Identification of quinoxalin-2(1 toggle="yes"H)-one derivatives as a novel class of multifunctional aldose reductase inhibitors

Aim: Targeting aldose reductase and oxidative stress with quinoxalin-2(1H)-one derivatives having a 1-hydroxypyrazole head as the bioisosteric replacement of carboxylic acid. Methodology & results: Aldose reductase inhibition, selectivity and antioxidant potency of all the synthesized compounds were evaluated, and binding modes were studied by molecular docking. Most of the derivatives showed potent and selective aldose reductase inhibition, and among them 13d was the most active (IC₅₀ = 0.107 μM), suggesting success of the bioisosteric strategy. Phenolic 3,4-dihydroxyl compound 13f showed strong antioxidant ability even comparable to that of the well-known antioxidant Trolox. Conclusion: The present study identified the excellent bioisostere of the 1-hydroxypyrazole head group along with phenolic hydroxyl and vinyl spacer in C3 side chain on constructing quinoxalinone-based multifunctional aldose reductase inhibitors.