Design, synthesis and biological evaluation of novel xanthine oxidase inhibitors bearing a 2-arylbenzo[b]furan scaffold

Abstract

Xanthine oxidase, which catalyzes the oxidative reaction of hypoxanthine and xanthine into uric acid, is a key enzyme to the pathogenesis of hyperuricemia and gout. In this study, for the purpose of discovering novel xanthine oxidase (XO) inhibitors, a series of 2-arylbenzo[b]furan derivatives (3a-3d, 4a-4o and 6a-6d) were designed and synthesized. All these compounds were evaluated their xanthine oxidase inhibitory and antioxidant activities by using in vitro enzymatic assay and cellular model. The results showed that a majority of the designed compounds exhibited potent xanthine oxidase inhibitory effects and antioxidant activities, and compound 4a emerged as the most potent xanthine oxidase inhibitor (IC₅₀ = 4.45 μM). Steady-state kinetic measurements of the inhibitor 4a with the bovine milk xanthine oxidase indicated a mixed type inhibition with 3.52 μM K_i and 13.14 μM K_is, respectively. The structure-activity relationship analyses have also been presented. Compound 4a exhibited the potent hypouricemic effect in the potassium oxonate-induced hyperuricemic mice model. A molecular docking study of compound 4a was performed to gain an insight into its binding mode with xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious in treatment of gout.

Keywords: 2-Arylbenzo[b]furan derivatives; Antioxidant; Molecular docking; Xanthine oxidase inhibitor.