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Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication

Stachulski, A. V., Pidathala, C., Row, E. C., Sharma, R., Berry, N. G., Lawrenson, A. S., Moores, S. L., Iqbal, M., Bentley, J., Allman, S., Edwards, G., Helm, A., Hellier, J., Korba, B. E., Semple, J. E. and Rossignol, J.-F. (2011) Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication. Journal of Medicinal Chemistry, 54 (24). pp. 8670-8680. ISSN 0022-2623

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To link to this item DOI: 10.1021/jm201264t


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.

Item Type:Article
Divisions:No Reading authors. Back catalogue items
Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Medicinal Chemistry Research Group
ID Code:88882
Publisher:American Chemical Society

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