title: Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication.
abstract: We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.
authors: Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK. andrew.stachulski@bioch.ox.ac.uk
authors: Andrew V
authors: AV
authors: Stachulski
authors: Chandrakala
authors: C
authors: Pidathala
authors: Eleanor C
authors: EC
authors: Row
authors: Raman
authors: R
authors: Sharma
authors: Neil G
authors: NG
authors: Berry
authors: Alexandre S
authors: AS
authors: Lawrenson
authors: Shelley L
authors: SL
authors: Moores
authors: Mazhar
authors: M
authors: Iqbal
authors: Joanne
authors: J
authors: Bentley
authors: Sarah A
authors: SA
authors: Allman
authors: Geoffrey
authors: G
authors: Edwards
authors: Alison
authors: A
authors: Helm
authors: Jennifer
authors: J
authors: Hellier
authors: Brent E
authors: BE
authors: Korba
authors: J Edward
authors: JE
authors: Semple
authors: Jean-Francois
authors: JF
authors: Rossignol
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C570544:2-acetoxybenzoyl-N-(5-chlorothiazol-2-yl)amide; D000577:Amides; D000998:Antiviral Agents; D013844:Thiazoles