Novel 3-nitro-1H-1,2,4-triazole-based piperazines and 2-amino-1,3-benzothiazoles as antichagasic agents

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.

Keywords: Antitrypanosomal agents; Benzothiazoles; Bnz; Chagas disease; HAT; IC(50); NTR; Nfx; Nitrotriazoles; Piperazines; SARs; SI; Structure–activity relationships; T. brucei; T. brucei NTR; T. cruzi; TDR; TbNTR; Tropical diseases research (http://www.who.int/tdr/en/); Trypanosoma brucei; Trypanosoma cruzi; benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide); concentration for 50% growth inhibition; human African trypanosomiasis; nifurtimox (4-(5-nitrofurfurylindenamino)-3-methylthio-morpholine-1,1-dioxide); selectivity index; type I nitroreductase.