Design, synthesis, and biological evaluation of novel triazolopyrimidine–1,2,3-triazole–acetamide hybrids as potent α-glucosidase inhibitors supported by in silico studies

Diabetes mellitus (DM) is a global metabolic disorder characterized by chronic hyperglycemia, and inhibition of α ‑glucosidase is an established strategy to manage postprandial blood glucose. However, current inhibitors such as acarbose are associated with gastrointestinal side effects and variable efficacy, necessitating the development of novel agents. To this aim, a new series of poly-substituted triazolo[1,5- a ]pyrimidines 13 conjugated with 1,2,3-triazol and substituted N -arylacetamides was designed and synthesized as potential α ‑glucosidase inhibitors. All compounds were evaluated for their inhibitory potency, and structure–activity relationship (SAR) studies were conducted. The most potent compound, 13n , was further assessed through enzyme kinetics, α ‑amylase inhibition, cytotoxicity (MTT assay), CD spectroscopy, fluorescence spectroscopy, thermodynamic analysis, molecular docking, 500 ns molecular dynamics simulations, and ADME analysis. Our findings identify the triazolo[1,5- a ]pyrimidine scaffold as a promising lead for the development of potent α -glucosidase inhibitors with selectivity over α -amylase, offering a potential pathway toward more effective antidiabetic agents.