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-triazole hybrids 8a-o were synthesized and evaluated against the α-glucosidase enzyme. All compounds showed significant in vitro inhibitory activity (IC 50 values of 1.19 ± 0.05 to 20.01 ± 0.02 μM) compared to the standard drug acarbose (IC 50 = 750.0 μM). Among them, 2-amino-4-(3-((1-benzyl-1 H -1,2,3-triazol-4-yl)methoxy)phenyl)-5-oxo-5,6-dihydro-4 H -pyrano[3,2- c ]quinoline-3-carbonitrile (compound 8k ) demonstrated the best inhibitory effect toward α-glucosidase (IC 50 = 1.19 ± 0.05 μM) with a competitive pattern of inhibition. Since compound 8k was synthesized as a racemic mixture, molecular docking and dynamics simulations were performed on R - and S -enantiomers of compound 8k . Based on the molecular docking results, both R - and S -enantiomers of compound 8k displayed significant interactions with key 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 located in the enzyme active site. The R -enantiomer formed a more stable complex with a higher binding affinity to the active site of α-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 interacted with the enzyme active site, while the pyrano[3,2- c ]quinoline moiety occupied the high solvent accessible entrance of the active site. Thus, the synthesized pyrano[3,2- c ]quinoline-1,2,3-triazole hybrids seem to be promising scaffolds for the development of novel α-glucosidase inhibitors.