Novel Pyrano[3,2-c]quinoline-1,2,3-triazole Hybrids as Potential Anti-Diabetic Agents: In Vitro α-Glucosidase Inhibition, Kinetic, and Molecular Dynamics Simulation

In this study, a novel series of pyrano[3,2-c]quinoline-1,2,3-triazolehybrids 8a-o were synthesized and evaluated againstthe & alpha;-glucosidase enzyme. All compounds showed significant invitro inhibitory activity (IC50 values of 1.19 & PLUSMN; 0.05to 20.01 & PLUSMN; 0.02 & mu;M) compared to the standard drug acarbose(IC50 = 750.0 & mu;M). Among them, 2-amino-4-(3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-oxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-3-carbonitrile(compound 8k) demonstrated the best inhibitory effecttoward & alpha;-glucosidase (IC50 = 1.19 & PLUSMN; 0.05 & mu;M)with a competitive pattern of inhibition. Since compound 8k was synthesized as a racemic mixture, molecular docking and dynamicssimulations were performed on R- and S-enantiomers of compound 8k. Based on the moleculardocking results, both R- and S-enantiomersof compound 8k displayed significant interactions withkey residues including catalytic triad (Asp214, Glu276, and Asp349)in the enzyme active site. However, an in silico study indicated that S- and R-enantiomers were inversely locatedin the enzyme active site. The R-enantiomer formeda more stable complex with a higher binding affinity to the activesite of & alpha;-glucosidase than that of the S- enantiomer.The benzyl ring in the most stable complex ((R)-compound 8k) was located in the bottom of the binding site and interactedwith the enzyme active site, while the pyrano[3,2-c]quinoline moiety occupied the high solvent accessible entrance ofthe active site. Thus, the synthesized pyrano[3,2-c]quinoline-1,2,3-triazole hybrids seem to be promising scaffoldsfor the development of novel & alpha;-glucosidase inhibitors.