3 and an oxygen function at C-6, such as the new ancistrobrevines K (5) and L (6). Furthermore, a new hybrid-type (i.e., mixed Ancistrocladaceae/Dioncophyllaceae-type) alkaloid was identified, named ancistrobrevine M (7), which is 3R-configured and 6-oxygenated. Remarkable was the discovery of its "inverse hybrid-type" counterpart, dioncoline A (8). It is the as yet only known 3S-configured naphthylisoquinoline lacking an O-functionality at C-6. The new jozibrevines A-C (1a-c) exhibited pronounced antiplasmodial activities in the submicromolar range, with 1a being the most potent compound (IC50, 0.012 μM). Furthermore, jozimine A2 (1d) showed cytotoxicity against human colon carcinoma (HT-29), fibrosarcoma (HT1080), and multiple myeloma (MM.1S) cancer cells, displaying IC50 values of 12.0, 9.0, and 5.0 μM, respectively, whereas jozibrevines A (1a) and B (1b) were nontoxic in this concentration range.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STI B900 measured after 72 hrs by alamar blue dye based fluorimetry analysis
|
Trypanosoma brucei rhodesiense
|
5.0
nM
|
|
Journal : J Nat Prod
Title : Structure, Biosynthesis, and Bioactivity of Photoditritide from Photorhabdus temperata Meg1.
Year : 2019
Volume : 82
Issue : 12
First Page : 3499
Last Page : 3503
Authors : Zhao L, Awori RM, Kaiser M, Groß J, Opatz T, Bode HB.
Abstract : A new cyclic peptide photoditritide (1), containing two rare amino acid d-homoarginine residues, was isolated from Photorhabdus temperata Meg1 after the nonribosomal peptide synthetase encoding gene pdtS was activated via promoter exchange. The structure of 1 was elucidated by HR-MS and NMR experiments. The absolute configurations of amino acids were determined according to the advanced Marfey's method after hydrolysis of 1. Bioactivity testing of 1 revealed potent antimicrobial activity against Micrococcus luteus with an MIC value of 3.0 μM and weak antiprotozoal activity against Trypanosoma brucei rhodesiense with an IC50 value of 13 μM. Additionally, the biosynthetic pathway of 1 was also proposed.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 amastigotes assessed as growth inhibition after 72 hrs by Alamar Blue dye-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
7.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A new chemotype with promise against Trypanosoma cruzi.
Year : 2020
Volume : 30
Issue : 1
First Page : 126778
Last Page : 126778
Authors : Wang X, Cal M, Kaiser M, Buckner FS, Lepesheva GI, Sanford AG, Wallick AI, Davis PH, Vennerstrom JL.
Abstract : Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure-activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi. Compound 2 and its active analogs had low to moderate metabolic stabilities in human and mouse liver microsomes.
|
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.
|
Antiprotozoal activity against trypomastigote stage of Trypanosoma brucei rhodesiense STIB900 after 72 hrs by Alamar Blue assay
|
Trypanosoma brucei rhodesiense
|
40.0
nM
|
|
Journal : J Nat Prod
Title : Antiprotozoal Isoprenoids from Salvia hydrangea.
Year : 2018
Volume : 81
Issue : 12
First Page : 2682
Last Page : 2691
Authors : Tabefam M, Moridi Farimani M, Danton O, Ramseyer J, Nejad Ebrahimi S, Neuburger M, Kaiser M, Salehi P, Potterat O, Hamburger M.
Abstract : Fractionation of the n-hexane extract of Salvia hydrangea afforded seven isoprenoids including six new compounds (1-6) and salvadione A (7). Their structures were established by comprehensive spectroscopic and spectrometric data analysis (1D and 2D NMR, HRMS). The absolute configuration of salvadione A (7) was established by single-crystal X-ray diffraction analysis with Cu/Kα radiation. In addition, the absolute configuration of all compounds was determined by electronic circular dichroism spectroscopy. A biosynthetic pathway for the formation of the scaffold of 1 is proposed. The antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum was determined, and cytotoxicity was assessed in rat myoblast L6 cells. Perovskone C (2) exhibited good activity against P. falciparum (IC50 0.6 μM) and a selectivity index of 62.2.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms after 72 hrs by Alamar blue staining-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
20.0
nM
|
|
Journal : J Nat Prod
Title : Methionine-Containing Rhabdopeptide/Xenortide-like Peptides from Heterologous Expression of the Biosynthetic Gene Cluster kj12ABC in Escherichia coli.
Year : 2018
Volume : 81
Issue : 10
First Page : 2292
Last Page : 2295
Authors : Zhao L, Cai X, Kaiser M, Bode HB.
Abstract : Seven new methionine-containing rhabdopeptide/xenortide-like peptides (1-7) were identified from Escherichia coli expressing the rhabdopeptide/xenortide-like peptide biosynthetic gene cluster kj12ABC from Xenorhabdus KJ12.1. Their structures were elucidated by detailed HPLC-HR-MS/MS analysis and confirmed by chemical synthesis. Bioactivity tests of these first rhabdopeptide/xenortide-like peptide derivatives (2-7) showing methionine building blocks compared to the usually found derivatives containing exclusively hydrophobic amino acids such as valine, leucine, or phenylalanine revealed good activities of 2-7 against protozoan parasites and no cytotoxicity against mammalian L6 cells.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes after 72 hrs by Alamar Blue dye-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
8.8
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of New 1-(Aryl-1 H-pyrrolyl)(phenyl)methyl-1 H-imidazole Derivatives as Antiprotozoal Agents.
Year : 2019
Volume : 62
Issue : 3
First Page : 1330
Last Page : 1347
Authors : Saccoliti F, Madia VN, Tudino V, De Leo A, Pescatori L, Messore A, De Vita D, Scipione L, Brun R, Kaiser M, Mäser P, Calvet CM, Jennings GK, Podust LM, Pepe G, Cirilli R, Faggi C, Di Marco A, Battista MR, Summa V, Costi R, Di Santo R.
Abstract : We have designed and synthesized a series of new imidazole-based compounds structurally related to an antiprotozoal agent with nanomolar activity which we identified recently. The new analogues possess micromolar activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar potency against Plasmodium falciparum. Most of the analogues displayed IC<sub>50</sub> within the low nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure-activity relationships and in vitro biological data for the new compounds are provided against a number of different protozoa. The mechanism of action for the most potent derivatives (5i, 6a-c, and 8b) was assessed by a target-based assay using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits were assessed in a T. cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal administration of 25 mg/kg/day dose for 4 consecutive days.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes incubated for 72 hrs by Alamar blue staining-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
7.0
nM
|
|
Journal : J Nat Prod
Title : Ealamines A-H, a Series of Naphthylisoquinolines with the Rare 7,8'-Coupling Site, from the Congolese Liana Ancistrocladus ealaensis, Targeting Pancreatic Cancer Cells.
Year : 2019
Volume : 82
Issue : 11
First Page : 3150
Last Page : 3164
Authors : Tshitenge DT, Bruhn T, Feineis D, Schmidt D, Mudogo V, Kaiser M, Brun R, Würthner F, Awale S, Bringmann G.
Abstract : From the twigs and leaves of the Central African liana Ancistrocladus ealaensis (Ancistrocladaceae), a series of ten 7,8'-coupled naphthylisoquinoline alkaloids were isolated, comprising eight new compounds, named ealamines A-H (4a, 4b, 5-10), and two known ones, 6-O-demethylancistrobrevine A (11) and yaoundamine A (12), which had previously been found in related African Ancistrocladus species. Only one of the new compounds within this series, ealamine H (10), is a typical Ancistrocladaceae-type alkaloid, with 3S-configuration at C-3 and an oxygen function at C-6, whereas seven of the new alkaloids are the first 7,8'-linked "hybrid-type" naphthylisoquinoline alkaloids, i.e., 3R-configured and 6-oxygenated in the tetrahydroisoquinoline part. The discovery of such a broad series of 7,8'-coupled naphthyltetrahydroisoquinolines is unprecedented, because representatives of this subclass of alkaloids are normally found in Nature quite rarely. The stereostructures of the new ealamines were assigned by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and quantum-chemical ECD investigations, and-in the case of ealamine A (4a)-also confirmed by X-ray diffraction analysis. Ealamines A-D exhibited distinct-and specific-antiplasmodial activities, and they displayed pronounced preferential cytotoxic effects toward PANC-1 human pancreatic cancer cells in nutrient-deprived medium, without causing toxicity under normal, nutrient-rich conditions, with ealamine C (5) as the most potent agent.
|
Antitrypanosomal activity against bloodstream Trypanosoma brucei rhodesiense STIB900 assessed as parasite growth inhibition measured after 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis, in-vitro antiprotozoal activity and molecular docking study of isothiocyanate derivatives.
Year : 2020
Volume : 28
Issue : 1
First Page : 115185
Last Page : 115185
Authors : Babanezhad Harikandei K, Salehi P, Ebrahimi SN, Bararjanian M, Kaiser M, Al-Harrasi A.
Abstract : Novel isothiocyanate derivatives were synthesized starting from noscapine, bile acids, amino acids, and some aromatic compounds. Antiparasitic activities of the synthesized derivatives were tested against four unicellular protozoa, i.e., Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. Interestingly, seven isothiocyanate analogues displayed promising antiparasitic activity against Leishmania donovani with IC<sub>50</sub> values between 0.4 and 1.0 µM and selectivity index (SI) ranged from 7.8 to 18.4, comparable to the standard drug miltefosine (IC<sub>50</sub> = 0.7 μM). Compound 7h demonstrated the best antileishmanial activity with an IC<sub>50</sub> value of 0.4 µM. Seven products exhibited inhibition activity against T. brucei rhodesiense with IC<sub>50</sub>s below 2.0 μM and SI between 2.7 and 29.3. Four primary amine derivatives of noscapine and five isothiocyanate derivatives exhibited antiplasmodial activity with IC<sub>50</sub>s in the range of 1.1-2.7 µM and SI values between 1.1 and 14.5. The isothiocyanate derivative 7c showed against T. cruzi with an IC<sub>50</sub> value of 1.9 µM and SI 4. Molecular docking and ADMET studies were performed to investigate the interaction between active ligands and T. brucei trypanothione reductase active site. The docking studies showed significant binding affinity of noscapine derivatives to enzyme active site and good compatibility with experimental data.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 incubated for 70 hrs by Alamar blue dye-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
14.0
nM
|
|
Journal : RSC Med Chem
Title : Investigation of thiazolyl-benzothiophenamides as potential agents for African sleeping sickness
Year : 2020
Volume : 11
Issue : 12
First Page : 1413
Last Page : 1422
Authors : Brown, Ronald W., Abdel-Megeed, Ashraf M., Keller, Paul A., Jones, Amy J., Sykes, Melissa L., Kaiser, Marcel, Baell, Jonathan B., Avery, Vicky M., Hyland, Christopher J. T.
Abstract : African sleeping sickness is a potentially fatal neglected disease affecting sub-Saharan Africa. High-throughput screening identified the thiazolyl-benzothiophenamide 1 to be active against the causative parasite, Trypanosoma brucei. This work establishes structure-activity relationships of 1, guiding the design of second generation derivatives. After screening against the clinically relevant species T. b. rhodesiense, the derivative 16 was identified as a suitable candidate for further investigation.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes by alamar blue staining-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
9.0
nM
|
|
Journal : Eur J Med Chem
Title : Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity.
Year : 2016
Volume : 123
First Page : 895
Last Page : 904
Authors : Papadopoulou MV,Bloomer WD,Rosenzweig HS,Wilkinson SR,Szular J,Kaiser M
Abstract : 3-Nitro-1H-1,2,4-triazole-based acetamides bearing a biphenyl- or a phenoxyphenyl moiety have shown remarkable antichagasic activity both in vitro and in an acute murine model, as well as substantial in vitro antileishmanial activity but lacked activity against human African trypanosomiasis. We have shown now that by inserting a methylene group in the linkage to obtain the corresponding propanamides, both antichagasic and in particular anti-human African trypanosomiasis potency was increased. Therefore, IC50 values at low nM concentrations against both T. cruzi and T. b. rhodesiense, along with huge selectivity indices were obtained. Although several propanamides were active against Leishmania donovani, they were slightly less potent than their corresponding acetamides. There was a good correlation between lipophilicity (clogP value) and trypanocidal activity, for all new compounds. Type I nitroreductase, an enzyme absent from the human host, played a role in the activation of the new compounds, which may function as prodrugs. Antichagasic activity in vivo was also demonstrated with representative propanamides.
|
Antitrypanosomal activity against bloodstream Trypanosoma brucei rhodesiense STIB900 assessed as parasite growth inhibition measured after 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
11.0
nM
|
|
Journal : Eur J Med Chem
Title : The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines.
Year : 2021
Volume : 209
First Page : 112871
Last Page : 112871
Authors : Robinson WJ,Taylor AE,Lauga-Cami S,Weaver GW,Arroo RRJ,Kaiser M,Gul S,Kuzikov M,Ellinger B,Singh K,Schirmeister T,Botana A,Eurtivong C,Bhambra AS
Abstract : Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC value of 0.38 μM and a promising off-target ADME-Tox profile in vitro. In silico molecular target investigations showed rhodesain to be a putative candidate, supported by STD and WaterLOGSY NMR experiments, however, in vitro evaluation of compound 13 against rhodesain exhibited low experimental inhibition. Therefore, our reported library of drug-like pyrimidines present promising scaffolds for further antikinetoplastid drug development for both phenotypic and target-based drug discovery.
|
Trypanocidal activity against Trypanosoma brucei rhodesiense STIB900 incubated for 70 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
3.9
nM
|
|
Journal : Eur J Med Chem
Title : Preparation of new 1,3-dibenzyl tetrahydropyridinylidene ammonium salts and their antimicrobial and anticellular activities.
Year : 2021
Volume : 210
First Page : 112969
Last Page : 112969
Authors : Petritsch M,Seebacher W,Mohsin NU,Dolensky J,Hochegger P,Kaiser M,Mäser P,Belaj F,Saf R,Kretschmer N,Alajlani M,Brantner A,Bauer R,Schühly W,Weis R
Abstract : New 1,3 dibenzyl -tetrahydropyridinylidene ammonium salts have been prepared from unsubstituted or N-benzylated tetrahydropyridinylidene ammonium salts. The antiplasmodial and antitrypanosomal activities as well as their cytotoxic effects were determined using microplate assays. In addition, their activities against two gram positive and two gram negative bacteria strains and a yeast strain were examined. Furthermore, anticancer effects against two cell lines were investigated. Physicochemical parameters were calculated and structure-activity-relationships discussed. One compound showed antiplasmodial activity against a multiresistant strain of Plasmodium falciparum in subnanomolar concentration. Antitrypanosomal activities were detected in low nanomolar concentrations. A single compound was active against grampositive and gramnegative bacteria, as well as yeast. One compound inhibited the growth of a HCT cell line in low concentration.
|
Trypanocidal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes incubated for 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
6.0
nM
|
|
Trypanocidal activity against Trypanosoma brucei rhodesiense STIB900 trypomastigotes incubated for 72 hrs by Alamar blue assay
|
Trypanosoma brucei rhodesiense
|
6.026
nM
|
|
Journal : Eur J Med Chem
Title : Palladium-catalysed synthesis of arylnaphthoquinones as antiprotozoal and antimycobacterial agents.
Year : 2020
Volume : 207
First Page : 112837
Last Page : 112837
Authors : Kalt MM,Schuehly W,Saf R,Ochensberger S,Solnier J,Bucar F,Kaiser M,Presser A
Abstract : Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 assessed as inhibition of parasite growth incubated for 72 hrs by Alamar blue dye-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
15.0
nM
|
|
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 incubated for 70 hrs by resazurin dye-based fluorometric analysis
|
Trypanosoma brucei rhodesiense
|
0.003
ug.mL-1
|
|
