Several cinnamic acid derivatives have been reported to exhibit antiviral activity. In this study, we prepared 17 synthetic cinnamic acid derivatives and screened them to identify an effective antiviral compound against hepatitis C virus (HCV). Compound 6, one of two hit compounds, suppressed the viral replications of genotypes 1b, 2a, 3a, and 4a with EC₅₀ values of 1.5–8.1 μM and SI values of 16.2–94.2. The effect of compound 6 on the phosphorylation of Tyr⁷⁰⁵ in signal transducer and activator of transcription 3 (STAT3) was investigated because a cinnamic acid derivative AG490 was reported to suppress HCV replication and the activity of Janus kinase (JAK) 2. Compound 6 potently suppressed HCV replication, but it did not inhibit the JAK1/2-dependent phosphorylation of STAT3 Tyr⁷⁰⁵ at the same concentration. Furthermore, a pan-JAK inhibitor tofacitinib potently impaired phosphorylation of STAT3 Tyr ⁷⁰⁵, but it did not inhibit HCV replication in the replicon cells and HCV-infected cells at the same concentration, supporting the notion that the phosphorylated state of STAT3 Tyr⁷⁰⁵ is not necessarily correlated with HCV replication. The production of reactive oxygen species (ROS) was induced by treatment with compound 6, whereas N-acetyl-cysteine restored HCV replication and impaired ROS production in the replicon cells treated with compound 6. These data suggest that compound 6 inhibits HCV replication via the induction of oxidative stress.

已经报道了几种肉桂酸衍生物表现出抗病毒活性。在这项研究中，我们制备了17种合成肉桂酸衍生物，并对其进行了筛选，以鉴定出有效的抗丙型肝炎病毒（HCV）的抗病毒化合物。化合物6是两种命中化合物之一，抑制基因型1b，2a，3a和4a的病毒复制，EC ₅₀值为1.5-8.1μM，SI值为16.2-94.2。研究了化合物6对信号转导子和转录激活子3（STAT3）中Tyr ⁷⁰⁵磷酸化的影响，因为据报道肉桂酸衍生物AG490抑制HCV复制和Janus激酶（JAK）2的活性。化合物6有效抑制HCV复制，但 在相同浓度下它不抑制STAT3 Tyr ⁷⁰⁵的JAK1 / 2依赖性磷酸化。此外，泛JAK抑制剂tofacitinib可能会削弱STAT3 Tyr ^705的磷酸化，但在相同浓度下它不会抑制复制子细胞和HCV感染细胞中的HCV复制，从而支持STAT3 Tyr ⁷⁰⁵的磷酸化状态不是这样的观点。必然与HCV复制有关。通过用化合物6处理诱导了活性氧（ROS）的产生，而在用化合物6处理的复制子细胞中，N-乙酰基半胱氨酸恢复了HCV复制并损害了ROS的产生。。这些数据表明化合物6通过诱导氧化应激抑制HCV复制。