Design, Synthesis, Biological Evaluation, and Computational Investigation of 2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxamide Derivatives as Novel α-Amylase Inhibitors

A series of substituted 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide derivatives (Va–Vm) was synthesized and evaluated for their α-amylase inhibitory activity as potential antidiabetic agents. In vitro screening identified Vg, Vd, and Vk as the most active derivatives, with IC₅₀ values of 197.5, 204.4, and 207.6 µg/mL, respectively, compared with 66.65 µg/mL for the reference inhibitor acarbose. Molecular docking studies against α-amylase revealed favorable binding affinities for the synthesized derivatives, ranging from −7.4 to −8.7 kcal/mol. Among the tested compounds, Vg exhibited the most favorable binding profile, engaging key catalytic and binding-site residues through hydrophobic, hydrogen-bonding, π–π stacking, halogen-bonding, and π–cation interactions. The stability of the Vg–α-amylase complex was further investigated by 100 ns molecular dynamics simulations, which demonstrated sustained ligand binding, limited structural fluctuations, and stable protein–ligand interactions throughout the simulation. MM/GBSA calculations further supported the favorable binding free energy of the lead compounds. In silico ADME profiling predicted favorable pharmacokinetic characteristics, including high gastrointestinal absorption, low topological polar surface area, blood–brain barrier permeability, and compliance with Lipinski’s rule of five. Furthermore, toxicity prediction indicated no major safety liabilities. Overall, the integrated experimental and computational results identify substituted 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides, particularly Vg, as promising lead structures for further optimization and development as α-amylase inhibitors for potential application in diabetes management.