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 (IC50 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 (IC50 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.
Papadopoulou, M. V.; Trunz, B. B.; Bloomer, W. D.; McKenzie, C.; Wilkinson, S. R.; Prasittichai, C.; Brun, R.; Kaiser, M. and Torreele, E. Novel 3-Nitro-1H-1,2,4-triazole-Based Aliphatic and Aromatic Amines as Anti-Chagasic Agents. Journal of Medicinal Chemistry (2011) 54 (23) 8214-8223. [DOI: 10.1021/jm201215n]