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.
BT - Frontiers in pharmacology C1 - https://www.ncbi.nlm.nih.gov/pubmed/42147305 DA - 04/2026 DO - 10.3389/fphar.2026.1812023 J2 - Front Pharmacol LA - ENG M3 - Article N2 -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.
PY - 2026 SP - 1 EP - 11 T2 - Frontiers in pharmacology TI - Structure-enabled enhancement of potency in a metronidazole-benznidazole hybrid: design, synthesis, and evaluation of antitrypanosomal activity of a benzylamide-linked 5-nitroimidazole. UR - https://pmc.ncbi.nlm.nih.gov/articles/PMC13171372/pdf/fphar-17-1812023.pdf VL - 17 SN - 1663-9812 ER -