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Quinoline-Piperazine Derivatives As Potential Α-Glucosidase Inhibitors: Synthesis, Biological Evaluation, and in Silico Studies Publisher



Ghasemi M1 ; Iraji A2, 3 ; Dehghan M4 ; Nosood YL1 ; Ghanavieh NF1 ; Hashempur MH3 ; Mojtabavi S5 ; Faramarzi MA5 ; Mahdavi M6 ; Alharrasi A1
Authors

Source: Journal of Molecular Structure Published:2025


Abstract

α-Glucosidase inhibitors are crucial therapeutic agents for managing postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). This study focuses on designing, synthesizing, and evaluating a new series of quinoline-piperazine-acetamide derivatives as potential α-glucosidase inhibitors. These derivatives introduce a unique combination of a quinoline core with a flexible piperazine linker, as new scaffold for α-glucosidase inhibition. This structural modification is hypothesized to enhance enzyme interaction. The synthesized derivatives were tested in vitro for their inhibitory activity, with compound 6m (benzyl) showing significant inhibition, with IC50 values of 280.0 µM compared to the standard drug acarbose (IC50 = 750.7 µM). Molecular docking studies revealed crucial pi-pi stacking and pi-cation interactions with key residues such as His239 and Phe231, along with hydrogen bonding with Lys155, Pro309, and Thr215, which enhanced the inhibitory potency of the active compounds. Furthermore, molecular dynamics simulations confirmed that 6m consistently maintained stability within the active site of α-glucosidase throughout the simulation. These findings suggest that the synthesized compounds hold promise as α-glucosidase inhibitors for adjusting blood sugar control and metabolic health. © 2024
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