Structure-Activity Relationships and Anti-inflammatory Activities of N-Carbamothioylformamide Analogues as MIF Tautomerase Inhibitors

被引：7

作者：

Zhang, Yu ^{[1
,2
]}

Xu, Lei ^{[3
,4
]}

Zhang, Zhiqiang ^{[1
,2
]}

Zhang, Zhiyu ^{[1
,2
]}

Zheng, Longtai ^{[1
,2
]}

Li, Dan ^{[3
]}

Li, Youyong ^{[5
]}

Liu, Feng ^{[1
,2
]}

Yu, Kunqian ^{[6
]}

Hou, Tingjun ^{[1
,2
,3
,5
]}

Zhen, Xuechu ^{[1
,2
]}

机构：

[1] Soochow Univ, Coll Pharmaceut Sci, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Suzhou 215123, Jiangsu, Peoples R China

[2] Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou 215123, Jiangsu, Peoples R China

[3] Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China

[4] Jiangsu Univ Technol, Sch Elect & Informat Engn, Inst Bioinformat & Med Engn, Changzhou 213001, Peoples R China

[5] Soochow Univ, Inst Funct Nano & Soft Mat FUNSOM, Suzhou 215123, Jiangsu, Peoples R China

[6] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2015年 / 55卷 / 09期

基金：

美国国家科学基金会; 中国博士后科学基金;

关键词：

TRADITIONAL CHINESE MEDICINES; DRUG-LIKENESS ANALYSIS; INFLAMMATORY RESPONSE; CRYSTAL-STRUCTURE; NITRIC-OXIDE; DISCOVERY; SHOCK; SITE; EXPRESSION; PREDICTION;

D O I：

10.1021/acs.jcim.5b00445

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is an attractive therapeutic target for the treatment of inflammatory diseases. In our previous study, 3-[(biphenyl-4-ylcarbonyl)carbamothioyl] amino benzoic acid (compound 1) was discovered as a potent inhibitor of MIF by docking-based virtual screening and bioassays. Here, a series of analogues of compound 1 derived from similarity search and chemical synthesis were evaluated for their MIF tautomerase activities, and their structure activity relationships were then analyzed. The most potent inhibitor (compound 5) with an IC50 of 370 nM strongly suppressed lipopolysaccharide (LPS)-induced production of TNF-alpha and IL-6 in a dose-dependent manner and significantly enhanced the survival rate of mice with LPS-induced endotoxic shock from 0 to 35% at 0.5 mg/kg and to 45% at 1 mg/kg, highlighting the therapeutic potential of the MIF tautomerase inhibition in inflammatory diseases.

引用

页码：1994 / 2004

页数：11

共 51 条

[1] ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis [J].