Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 12, Pages 4119-4132Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm200153p
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Funding
- Romark Laboratories at the University of Liverpool, U.K.
- University of Oxford, U.K.
- NIAID [NO1-AI-30046]
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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 (EC50 = 0.33 mu m) 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 EC90 for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazofides in relation to the present results.
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