Thiazolides as Novel AntiviralAgents. 2. Inhibitionof Hepatitis C Virus Replication.

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–activityrelationships (SARs) of thiazolides against HCV are less predictablethan against hepatitis B virus (HBV), though an electron-withdrawinggroup at C(5′) generally correlates with potency. Among therelated salicyloylanilides, the m-fluorophenyl analoguewas most promising; niclosamide and close analogues suffered fromvery low solubility and bioavailability. Nitazoxanide (NTZ) 1has performed well in clinical trials against HCV. We showhere that the 5′-Cl analogue 4has closely comparablein vitro activity and a good cell safety index. By use of supportvector analysis, a quantitative structure–activity relationship(QSAR) model was obtained, showing good predictive models for cellsafety. We conclude by updating the mode of action of the thiazolidesand explain the candidate selection that has led to compound 4entering preclinical development. [ABSTRACT FROM AUTHOR]