2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleoside inhibitors of HCV NS5B polymerase

• HCV NS5B (RdRp) is an attractive target for discovery of new antiviral drugs.
• Twenty novel 4-thiazolidinone derivatives were synthesized.
• Eleven compounds inhibited NS5B higher than 50% at 100 μM.
• Compounds 15 (IC50: 19.8 μM) and 24 (IC50: 5.6 μM) were the most potent inhibitors.
• Molecular modeling data provided clues for future SAR optimization.

Hepatitis C virus (HCV) NS5B polymerase is an important and attractive target for the development of anti-HCV drugs. Here we report on the design, synthesis and evaluation of twenty-four novel allosteric inhibitors bearing the 4-thiazolidinone scaffold as inhibitors of HCV NS5B polymerase. Eleven compounds tested were found to inhibit HCV NS5B with IC50 values ranging between 19.8 and 64.9 μM. Compound 24 was the most active of this series with an IC50 of 5.6 μM. A number of these derivatives further exhibited strong inhibition against HCV 1b and 2a genotypes in cell based antiviral assays. Molecular docking analysis predicted that the thiazolidinone derivatives bind to the NS5B thumb pocket-II (TP-II). Our results suggest that further optimization of the thiazolidinone scaffold may be possible to yield new derivatives with improved enzyme- and cell-based activity.

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