Novel Multifunctional Aldose Reductase Inhibitors Based on Quinoxalin‐2(1 <i>H</i> )‐one Scaffold for Treatment of Diabetic Complications: Design, Synthesis, and Biological Evaluation

Diabetic complications, such as nephropathy, cataracts, and retinopathy, are the main threat and primary reason for death in diabetic patients. Numerous pieces of evidence demonstrated aldose reductase (ALR2) and oxidative stress are the two most important intervention targets for the treatment of diabetic complications. We designed a new type of multifunctional ALR2 inhibitor (ARI) based on the quinoxalin-2(1H)-one scaffold, which combined the inhibition of aldose reductase and direct antioxidation into an organic whole. Most of the compounds 6 showed potent ALR2 inhibition with IC₅₀ values ranging from 0.091 to 10.214 µM, and 2-(4-(4-bromo-2-fluorobenzyl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetic acid (6g) was the most active. All compounds were slightly active with an aldehyde reductase inhibition percentage of no more than 40.7%, demonstrating good selectivity for ALR2. Further introduction of a phenolic hydroxyl group to obtain compounds (6j-l), (6l) containing phenolic 3,5-dihydroxyl showed the best antioxidant activity with 2,2-diphenyl-1-picrylhydrazyl radical scavenging 94.62%, 90.21%, and 82.75% at the concentration of 100, 50, and 10 µM, respectively, even as strong as the well-known antioxidant Trolox. Molecular docking was also consistent with the biological data and explained the ALR2 inhibition and selectivity reasonably. Therefore, these results suggested success in the construction of multifunctional ARIs having potency for ALR2 inhibition and antioxidation.