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 (ΔGbinding), 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.