What question did this study set out to answer?

The aim is to identify and evaluate new α-glucosidase inhibitors based on imidazo[1,2-a]pyridine derivatives.

July 13, 2026Open Access

Novel imidazo1,2-apyridine-based α-glucosidase inhibitors: synthesis, biological evaluations, and computational studies

MNMaryam NorouzbahariFinal International University ZEZahra EmamgholipourTehran University of Medical Sciences FPFariba PeytamTehran University of Medical Sciences

Key Points

The aim is to identify and evaluate new α-glucosidase inhibitors based on imidazo[1,2-a]pyridine derivatives.
Synthesized a series of 10 substituted imidazo[1,2-a]pyridine derivatives and assessed their inhibitory activity against α-glucosidase.
Conducted SAR analysis, circular dichroism, fluorescence spectroscopy, and molecular docking studies to evaluate compound interaction and selectivity.
Utilized 200 ns MD simulations and MM-GBSA calculations to support stable binding of compounds in the enzyme active site.
Most potent compound 10s exhibited IC50 = 12.01 µM and Ki = 21 µM, showing competitive inhibition.
Results show no cytotoxicity up to 100 µM, indicating safety at effective doses.
Hydrophobic interactions were identified as primary drivers of binding affinity.

Abstract

Abstract In an attempt to identify novel α‑glucosidase inhibitors, a new series of substituted imidazo1,2‑apyridine derivatives (10a–10ab) was designed, synthesized, and evaluated for their inhibitory activities. All compounds exhibited potent inhibition, with IC 50 values ranging from 12.01 to 93.01 µM, significantly better than acarbose IC 50 = 750.02 µM). SAR analysis highlighted the critical role of para‑substitution on the benzamide ring, especially methoxy groups. The most potent compound, 10s (IC 50 = 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 imidazo1,2- a pyridine derivative 10s as a promising lead compound for the development of novel α-glucosidase inhibitors in further studies.

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