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Jatrophane Diterpenes as Inhibitors of Chikungunya Virus Replication: Structure–Activity Relationship and Discovery of a Potent Lead

Nothias-Scaglia, Louis-Félix, Retailleau, Pascal, Paolini, Julien, Pannecouque, Christophe, Neyts, Johan, Dumontet, Vincent, Roussi, Fanny, Leyssen, Pieter, Costa, Jean, Litaudon, Marc
Journal of natural products 2014 v.77 no.6 pp. 1505-1512
Chikungunya virus, Euphorbia amygdaloides, Human immunodeficiency virus 1, Human immunodeficiency virus 2, Semliki Forest virus, Sindbis virus, X-radiation, antiviral properties, diterpenoids, ethyl acetate, inhibitory concentration 50, mechanism of action, median effective concentration, spectral analysis, structure-activity relationships, virus replication, viruses
Bioassay-guided purification of an EtOAc extract of the whole plant of Euphorbia amygdaloides ssp. semiperfoliata using a chikungunya virus-cell-based assay led to the isolation of six new (1–4, 9, and 10) and six known (5–7, 8, 11, and 12) jatrophane esters. Their planar structures and relative configurations were determined by extensive spectroscopic analysis, and their absolute configurations by X-ray analysis. These compounds were investigated for selective antiviral activity against chikungunya virus (CHIKV), Semliki Forest virus, Sindbis virus, and HIV-1 and HIV-2 viruses. Compound 3 was found to be the most potent and selective inhibitor of the replication of CHIKV and of HIV-1 and HIV-2 (EC₅₀ = 0.76, IC₅₀ = 0.34 and 0.043 μM, respectively). A preliminary structure–activity relationship study demonstrated that potency and selectivity are very sensitive to the substitution pattern on the jatrophane skeleton. Although replication strategies of CHIK and HIV viruses are quite different, the mechanism of action by which these compounds act may involve a similar target for both viruses. The present results provide additional support for a previous hypothesis that the anti-CHIKV activity could involve a PKC-dependent mechanism.