Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 151, Issue -, Pages 849-860Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.01.096
Keywords
2-Arylbenzo[b]furan derivatives; Xanthine oxidase inhibitor; Antioxidant; Molecular docking
Categories
Funding
- National Natural Science Foundation of China [81573705, 81421005, 81573338]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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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-arylbenzolbjfuran 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 mu M). Steady-state kinetic measurements of the inhibitor 4a with the bovine milk xanthine oxidase indicated a mixed type inhibition with 3.52 mu M K-i and 13.14 mu M 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. (C) 2018 Elsevier Masson SAS. All rights reserved.
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