Synthesis, Biological Evaluation, and in Silico Studies of Novel Triazole- and Oxadiazole-Based Acetamides as Urease and α-Glucosidase Inhibitors.

Abstract

This study investigated the therapeutic potential of novel 1,2,4-triazole- and 1,3,4-oxadiazole-based acetamide derivatives as dual-target inhibitors of urease and α-glucosidase, two enzymes implicated in gastrointestinal disorders and type 2 diabetes, respectively. An integrated approach combining multistep organic synthesis, in vitro biological evaluation, molecular docking, in silico ADME prediction, and density functional theory (DFT) analysis was employed to identify potent lead compounds with favorable pharmacokinetic properties. Starting from benzoic acid, a series of 1,2,4-triazole derivatives (8a-c) and 1,3,4-oxadiazole derivatives (9d-f) bearing substituted acetamide moieties were successfully synthesized. All compounds exhibited inhibitory activity against both target enzymes. Compound 8c was the most potent urease inhibitor (IC₅₀ = 6.14 ± 1.06 µM), while compound 9e showed the strongest α-glucosidase inhibition (IC₅₀ = 27.29 ± 0.41 µM), surpassing the reference inhibitor acarbose (IC₅₀ = 38.25 ± 0.12 µM). Computational analyses supported the experimental findings: ADME predictions indicated favorable drug-like properties, and molecular docking demonstrated strong binding interactions, with compound 8a exhibiting the highest affinity for α-glucosidase (-7.165 kcal/mol) and compound 9e showing the strongest binding to urease (-7.30 kcal/mol). DFT calculations further correlated biological activity with electronic properties, revealing relatively small HOMO-LUMO energy gaps for the most active compounds, 8c (0.14831 a.u.) and 9e (0.14302 a.u.). Collectively, these findings identify compounds 8c and 9e as promising lead scaffolds for the development of next-generation inhibitors of urease and α-glucosidase.