01998nas a2200301   4500000000100000008004100001260001200042653001900054653002200073653002400095653001600119653002800135653001900163100001200182700001300194700001200207700001200219700001300231700002100244700002100265700001100286245019000297856007900487300001100566490000700577520109800584022001401682       2026                            d  c04/202610aChagas disease10aTrypanosoma cruzi10aantiparasitic drugs10aDrug Design10aMolecular hybridization10anitroimidazole1 aVelez A1 aChaves O1 aCosta T1 aSerpa C1 aBorges J1 aFreire-de-Lima C1 aDecote-Ricardo D1 aLima M00aStructure-enabled enhancement of potency in a metronidazole-benznidazole hybrid: design, synthesis, and evaluation of antitrypanosomal activity of a benzylamide-linked 5-nitroimidazole.  uhttps://pmc.ncbi.nlm.nih.gov/articles/PMC13171372/pdf/fphar-17-1812023.pdf  a1 - 110 v173 a<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>
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