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

Abstract

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 28 compounds were synthesized via click chemistry in satisfactory yields. Overall, analogs 15a‐x exhibited relevant in vitro anti‐trypanosomatid activity against amastigote forms of T. cruzi and without cytotoxic effect on LLC‐MK2 cells. Analogs 15b (R1 = 4‐Cl‐Ph; IC50 = 1.63 µM, SI = > 30.65), 15m (R1 = 3,4‐di‐Cl‐Ph; IC50 = 0.63 µM, SI= >78.96), and 15s (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 15b (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 15b and 15m were evaluated against Salmonella typhimurium strains (TA98, TA100 and TA102). Compound 15b exhibited mutageniticy only at a concentration of 500 mg/plate for the TA100 strain, wheras compound 15m 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.