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

Abstract

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.

Discovery of dual-action phenolic 4-arylidene-isoquinolinones with antioxidant and α-glucosidase inhibition activities

“…It is worth noting that none of the tested isoquinolinones showed an appreciable cytotoxicity against the healthy cell line COS-7 (see Table S3 in the ESI†) nor any toxicity when administered in vivo . We have discussed the relationship between diabetes and inflammation, so biochemical related parameters (like TNF-α and IL-6) 44 after administration of 10f will be quantified in future works.…”

Design, Synthesis, and Biological Evaluation of 1,4-Dihydropyridine–Indole as a Potential Antidiabetic Agent via GLUT4 Translocation Stimulation

“…Sidhom et al have synthesized 1,4-dihydropyridine derivatives and screened them using an in vivo blood glucose test. It was reported that compound D showed the most prominent antidiabetic effect with a potency of 218%, compared to glimepiride . Niaz and co-workers identified an antidiabetic (compound E ) with potent inhibitory activity against yeast α-glucosidase with an IC 50 value of 35 ± 0.17 μM, in comparison with the standard drug acarbose (IC 50 = 937 ± 1.60 μM) .…”

“…It was reported that compound D showed the most prominent antidiabetic effect with a potency of 218%, compared to glimepiride. 21 Niaz and co-workers identified an antidiabetic (compound E) with potent inhibitory activity against yeast αglucosidase with an IC 50 value of 35 ± 0.17 μM, in comparison with the standard drug acarbose (IC 50 = 937 ± 1.60 μM). 22 Moreover, acridinedione derivative (compound F) has the ability to activate and upregulate GPR40 protein expression, which can enhance insulin sensitivity by improving glucose consumption by the liver and muscle tissues and stimulate insulin secretion through a GPR40-PPAR-PI3K/Akt-GLUT4 signaling mechanism.…”