The protozoan parasites Trypanosoma cruzi, Trypanosoma brucei and various Leismania species are the causative agents of Chagas disease, human African trypanosomiasis (HAT) and different forms of Leishmaniasis, respectively. Over 10 million people are infected by T. cruzi and up to 80,000 by T.b.gambiense or T.b.rhodesiense, resulting in more than 40,000 deaths per year. Drugs currently used in the treatment of Chagas are old, active mainly in the acute rather than chronic stage of the disease and require a long treatment period with significant dose-dependent toxicity. We have demonstrated in previous work that 3-nitro-1,2,4-triazole-based amides and sulfonamides demonstrate significant antichagasic activity, and in some cases anti-HAT activity. Exploring further this class of compounds we have synthesized 15 more analogs (including a urea) to further evaluate their in vitro antiprotozoan activity and establish additional SARs. Nine out of 15 compounds were active against T. cruzi (IC50 < 4 �M) with selectivity indexes (SI=toxicity to L6 cells/toxicity against T. cruzi amastigotes)  between 66-747 while the rest of the compounds were moderately active (IC50 from 6.0 -60 �M) but with SI < 50. Three of the active compounds against T. cruzi were also active (IC50 <0.5 �M) or moderately active (IC50 from 0.5-6.0 �M) against T.b. rhodesiense, with SI between 121-235. The moderately active compounds against T.b. rhodesiense were also moderately active against T.b. brucei. However, the anti-HAT activity of these compounds was increased 19 to 23 fold in bloodstream-form T.b. brucei, overexpressing the type I nitroreductase, suggesting the involvement of this enzyme in their activation.  Finally, 3 compounds with or without antichagasic activity were moderately active against L. donovani (IC50 from 1.0-6.0 �M). Seven antichagasic compounds were more potent than the reference compound benznidazole. Detailed SARs will be presented.

Novel nitrotriazole-based amides and sulfonamides as potential antitrypanosomal drugs.

243rd National Meeting (2012)

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