Design, synthesis, α-glucosidase inhibition, and molecular modeling of new coumarin fused pyridine derivatives as novel anti-diabetic agents

Background and Objective: Inhibition of α-glucosidase, a key carbohydrate hydrolyzing enzyme, leads to a decrease in postprandial hyperglycemia by reducing glucose absorption through delaying the digestion and absorption of carbohydrates. Thus, the inhibition of α-glucosidase is the simplest way for the treatment of type 2 diabetes (non-insulin-dependent diabetes). Today, a number of α-glucosidase inhibitors such as acarbose, voglibose, and miglitol, are on the market for treating type 2 diabetes. Considering the many adverse effects and low potency of available α-glucosidase inhibitors, here, we want to introduce a new series of novel and efficient α-glucosidase inhibitors. Materials and Methods: The designed coumarin fused pyridine derivatives were prepared through a three-component reaction. Heating the mixture of 4-hydroxycoumarins and ammonium acetate in N, N-dimethylformamide gave the corresponding 4-aminocoumarins, which subsequently went through Michael addition-cyclocondensation with α-azidochalcone derivatives to produce our desired products 4a-p in high yields. The in vitro activity of all the synthesized compounds was evaluated for their ability to inhibit α-glucosidase by a standard method and compared with acarbose as the reference drug. Also, kinetic study and molecular modeling of the synthesized were performed. Findings: All newly synthesized compounds displayed potent α-glucosidase inhibitory activity in the range of 101.0±2.0 to 227.3±1.4μM against the α-glucosidase enzyme when compared to the standard drug acarbose (IC50=750.0±1.5μM). Among the synthesized compounds, compound 4i depicted the most potent anti-α-glucosidase activity with IC50 value of 101.0 ± 2.0 μM, which was 7.42-fold more potent than acarbose. Kinetic study of the most potent compound 4i revealed that it inhibited α-glucosidase in a competitive mode. Conclusion: We have designed, synthesized, and evaluated new coumarin fused pyridine derivatives that all of compounds showed high anti-α-glucosidase activity in comparison to acarbose as standard drug. The molecular docking simulations of the most potent compound 4i showed a good correlation between anti-α-glucosidase activity and structure of this compound.

کلیدواژه ها:

Anti-diabetic agents ، Acarbose ، Coumarin ، Pyridine ، kinetic study ، Docking study