Synthesis and structure–activity relationship studies of 1,2,4-triazole–benzoxazepine hybrids as α-glucosidase inhibitors: molecular docking and biological evaluation

Abstract

A novel series of 1,2,4-triazole–benzoxazepine hybrid derivatives was designed, synthesized, and biologically evaluated as α-glucosidase inhibitors using an in vitro enzyme inhibition assay with acarbose as a reference standard. Several compounds demonstrated significant inhibitory activity, with compound 14 emerging as the most potent inhibitor (IC₅₀ = 49.26 µM), surpassing acarbose by approximately 3.6-fold, while compound 28 also showed notable activity (IC₅₀ = 72.14 µM). Structure–activity relationship analysis revealed that halogen substitution, particularly at the ortho position, plays a critical role in enhancing inhibitory potency. Molecular docking studies (PDB ID: 7KB6) provided mechanistic insights into ligand–enzyme interactions, showing that the most active compounds establish key π–π stacking interactions with residues TRP423, TRP525, and PHE307, along with π-anion interactions involving ASP640 and ASP564, and extensive hydrophobic contacts with PHE571, PHE673, MET565, and ARG624. Additionally, water-mediated hydrogen bonding (e.g., HOH1356, HOH1625) helps stabilize the ligand within the active site. These interactions enable simultaneous engagement of the catalytic active site and peripheral regions, supporting strong binding affinity. Overall, these results define clear structure–activity relationships and identify 1,2,4-triazole–benzoxazepine hybrids as promising lead scaffolds for further optimization toward novel antidiabetic agents.