Abstract
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-(beta-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 mu M 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.