@article{103558,
  keywords = {Chagas disease, Trypanosoma cruzi, antiparasitic drugs, Drug Design, Molecular hybridization, nitroimidazole},
  author = {Velez A and Chaves O and Costa T and Serpa C and Borges J and Freire-de-Lima C and Decote-Ricardo D and Lima M},
  title = {Structure-enabled enhancement of potency in a metronidazole-benznidazole hybrid: design, synthesis, and evaluation of antitrypanosomal activity of a benzylamide-linked 5-nitroimidazole.},
  abstract = {<p>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&nbsp;µM) than for (&gt;100&nbsp;µM). Despite hybrid having an activity 45-fold lower than that of , the results provide insights for future hybrid optimization.</p>
},
  year = {2026},
  journal = {Frontiers in pharmacology},
  volume = {17},
  pages = {1 - 11},
  month = {04/2026},
  issn = {1663-9812},
  url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC13171372/pdf/fphar-17-1812023.pdf},
  doi = {10.3389/fphar.2026.1812023},
  language = {ENG},
}