Novel imidazo[1,2-a]pyridine-based α-glucosidase inhibitors: synthesis, biological evaluations, and computational studies

In an attempt to identify novel α‑glucosidase inhibitors, a new series of substituted imidazo[1,2‑a]pyridine derivatives (10a-10ab) was designed, synthesized, and evaluated for their inhibitory activities. All compounds exhibited potent inhibition, with IC₅₀ values ranging from 12.01 to 93.01 µM, significantly better than acarbose IC₅₀ = 750.02 µM). SAR analysis highlighted the critical role of para‑substitution on the benzamide ring, especially methoxy groups. The most potent compound, 10s (IC₅₀ = 12.01 µM), acted as a competitive inhibitor (K_i = 21 µM) with no α‑amylase inhibition, indicating high selectivity. It was non‑cytotoxic up to 100 µM. Circular dichroism, fluorescence spectroscopy, and thermodynamic analysis revealed strong ligand-enzyme interactions mainly driven by hydrophobic forces. Molecular docking and 200 ns MD simulations, including MM‑GBSA calculations, supported stable binding of 10s within the active site. Collectively, these results introduce imidazo[1,2-a]pyridine derivative 10s as a promising lead compound for the development of novel α-glucosidase inhibitors in further studies.