Synthesis and evaluation of xanthine oxidase inhibitory and antioxidant activities of 2-arylbenzo[b]furan derivatives based on salvianolic acid C.
Xanthine oxidase (XO) is the key enzyme in humans which is related to a variety of diseases such as gout, hyperuricemia and cardiovascular diseases. In this work, a series of 2-arylbenzo[b]furan derivatives were synthesized based on salvianolic acid C, and they were evaluated for xanthine oxidase inhibitory and antioxidant activities. Compounds 5b, 6a, 6e and 6f showed potent xanthine oxidase inhibitory activities with IC50values ranging from 3.99 to 6.36 μM, which were comparable with that of allopurinol. Lineweaver-Burk plots analysis revealed that the representative derivative 6e could bind to either xanthine oxidase or the xanthine oxidase-xanthine complex, which exhibited a mixed-type competitive mechanism. A DPPH radical scavenging assay showed most of the hydroxyl-functionalized 2-arylbenzo[b]furan derivatives possessed the potent antioxidant activity, which was further validated on LPS-stimulated RAW 264.7 macrophages model. The structure-activity relationships were preliminary analyzed and indicated that the structural skeleton of 2-arylbenzo[b]furan and phenolic hydroxyl groups played an important role in maintaining xanthine oxidase inhibitory effect and antioxidant property for the series of derivatives. Meanwhile, molecular docking studies were performed to further confirm the structure-activity relationships and investigate the proposed binding mechanisms of compounds 5d, 6d and 10d binding to the protein.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Hong-Jin
HJ
Tang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Xiao-Wei
XW
Zhang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Lin
L
Yang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Wei
W
Li
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, PR China.
Jia-Huang
JH
Li
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Jin-Xin
JX
Wang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: chenj2002cpu@126.com.
Jun
J
Chen
D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D059808:Polyphenols / Q000737:chemistry*; D000067996:RAW 264.7 Cells; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D001572:Benzofurans
D000475:Alkenes; D000975:Antioxidants; D004791:Enzyme Inhibitors; D005663:Furans; D059808:Polyphenols; D014969:Xanthine Oxidase; C000597819:salvianolic acid C; D001572:Benzofurans
2-arylbenzo[b]furan derivatives; Antioxidant; Molecular docking; Salvianolic acid C; Xanthine oxidase inhibitor