Thiazolides as Novel Antiviral Agents. 2. Inhibition of Hepatitis C Virus Replication

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• 作者：Andrew V. Stachulski ; Chandrakala Pidathala ; Eleanor C. Row ; Raman Sharma ; Neil G. Berry ; Alexandre S. Lawrenson ; Shelley L. Moores ; 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：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8670-8680
• 全文大小：340K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure鈥揳ctivity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5鈥? generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5鈥?Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure鈥揳ctivity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.