Thiazolides as Novel Antiviral Agents: I. Inhibition of Hepatitis B Virus Replication

• Published in: Journal of medicinal chemistry Vol. 54; no. 12; pp. 4119 - 4132
• Main Authors: Stachulski, Andrew V., Pidathala, Chandrakala, Row, Eleanor C., Sharma, Raman, Berry, Neil G., 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: 23.05.2011
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200153p

We report the syntheses and activities of a wide range of thiazolides [viz. 2-hydroxyaroyl- N -(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl- N -(5-nitrothiazol-2-yl)amide; NTZ] 1 is a broad spectrum antiinfective agent, effective against anaerobic bacteria, viruses and parasites. By contrast, 2-hydroxybenzoyl- N -(5-chlorothiazol-2-yl)amide 3 is a novel, potent and selective inhibitor of hepatitis B replication (EC 50 = 0.33 μm) but is inactive against anaerobes. Several 4′- and 5′-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1 , viz. the O -acetate is an effective prodrug and the O -aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC 90 s for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.