| Literature DB >> 22059983 |
Andrew V Stachulski1, 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.
Abstract
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.Entities:
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Year: 2011 PMID： 22059983 DOI： 10.1021/jm201264t
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446