QUINOXALINE DERIVATIVES AS -GLUCOSIDASE INHIBITORS: SYNTHESIS AND BIOLOGICAL EVALUATION

Objective: The primary aim of this study is to develop novel α-glucosidase inhibitors with high efficacy through rational design and synthesis strategies utilizing pharmacophoric scaffolds previously defined in the literature. This research aims to contribute to the discovery of clinically relevant potential drug candidates for the treatment of diabetes mellitus. Towards this end, some quinoxaline-hydrazone derivatives were synthetized, and their α-glucosidase inhibition were experimentally investigated. Furthermore, to elucidate the enzyme inhibition mechanism and the ligand-enzyme interactions at the molecular level, molecular docking studies and enzyme inhibition kinetic analyses were conducted on the most active compound. Material and Method: The quinoxaline-hydrazone derivatives were synthesized via a three-step procedure. The structures of the synthesized compounds were confirmed by spectral analysis, including FT-IR, ¹H NMR, ¹³C NMR and HR-MS techniques. The α-glucosidase inhibition and enzyme kinetic study were conducted in vitro with a standard colorimetric assay, using p-nitrophenyl-α-D-glucopyranoside (pNPG) as the substrate. Acarbose was used as a reference standard. Inhibiton % and the IC50 values were calculated to assess the inhibitory potency of the compounds. Molecular docking study was executed by the GOLD 5.2 program. Result and Discussion: The biological activity assessment showed that the synthesized quinoxaline-hydrazone derivatives exhibited inhibitory activity with varying percentages against the α-glucosidase. Among the compounds tested, 2 bearing p-hydroxy subtituent on the N-phenyl ring is the most effective compound and displayed a stronger α-glucosidase inhibitory activity with IC50 value of 0.413 ± 0.048 mM compared to the standard drug acarbose (IC50=1.211 ± 0.08 mM). Furthermore, the kinetic study showed that the most active compound 2 acted as a competitive inhibitor of the α-glucosidase enzyme, with a Ki value of 115.6 µM. Additionally, molecular docking analysis showed that the molecular interactions between compound 2 and the enzyme's active site, and these interactions were observed to be consistent with the biological activity and kinetic results. These findings suggest that the quinoxaline-hydrazone scaffold could serve as a promising lead structure for the development of novel potent antidiabetic agents.