Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents

Journal of Medicinal Chemistry
Maria V PapadopoulouJean-Robert Ioset

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.

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Citations

Sep 10, 2013·Bioorganic & Medicinal Chemistry·Maria V PapadopoulouJean-Robert Ioset
Jul 30, 2014·European Journal of Medicinal Chemistry·Anna KryshchyshynRoman Lesyk
Oct 23, 2013·Future Medicinal Chemistry·Maria V PapadopoulouAna Rodriguez
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Sep 8, 2015·Bioorganic & Medicinal Chemistry·Maria V PapadopoulouJean-Robert Ioset
Sep 14, 2015·European Journal of Medicinal Chemistry·Maria V PapadopoulouMarcel Kaiser
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Related Concepts

Nitrobenzene nitroreductase
Amides
Leishmania donovani
Nitrated Compounds
Nitroreductases
Prodrugs
Structure-Activity Relationship
Sulfonamides
Triazoles
Trypanocidal Agents

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