Synthesis and bioevaluation of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acids as potent xanthine oxidase inhibitors

被引：64

作者：

Guan, Qi ^{[1
]}

Cheng, Zengjin ^{[1
]}

Ma, Xiaoxue ^{[2
]}

Wang, Lijie ^{[2
]}

Feng, Dongjie ^{[1
]}

Cui, Yuanhang ^{[1
]}

Bao, Kai ^{[1
,3
,4
]}

Wu, Lan ^{[2
]}

Zhang, Weige ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China

[2] China Med Univ, Affiliated Hosp 1, Dept Geratol, Shenyang 110001, Peoples R China

[3] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA

[4] Harvard Univ, Sch Med, Boston, MA 02215 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 85卷

基金：

中国国家自然科学基金;

关键词：

Xanthine oxidase inhibitors; 2-Phenyl-4-methyl-1,3-selenazole-5-carboxylic acid; Synthesis; Structure-activity relationship; Molecular modeling; OXIDOREDUCTASE; ALLOPURINOL; DISCOVERY; MECHANISM;

D O I：

10.1016/j.ejmech.2014.08.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：508 / 516

页数：9

共 20 条

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