Bicyclic octahydrocyclohepta[b]pyrrol-4(1H)one derivatives as novel selective anti-hepatitis C virus agents

• New anti-HCV compounds possessing an octahydrocyclohepta[b]pyrrol-4(1H)-one core were identified within the EDASA library.
• Compound 34 was the most potent derivative against both genotypes 1b and 2a.
• Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors.

We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new chemotype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC50 values of 1.8 μM and 4.5 μM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI = 112.4; gt 2a SI = 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds.

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