Development of new imidazopyridine-based chalcones hybrids as potent antidiabetic and antioxidant agents: synthesis, in silico and in vitro evaluation

Nowadays, diabetes mellitus (DM) is a rapidly growing global health concern. In this study, we synthesized a novel series of six imidazopyridine-based chalcone hybrids (5a-f) and evaluated their in vitro biological activities, including total antioxidant capacity, iron-reducing power, and radical scavenging (DPPH, ABTS, NO), as well as antidiabetic potential against α-amylase, α-glucosidase, and aldose reductase. All compounds showed moderate to potent activity, with derivatives 5c and 5f being the most effective. Compound 5f exhibited the highest antioxidant performance (total capacity: 78.63 mg GAE/g; reducing power: 68.88 µg/ml) and strong radical scavenging (IC50: 5.68, 4.75, and 6.52 µg/ml for DPPH, ABTS, and NO, respectively), comparable to ascorbic acid. It also potently inhibited α-amylase, α-glucosidase, and aldose reductase (IC50: 6.71, 4.78, and 4.04 µg/ml). Molecular docking and 100 ns MD simulations further supported these findings: compound 5f showed the best aldose reductase binding (-8.97 kcal/mol), outperforming reference IDD594, while 5c bound favorably to α-amylase and α-glucosidase (-7.28 and - 6.64 kcal/mol) through π-interactions, ionic contacts, and key hydrogen bonds. The 5f-aldose reductase complex remained stable throughout the simulation, with maintained active-site and loop conformations after minor early fluctuations.