Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
J Med Chem. 2011 Jun 23;54(12):4119-32. doi: 10.1021/jm200153p. Epub 2011 May 23.
We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.
我们报告了一系列噻唑烷[即 2-羟基芳酰基-N-（噻唑-2-基）酰胺]的合成和抗乙型肝炎病毒复制活性，并对我们的结果进行了定量构效关系分析。典型的噻唑烷，硝唑尼特[2-羟基苯甲酰基-N-（5-硝基噻唑-2-基）酰胺，NTZ]1 是一种广谱抗感染药物，对厌氧菌、病毒和寄生虫均有效。相比之下，2-羟基苯甲酰基-N-（5-氯噻唑-2-基）酰胺 3 是一种新型、有效且选择性的乙型肝炎病毒复制抑制剂（EC（50）=0.33μm），但对厌氧菌无活性。一些 4'-和 5'-取代的噻唑烷对 HBV 具有良好的活性；相比之下，一些相关的水杨酰苯胺则显示出较窄的活性谱。3 的 ADME 性质与 1 相似；即，O-乙酸酯是一种有效的前药，O-芳基葡萄糖醛酸酯是主要代谢物。QSAR 研究表明，观察到的细胞内病毒的 EC（90）与噻唑烷结构参数之间存在良好的相关性。最后，我们讨论了噻唑烷的作用机制与目前结果的关系。
