6-Chlorocoumarin Conjugates with Nucleobases and Nucleosides as Potent Anti-Hepatitis C Virus Agents

On the basis of a "chemo-combination strategy", (6-chloro)coumarin was incorporated to purines and pyrimidines, as well as their corresponding nucleosides, with a -SCH₂- linker at different positions under alkaline conditions. These conjugates were found to exert an antiviral effect on the 1b subgenomic replicon replication of the hepatitis C virus (HCV) in Huh 5-2 and Huh 9-13 cells. In this compound library containing 14 new compounds, 6-[(6'-chlorocoumarin-3'-yl)methylthio]purine, 6-(6'-chlorocoumarin-3'-yl)methylthio-9-(β-D-ribofuranos-1″-yl)purine, and 2-[(6'-chlorocoumarin-3'-yl)methylthio]uracil showed great inhibitory abilities, with EC₅₀ values between 6.6 and 9.4 μM and selectivity indexes >16-41. Moreover, the structure-activity relationship between purines and pyrimidines is elucidated, which reveals the critical factor of the attachment of the coumarin moiety at different positions in purines and pyrimidines.