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

被引：37

作者：

Stachulski, Andrew V. ^{[1
]}

Pidathala, Chandrakala ^{[1
]}

Row, Eleanor C. ^{[1
]}

Sharma, Raman ^{[1
]}

Berry, Neil G. ^{[1
]}

Lawrenson, Alexandre S. ^{[1
]}

Moores, Shelley L. ^{[1
]}

Iqbal, Mazhar ^{[1
]}

Bentley, Joanne ^{[1
]}

Allman, Sarah A. ^{[2
]}

Edwards, Geoffrey ^{[3
]}

Helm, Alison ^{[3
]}

Hellier, Jennifer ^{[3
]}

Korba, Brent E. ^{[4
]}

Semple, J. Edward ^{[5
]}

Rossignol, Jean-Francois ^{[2
,5
,6
]}

机构：

[1] Univ Liverpool, Dept Chem, Robert Robinson Labs, Liverpool L69 7ZD, Merseyside, England

[2] Univ Oxford, Inst Glycobiol, Dept Biochem, Oxford OX1 3QU, England

[3] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 7ZD, Merseyside, England

[4] Georgetown Univ, Med Ctr, Dept Mol Microbiol & Immunol, Washington, DC 20057 USA

[5] Romark Labs LC, Tampa, FL 33607 USA

[6] Stanford Univ, Med Ctr, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 24期

关键词：

BIOLOGICAL EVALUATION; RNA REPLICATION; PLUS RIBAVIRIN; IN-VITRO; B-VIRUS; NITAZOXANIDE; RESISTANCE; PEGINTERFERON; INTERFERON-ALPHA-2B; SALICYLANILIDES;

D O I：

10.1021/jm201264t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') 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'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure activity 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.

引用

页码：8670 / 8680

页数：11

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