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

• Published in: Journal of medicinal chemistry Vol. 54; no. 24; pp. 8670 - 8680
• Main Authors: 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, Rossignol, Jean-Francois
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.12.2011
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Line; Hepacivirus - drug effects; Hepacivirus - genetics; Hepacivirus - physiology; Humans; Quantitative Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• 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.