New coumarin–chalcone–triazole hybrids as promising anti-diabetic agents: from molecular design to <i>in vivo</i> validation

A series of coumarin-chalcone-1,2,3-triazoles were designed and synthesized as potential antidiabetic agents targeting α-glucosidase. Among them, compound 20q exhibited exceptional inhibitory potency (IC₅₀ = 0.50 ± 0.04 µM), significantly outperforming acarbose (IC₅₀ = 750.08 ± 1.52 µM). Kinetic analyses confirmed a competitive inhibition mechanism, and computational studies-including deep-learning prediction, molecular docking, and molecular dynamics simulations-revealed strong and stable interactions of 20q with the enzyme active site, supporting its efficacy. This compound showed no cytotoxicity and α-amylase inhibition even at high concentrations, indicating its favorable safety profile with high selectivity. CD and fluorescence studies demonstrated that its binding induced a more ordered enzyme conformation (increased α-helix, reduced β-sheet/coil) through static, electrostatic interactions. <i>In vivo</i> assessments with compound 20q showed no acute toxicity at doses up to 1000 mg kg^-1 and a dose-dependent antihyperglycemic effect, restoring fasting blood glucose and HbA₁c levels to near-normal values, and improving liver and pancreas histopathology at 8 mg kg^-1 BW, outperforming acarbose at a comparable dose. These comprehensive findings identify compound 20q as a highly potent, selective, and safe α-glucosidase inhibitor with significant potential for further development as an antidiabetic agent.