Design, Synthesis, and Biological Evaluation of Itaconic Acid Derivatives as Potential Anti-Influenza Agents
Design, Synthesis, and Biological Evaluation of Itaconic Acid Derivatives as Potential Anti-Influenza Agents
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DOI：
10.1021/acs.jmedchem.8b01683
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发表时间：
2019-03-14
影响因子：
7.3
通讯作者：
Hsieh, Pei-Wen
中科院分区：
文献类型：
--
作者：
Sethy, Bidyadhar;Hsieh, Chung-Fan;Hsieh, Pei-Wen
甲型流感病毒（iav）通过重新组合和产生耐药突变体，使抗病毒药物和目前的疫苗接种不再可用，造成了世界范围的流行病和大流行。在这项研究中，通过进行基于细胞的筛选试验，从2万种化合物的化学文库中鉴定出衣康酸衍生物1，作为具有抗甲型流感活性的先导剂。据此，采用合理的设计策略，设计合成了一系列衣康酸衍生物，以获得更有效的抗流感药物。体外药理学研究结果表明，化合物4和8在Madin-Darby犬肾细胞中的抗iav作用最强，半最大有效浓度分别为0.14 μ M和0.11 μ M。作用机制研究表明，铅剂1和铅剂4通过直接靶向IAV核蛋白和破坏病毒核糖核蛋白从细胞核向细胞质的输出来减少病毒复制。化合物4具有很高的抗iav潜力，其选择性指数为bbb785，是进一步开发抗iav的候选化合物。
Influenza A viruses (IAVs) have caused worldwide epidemics and pandemics by reassortment and generation of drug-resistant mutants, which render antivirals and current vaccinations no longer usable. In this study, an itaconic acid derivative 1 was identified from a chemical library of 20 000 compounds, by performing a cell-based screening assay, as a lead agent exhibiting anti-influenza A activity. Accordingly, a series of itaconic acid derivatives were designed and synthesized by adopting a rational design strategy to obtain more potent anti-influenza agents. The results of an in vitro pharmacological study showed that compounds 4 and 8 exhibited the most potent anti-IAV effect with half-maximal effective concentration values of 0.14 and 0.11 mu M, respectively, in Madin-Darby canine kidney cells. The mechanism of action studies showed that lead agents 1 and 4 reduced virus replication by directly targeting IAV nucleoproteins and disrupting virus ribonucleoprotein export from the nucleus to the cytosol. On the basis of its high potential as an anti-IAV agent and its selectivity index >785, compound 4 was found to be a promising candidate for further development against IAVs.