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

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• 作者：Louis-F茅lix Nothias-Scaglia ; Pascal Retailleau ; Julien Paolini ; Christophe Pannecouque ; Johan Neyts ; Vincent Dumontet ; Fanny Roussi ; Pieter Leyssen ; Jean Costa ; Marc Litaudon
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：June 27, 2014
• 年：2014
• 卷：77
• 期：6
• 页码：1505-1512
• 全文大小：322K
• ISSN：1520-6025

文摘

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鈥?b>4, 9, and 10) and six known (5鈥?b>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 渭M, respectively). A preliminary structure鈥揳ctivity 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.