Thiazolides as Novel Antiviral Agents. 1. Inhibition of Hepatitis B Virus Replication

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• 作者：Andrew V. Stachulski ; Chandrakala Pidathala ; Eleanor C. Row ; Raman Sharma ; Neil G. Berry ; Mazhar Iqbal ; Joanne Bentley ; Sarah A. Allman ; Geoffrey Edwards ; Alison Helm ; Jennifer Hellier ; Brent E. Korba ; J. Edward Semple ; Jean-Francois Rossignol
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4119-4132
• 全文大小：1049K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

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 (EC₅₀ = 0.33 渭m) but is inactive against anaerobes. Several 4鈥? and 5鈥?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 EC₉₀ for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.