Design, synthesis, and aldose reductase inhibition assessment of novel Quinazolin-4(3H)-one derivatives with 4-Bromo-2-Fluorobenzene functionality.

Aldose reductase (ALR2) inhibition is a promising therapeutic strategy for managing diabetes-related complications, including neuropathy, retinopathy, and nephropathy. This study reports the design, synthesis, and biological evaluation of eighteen novel quinazolin-4(3H)-one derivatives incorporating a 4-bromo-2-fluorobenzylidene moiety as ALR2 inhibitors. Among the synthesized compounds, the cyclohexyl-substituted derivative (compound 9) exhibited the highest potency as a competitive ALR2 inhibitor, with a Ki of 0.064 μM-15 times more effective than the standard inhibitor epalrestat (EPR) (Ki = 0.967 μM). Molecular docking and dynamics simulations revealed stable binding interactions between compound 9 and key residues in the ALR2 active site, such as Trp-111, Tyr-209, Trp-20, and Ser-302. Cytotoxicity assays on HUVEC and BEAS-B2 cell lines demonstrated that the most active compounds, were non-toxic at therapeutic concentrations. ADME-T analyses highlighted the favorable drug-likeness and pharmacokinetic properties of compound 9, including high oral absorption and minimal toxicity risks, though limited solubility was identified as a challenge. While minor toxicological concerns were observed for other compounds, these were within manageable levels. Overall, compound 9 emerges as a potent and selective ALR2 inhibitor with significant potential for further optimization. Future studies will focus on enhancing its solubility and refining its pharmacokinetic and pharmacodynamic profiles to support its development as a therapeutic candidate for diabetes-associated complications.