Design and Synthesis of Novel 3-Nitro-1H-1,2,4-triazole-1,2,3-triazole-1,4-disubstituted Analogs as Promising Antitrypanosomatid Agents: Evaluation of In Vitro Activity against Chagas Disease and Leishmaniasis

A series of 28 compounds, 3-nitro-1H-1,2,4-triazole, were synthesized by click-chemistry with diverse substitution patterns using medicinal chemistry approaches, such as bioisosterism, Craig-plot, and the Topliss set with excellent yields. Overall, the analogs demonstrated relevant in vitro antitrypanosomatid activity. Analog 15g(R1= 4-OCF3–Ph, IC50= 0.09 μM, SI = >555.5) exhibited an outstanding antichagasic activity (Trypanosoma cruzi, Tulahuen LacZ strain) 68-fold more active than benznidazole (BZN, IC50= 6.15 μM, SI = >8.13) with relevant selectivity index, and suitable LipE = 5.31. 15gwas considered an appropriate substrate for the type I nitro reductases (TcNTR I), contributing to a likely potential mechanism of action for antichagasic activity. Finally, 15gshowed nonmutagenic potential against Salmonella typhimuriumstrains (TA98, TA100, and TA102). Therefore, 3-nitro-1H-1,2,4-triazole 15gis a promising antitrypanosomatid candidate for in vivo studies.