Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replicationStachulski, 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 Full text not archived in this repository. It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing. To link to this item DOI: 10.1021/jm201264t Abstract/SummaryWe 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.
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