Novel Pyrano[3,2-<i>c</i>]quinoline-1,2,3-triazole Hybrids as Potential Anti-Diabetic Agents: <i>In Vitro</i> α-Glucosidase Inhibition, Kinetic, and Molecular Dynamics Simulation
Soheila Esmaili, Ahmad Ebadi, Ardeshir Khazaei, Hamideh Ghorbani, Mohammad Ali Faramarzi, Somayeh Mojtabavi, Mohammad Mahdavi, Zahra Najafi
Abstract
High Resolution Image Download MS PowerPoint Slide 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.