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

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.

本研究以基孔肯雅病毒-细胞测定法为活性导向，对钩腺大戟（Euphorbia amygdaloides ssp. semiperfoliata）全株的乙酸乙酯（EtOAc）提取物进行生物活性导向分离纯化，最终得到6个全新的续随子烷酯类化合物（编号1~4、9及10）与6个已知续随子烷酯类化合物（编号5~7、8、11及12）。通过详尽的波谱分析确定了所有化合物的平面结构与相对构型，并借助X射线单晶衍射分析明确了其绝对构型。随后对上述化合物开展了针对基孔肯雅病毒（chikungunya virus, CHIKV）、塞姆利基森林病毒、辛德毕斯病毒以及人类免疫缺陷病毒1型（HIV-1）和2型（HIV-2）的选择性抗病毒活性评价。活性筛选结果显示，化合物3是针对基孔肯雅病毒、HIV-1及HIV-2复制过程最为强效且选择性最优的抑制剂，其半数有效浓度（EC₅₀）分别为0.76、0.34与0.043 μM，对应半数抑制浓度（IC₅₀）亦与之匹配。初步构效关系研究表明，续随子烷骨架上的取代模式对化合物的活性与选择性具有显著影响。尽管基孔肯雅病毒与人类免疫缺陷病毒的复制策略存在显著差异，但此类化合物对二者的作用机制可能靶向相似的靶点。本研究结果为此前提出的“抗基孔肯雅病毒活性可能依赖蛋白激酶C（Protein Kinase C, PKC）介导的机制”这一假说提供了新的实验依据。