Rational design of 3,4,5-trimethoxyphenyl-phenoxy-triazole derivatives as highly potent α-glucosidase inhibitors

α-Glucosidase inhibitors are essential for better management of postprandial hyperglycemia in patients with type 2 diabetes mellitus. In this context, a novel series of fifteen 3,4,5-trimethoxyphenyl-phenoxy-1,2,3-triazole acetamide hybrids ( 11a-o ) was designed, synthesized, and evaluated for α-glucosidase inhibitory activity. These compounds exhibited strong enzyme inhibition, with IC 50 values ranging from 0.15 to 60.41 μM, compared with the positive control, acarbose. Structure-activity relationship (SAR) analysis indicated that the type and position of substituents on the phenyl ring significantly affect potency, with 3-methyl, 2,4-dimethyl and 2,4-dimethoxy groups being the optimal substitutions to improve potency. Compound 11c was the most active analog (IC 50 = 0.15 ± 0.01 μM) and exhibits competitive inhibition kinetics. Molecular docking showed that 11c forms multiple stabilizing hydrogen bonds, π-π interactions, and π-cation interactions within the enzyme active site, while molecular dynamics simulations confirmed a stable protein-ligand complex over 100 ns. In silico ADME/T profiling showed good drug likeness, good intestinal absorption, low toxicity prediction, and acceptable pharmacokinetic parameters. Cytotoxicity studies in HEK-293 showed that all derivatives were minimally toxic at the cellular level. In summary, the results show that 3,4,5-trimethoxyphenyl-phenoxy-triazole acetamide hybrids, particularly 11c , are ideal candidates for the future development of credible and potent α-glucosidase inhibitors with a safety profile and oral bioavailability.