Design and Synthesis of 2‐Nitroimidazole‐1,2,3‐triazole Sulfonamide Hybrids as Potent and Selective Anti‐Trypanosomatid Agents

A series of 2-nitroimidazole-1,2,3-triazole sulfonamide hybrid analogs were designed using medicinal chemistry approaches, such as bioisosterism, molecular hybridization, Topliss tree decision, and Craig plot. A total of 24 compounds were synthesized via click chemistry in satisfactory yields. Overall, analogs 15 a-x exhibited relevant in vitro anti-trypanosomatid activity against amastigote forms of T. cruzi and without cytotoxic effect on LLC-MK2 cells. Analogs 15 b (R₁=4-Cl-Ph; IC₅₀=1.63 μM, SI=>30.65), 15 m (R₁=3,4-di-Cl-Ph; IC₅₀=0.63 μM, SI=>78.96), and 15 s (R₁=Ph-4-O-Ph; IC₅₀=0.63 μM, SI=>79.90) demonstrated pronounced antitrypanosomal activity, more active than the reference drug, benznidazole and with good selectivity indexes. Furthermore, analog 15 b (R₁=4-Cl-Ph; IC₅₀=0.5 μM, SI=>100) exhibited an outstanding antileishmanial activity against amastigote forms of Leishmania (L.) amazonensis and impressive selectivity index, comparable to the reference compound amphotericin B. The mutagenicity of compounds 15 b and 15 m were evaluated against Salmonella typhimurium strains (TA98, TA100 and TA102). Compound 15 b exhibited mutageniticy only at a concentration of 500 μg/plate for the TA100 strain, whereas compound 15 m was considered non-mutagenic. These findings suggest that 2-nitroimidazoles-1,2,3-triazole sulfonamide hybrid analogs are promising anti-trypanosomatid candidates for future in vivo studies.