Potent and selective α-glucosidase inhibition by coumarin–triazole conjugates: design, in vivo evaluation, and computational insights

Abstract

Diabetes mellitus is a worldwide health problem, and high blood sugar is one of its hallmarks. Although α-glucosidase inhibitors such as acarbose are crucial for controlling postprandial blood glucose levels, their use is usually limited by digestive adverse effects. As a part of extensive efforts to identify potential anti-diabetic agents, a series of coumarin–triazole conjugates was designed and synthesized. They were evaluated for through in vitro inhibitory assays against α-glucosidase, achieving IC₅₀ values ranging from 1.0 to 223 µM, significantly superior to that of acarbose (IC₅₀ = 750 µM). Among them, compound 12q (bearing 3-CN) emerged as the most potent derivative (IC₅₀ = 1.0 µM) and demonstrated selective inhibition of α-glucosidase over α-amylase. Kinetic studies confirmed 12q as a competitive inhibitor (K_i = 1000 nM), which allowed for its in silico evaluation in the active site. Molecular docking and dynamics simulations revealed the compounds' stable binding in the active site by interactions with critical catalytic residues such as Glu276 and Asp214. Fluorescence and circular dichroism studies supported high-affinity binding without major conformational changes in α-glucosidase. In vivo evaluation in a diabetic mouse model confirmed the significant antihyperglycemic efficacy of compound 12q, which outperformed acarbose in reducing fasting blood glucose and improving glucose tolerance. Collectively, these findings highlight this series of coumarin–triazole hybrids, particularly compound 12q, as promising candidates for the further structural development of safe and potent α-glucosidase inhibitors for diabetes management.