Structure-enabled enhancement of potency in a metronidazole-benznidazole hybrid: design, synthesis, and evaluation of antitrypanosomal activity of a benzylamide-linked 5-nitroimidazole

Benznidazole remains the primary antiparasitic drug used clinically for Chagas disease, underscoring the need to discover novel treatments targeting infection. In this sense, the present work reports the design of a novel hybrid containing the 5-nitroimidazole core from the commercial antiparasitic drug metronidazole and the -benzylacetamide moiety from. These structural motifs were designed to target nitroreductase type I (TcNTR) for activation and to boost intracellular drug levels (lipophilicity). The predictions suggested that the presence of the -benzylacetamide moiety might enhance the anti-T activity of and improve the drug-likeness. To validate the predictions, hybrid was synthesized with a yield of 53% and structurally characterized (melting point, H and C NMR, and HRMS). The assays of hybrid against amastigotes (Tulahuen strain C2C4 ) supported the predictions, showing a lower IC for (67.73 ± 8.98 µM) than for (>100 µM). Despite hybrid having an activity 45-fold lower than that of , the results provide insights for future hybrid optimization.