A new 3-nitro-1,2,4-triazole derivative is more potent and selective than benznidazole against Trypanosoma cruzi

The aim of this work was the development of substances containing 1,2,4-triazole, 3-nitro-1,2-4-triazole and 2-nitroimidazole nuclei to evaluate the contribution of these heterocycles to the activity against Trypanosoma cruzi (Tc), the causative of Chagas disease. Such compounds were based on the structure of substance 1 and fluconazole, substances with important anti-Tc activity,1 as well as benznidazole, the reference antichagasic drug (Fig.1). The derivatives were obtained through a simple two or three-step route. The in vitro evaluation was carried out in an intracellular model containing both amastigote and trypomastigote forms of Tc. The results showed that the 3-nitro-1,2,4-triazole nucleus promotes higher potency than 2-nitroimidazole, in addition, both are superior to 1,2,4-triazole, emphasizing that the presence of the nitro group is important for anti-Tc activity. Another interesting result is that when the derivatives had their carbonyls reduced to hydroxyls, there was an increase in anti-Tc potency. The derivatives containing the biphenyl moiety are in biological evaluation at the present date. The most promising substance in the series was the 3-nitro-1,2-4-triazole derivative 6 with the hydroxyl derivative, whose IC50 was 0.39 μM, being approximately 4-fold more potent than benznidazole. In addition, this derivative showed low cytotoxicity, with CC50 of 1200 μM, which led to a high selectivity index of 3080, more than twice as high as benznidazole.