Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 85, Issue -, Pages 508-516Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.08.014
Keywords
Xanthine oxidase inhibitors; 2-Phenyl-4-methyl-1,3-selenazole-5-carboxylic acid; Synthesis; Structure-activity relationship; Molecular modeling
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Funding
- National ST Major Project [2012ZX09103101-060]
- National Natural Science Foundation of China [30973614]
- Key Science and Technology Project of Liaoning Province [2009225012]
- Shenyang Science & Technology Bureau Item [F12-277-1-23]
- Program for Innovative Research Team of the Ministry of Education
- Program for Liaoning Innovative Research Team in University
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A series of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acid derivatives (8a-f, 9a-m) were synthesized and evaluated for inhibitory activity against xanthine oxidase in vitro. Structure activity relationship analyses have also been presented. Most of the target compounds exhibited potency levels in the nanomolar range. Compound 9e emerged as the most potent xanthine oxidase inhibitor (IC50 = 5.5 nM) in comparison to febuxostat (IC50 = 18.6 nM). Steady-state kinetics measurements with the bovine milk enzyme indicated a mixed type inhibition with K-i and K-i(') values of 0.9 and 2.3 nM, respectively. A molecular modeling study on compounds 9e was performed to gain an insight into its binding mode with xanthine oxidase, and to provide the basis for further structure-guided design of new non-purine xanthine oxidase inhibitors related with 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acid scaffold. (C) 2014 Elsevier Masson SAS. All rights reserved.
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