Design and Synthesis of Novel 3-Nitro-1<i>H</i>-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
Bruno Ivo Pelizaro, Jaqueline C. Z. Batista, Gisele Bulhões Portapilla, Amarith R. das Neves, Fernanda Silva, Diego B. Carvalho, Cristiane Y. Kawasoko, Lucas Roberto Pessatto, Edgar Julian Paredes‐Gamero, Iara Aimê Cardoso, Pedro H. Luccas, Maria Cristina Nonato, Norberto Peporine Lopes, Fernanda Galvão, Kelly Mari Pires de Oliveira, Nadla Soares Cassemiro, Denise Brentan Silva, Eliane Mattos Piranda, Carla Cardozo Pinto de Arruda, Sérgio de Albuquerque, Adriano C. M. Baroni
Abstract
A series of 28 compounds, 3-nitro-1 H -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 (R 1 = 4-OCF 3 –Ph, IC 50 = 0.09 μM, SI = >555.5) exhibited an outstanding antichagasic activity ( Trypanosoma cruzi, Tulahuen LacZ strain) 68-fold more active than benznidazole (BZN, IC 50 = 6.15 μM, SI = >8.13) with relevant selectivity index, and suitable LipE = 5.31. 15g was considered an appropriate substrate for the type I nitro reductases (TcNTR I), contributing to a likely potential mechanism of action for antichagasic activity. Finally, 15g showed nonmutagenic potential against Salmonella typhimurium strains (TA98, TA100, and TA102). Therefore, 3-nitro-1 H -1,2,4-triazole 15g is a promising antitrypanosomatid candidate for in vivo studies.