title: Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication.
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.
authors.affiliation: Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK. andrew.stachulski@bioch.ox.ac.uk
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Stachulski
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Pidathala
authors.forename: Eleanor C
authors.initials: EC
authors.lastname: Row
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.forename: Mazhar
authors.initials: M
authors.lastname: Iqbal
authors.forename: Joanne
authors.initials: J
authors.lastname: Bentley
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Allman
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Edwards
authors.forename: Alison
authors.initials: A
authors.lastname: Helm
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hellier
authors.forename: Brent E
authors.initials: BE
authors.lastname: Korba
authors.forename: J Edward
authors.initials: JE
authors.lastname: Semple
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Rossignol
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D020719:Glucuronides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012457:Salicylamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014771:Virion / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication
chemical_list: C561053:2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide; D000577:Amides; D000998:Antiviral Agents; D020719:Glucuronides; D011355:Prodrugs; D012457:Salicylamides; D013844:Thiazoles