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

Abstract

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-1H-1,2,3-triazol-4yl)methoxy)phenyl)-5-oxo-5,6-dihydro-4H-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 Renantiomers 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.

Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection

“…A docking investigation is conducted to determine the binding interaction between MDC and ADC and the residues in the active sites of MPO, DPP-4, and α-GD Table provides examples of the ligand–protein interactions and binding energies of MDC and ADC to the proteins.…”

“…A docking investigation is conducted to determine the binding interaction between MDC and ADC and the residues in the active sites of MPO, DPP-4, and α-GD. 75 Table 7 provides examples of the ligand–protein interactions and binding energies of MDC and ADC to the proteins. Salicylhydroxamic acid, sitagliptin, and acarbose, recognized for inhibiting MPO, DPP-4, and α-GD, are used as positive controls.…”