2,3-Dihydroquinazolin-4(1H)-one derivatives as potent aldose reductase inhibitors: a combined experimental and computational study

A series of sixteen 2,3-dihydroquinazolin-4(1 H )-one derivatives was designed and synthesized to evaluate their potential as aldose reductase (ALR2) inhibitors for the management of diabetic complications. The synthesized compounds were structurally characterized by FT-IR, NMR, and HRMS analyses, and their inhibitory activities were assessed through in vitro enzyme assays. All compounds exhibited notable ALR2 inhibition, with K i values ranging from 0.052 to 1.272 μM. Among them, compound 9 demonstrated the highest potency ( K i = 0.052 μM), showing approximately 21-fold stronger activity than the reference inhibitor epalrestat ( K i = 1.124 μM). Structure-activity relationship analysis revealed that para-positioned electron-donating substituents and optimally positioned hydrogen-bond donor groups significantly enhance inhibitory activity, while ortho substitution adversely affects binding due to steric and conformational constraints. The most active inhibiyors exhibited low cytotoxicity against HUVEC cells, with IC50 values ranging from 36.18 to 55.41 μM, indicating that they are not cytotoxic at the concentrations required for effective ALR2 inhibition. Molecular docking and MM-GBSA analyses supported the experimental findings, indicating strong binding affinities for the most active compounds, particularly compounds 9 and 16 . Molecular dynamics simulations further confirmed the stability of the 9 -ALR2 complex, demonstrating low structural deviations and persistent interactions with key residues, including Trp-20, Val-47, His-110, Trp-219, and Leu-300. In addition, ADME and toxicity predictions suggested that the majority of the compounds possess favorable pharmacokinetic properties and low predicted toxicity profiles. These results highlight the 2,3-dihydroquinazolin-4(1 H )-one scaffold as a promising framework for the development of potent ALR2 inhibitors.