| Literature DB >> 21553812 |
Andrew V Stachulski1, Chandrakala Pidathala, Eleanor C Row, Raman Sharma, Neil G Berry, 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 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) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.Entities:
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Year: 2011 PMID： 21553812 PMCID： PMC3124649 DOI： 10.1021/jm200153p
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446