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

Stachulski, Andrew V.; Pidathala, Chandrakala; Row, Eleanor C.; Sharma, Raman; Berry, Neil G.; Lawrenson, Alexandre S.; Moores, Shelley L.; Iqbal, Mazhar; Bentley, Joanne; Allman, Sarah A.; Edwards, Geoffrey; Helm, Alison; Hellier, Jennifer; Korba, Brent E.; Semple, J. Edward and Rossignol, Jean-Francois (2011). Thiazolides as novel antiviral agents. 2. Inhibition of Hepatitis C virus replication. Journal of Medicinal Chemistry, 54(24) pp. 8670–8680.

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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: Journal Item
Copyright Holders: 2011 American Chemical Society
ISSN: 1520-4804
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 38324
Depositing User: Sarah Allman
Date Deposited: 03 Sep 2013 11:03
Last Modified: 07 Dec 2018 10:18
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