Synthesis and Evaluation of Novel Quinazolinone-Conjugated Triazole Hybrids as Anti-Glycation Agents: An Integrated Experimental and in Silico Approach

Abstract

In the present study, a series of Quinazolinone-triazole hybrids (2a-j) were developed and assessed as multi-therapeutic compounds against hyperglycemia and glycation-induced diabetic complications. These agents are designed to competitively halt the bonds between monosaccharides and serum proteins in the glycation process.  Structural elucidation was carried out by various spectroscopic techniques, and their biological activities were evaluated in vitro through UV-visible spectroscopy-based assays. The most active α-glycosidase inhibitory activity of compounds 2d and 2h, with IC₅₀ values 58.33±0.88 µM and 46.00±1.15 µM, respectively, was found among these synthesized hybrids with improved activity compared to the standard rutin (IC₅₀= 75.33±1.45 µM). These potent compounds also blocked the production of advanced glycation end products (ACEs) as evidenced by their fructosamine level estimation (IC₅₀: 2d = 66.66±0.88µM, and 2h = 53.33±1.76 µM). Further, these derivatives represented the strong antioxidant potential (IC₅₀: 2d=25.66±0.88 µM and 2h=34.00±1.00 µM) over ascorbic acid. The result of biological activity suggested that the electron-donating groups, especially the alkyl group, exhibited strong activity over the electron-withdrawing group. The simulation results of molecular docking supported that the stronger molecular interaction could be attributed to the introduction of the electron-donating groups that led to a higher bioactivity of these derivatives. Overall, the findings suggest that Quinazolinone-triazole hybrids are potentially useful multi-therapeutic agents in the treatment of diabetic conditions and the glycation process-related complications.