Mechanistic Insight of Synthesized 1,4-Dihydropyridines as an Antidiabetic Sword against Reactive Oxygen Species

The pharmacologically privileged DHP derivatives were synthesized using the pragmatic multicomponent Hantzsch synthesis to screen the antidiabetic activity. Initially, the candidates were screened using an in vivo blood glucose test, where compound 8b showed the most prominent antidiabetic effect (% potency = 218%) compared to glimepiride. Then, a propositioned structure-activity relationship study was executed to reveal that longer side chains decreased the DHP's antidiabetic action. Mechanistically, compound 8b diminished ROS in β-cells and muscle cells simultaneously, which was proved by enhanced serum biochemical markers. Also, compound 8b decreased blood glucose by α-glucosidase inhibition (IC₅₀ = 4.48 ± 0.32 μM), compared to acarbose (7.40 ± 0.41 μM), based selectively on the plasma window of 8b. Acarbose demonstrated auspicious inhibitor activity according to the binding affinity (ΔG_binding), which was slightly lower than that of compound 8b (-54.7 and -46.8 kcal/mol, respectively). During the 100 ns molecular dynamics simulations, the structural and energetic assessments exposed the high consistency of compound 8b to bind to the α-glucosidase.