Identification of novel quinoxaline linked oxadiazole derivatives as α-glucosidase inhibitors through homology modelling based in silico screening and in vitro evaluation.

Inhibition of the α-glucosidase enzyme is an established therapeutic strategy for managing type 2 diabetes mellitus (T2DM) by delaying carbohydrate digestion and attenuating postprandial hyperglycemia. Quinoxaline and oxadiazole scaffolds, recognized for their diverse pharmacological relevance, have emerged as promising structural motifs for the development of improved α-glucosidase inhibitors. In this study, a library of 108 rationally designed quinoxaline-oxadiazole hybrids was constructed and systematically evaluated to identify potent antidiabetic candidates. A comprehensive in silico workflow was employed, beginning with homology modelling of human α-glucosidase and site-map analysis to define the active binding pocket. The designed compounds were subsequently assessed through molecular docking, MM-GBSA binding free energy calculations, ADME prediction, molecular dynamics simulations, and density functional theory analysis. Among the screened compounds, two candidates (1 and 2) emerged as the most promising, exhibiting docking scores of -7.25 and -7.24 kcal/mol, respectively, compared with -5.40 kcal/mol for the reference inhibitor acarbose. Both compounds formed key interactions with Trp1685, consistent with critical binding features of acarbose, and displayed favorable drug-likeness profiles. Molecular dynamics simulations over 300 ns confirmed the stability of the protein-ligand complexes, supported by RMSD, RMSF, radius of gyration, hydrogen bonding and solvent-accessible surface area analyses. The two hit compounds were synthesized and experimentally validated, showing potent α-glucosidase inhibition with IC50 values of 39.69 ± 0.076 and 103.7 ± 0.035 μg/mL, outperforming acarbose (IC50 = 125.9 ± 0.024 μg/mL). Cytotoxicity evaluation against HepG-2 cells indicated low hepatocellular toxicity for both the compounds. Overall, this integrated computational and experimental study identifies quinoxaline-oxadiazole hybrids as promising leads for further development of safer and more effective α-glucosidase inhibitors.