The dichloromethane extract of the leaves of Bupleurum fruticosum was found to inhibit the replication of human rhinovirus (HRV) serotypes 14 and 39. Bioassay-guided fractionation led to the isolation of seven phenylpropenol derivatives (3-9), two polyacetylenes (1 and 2), and one monoterpene (10). Compounds 1 and 10 were identified as previously undescribed secondary metabolites after extensive 1D and 2D NMR experiments as well as high-resolution mass spectrometry. Compounds 2, 4, and 5 showed a selective inhibition of viral replication against HRV39 serotype, with 2 and 4 being the most active, with EC50 values of 1.8 +/- 0.02 and 2.4 +/- 0.04 muM. Mechanism of action studies indicated that 4 behaves not only as a capsid binder, interfering with the early phases of virus replication, but also as a late-phase replication inhibitor. Docking experiments were performed to confirm the ability of the antiviral phenylpropenoids to selectively fit into the hydrophobic pocket of VP1-HRV39.