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Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication

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 and Rossignol, Jean-Francois (2011). Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication. Journal of Medicinal Chemistry, 54(12) pp. 4119–4132.

DOI (Digital Object Identifier) Link: https://doi.org/10.1021/jm200153p
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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 (EC50 = 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 EC90 for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.

Item Type: Journal Item
Copyright Holders: 2011 American Chemical Society
ISSN: 1520-4804
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetRomark Laboratories
Not SetNot SetUniversity of Oxford
Not SetContract NO1-AI-30046NIAID
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 38118
Depositing User: Sarah Allman
Date Deposited: 07 Aug 2013 11:41
Last Modified: 07 Dec 2018 10:17
URI: http://oro.open.ac.uk/id/eprint/38118
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