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

详细信息    查看全文

• 作者：Yu Zhang ; Lei Xu ; Zhiqiang Zhang ; Zhiyu Zhang ; Longtai Zheng ; Dan Li ; Youyong Li ; Feng Liu ; Kunqian Yu ; Tingjun Hou ; Xuechu Zhen
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2015
• 出版时间：September 28, 2015
• 年：2015
• 卷：55
• 期：9
• 页码：1994-2004
• 全文大小：580K
• ISSN：1549-960X

文摘

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鈥揳ctivity relationships were then analyzed. The most potent inhibitor (compound 5) with an IC₅₀ of 370 nM strongly suppressed lipopolysaccharide (LPS)-induced production of TNF-伪 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.