Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction
Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction
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DOI：
10.1021/acs.jmedchem.1c01527
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发表时间：
2021-12-14
影响因子：
7.3
通讯作者：
Watanabe，Ken
中科院分区：
文献类型：
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作者：
Mizuta，Satoshi;Otaki，Hiroki;Watanabe，Ken
流感病毒是人类传染性呼吸道疾病的罪魁祸首，在全球范围内引起季节性流行病和偶尔的大流行。在此之前，我们鉴定了一种喹啉酮衍生物PA-49，它通过靶向PA-PB 1相互作用抑制流感病毒RNA依赖的RNA聚合酶（RdRp）。本文对PA-49进行了结构优化，得到了具有更强抗流感病毒活性的3-（（二苄氨基）甲基）喹啉酮衍生物。在优化过程中，确定了比PA-49活性更高的目标化合物89。进一步的优化和89的骨架跳跃分别产生了最有效的化合物100和1，8-萘啶酮衍生物118。我们最终确定化合物100和118抑制流感病毒的复制，并且在50%有效浓度（EC 50）= 0.061-0.226 μM的范围内表现出针对A型和B型流感病毒的抗流感病毒活性，具有低毒性（50%细胞毒性浓度（CC 50）>10 μM）。
Influenza viruses are responsible for contagious respiratory illnesses in humans and cause seasonal epidemics and occasional pandemics worldwide. Previously, we identified a quinolinone derivativePA-49, which inhibited the influenza virus RNA-dependent RNA polymerase (RdRp) by targeting PA–PB1 interaction. This paper reports the structure optimization ofPA-49, which resulted in the identification of 3-((dibenzylamino)methyl)quinolinone derivatives with more potent anti-influenza virus activity. During the optimization, the hit compound89, which was more active thanPA-49, was identified. Further optimization and scaffold hopping of89led to the most potent compounds100and a 1,8-naphthyridinone derivative118, respectively. We conclusively determined that compounds100and118suppressed the replication of influenza virus and exhibited anti-influenza virus activity against both influenza virus types A and B in the range of 50% effective concentration (EC50) = 0.061–0.226 μM with low toxicity (50% cytotoxic concentration (CC50) >10 μM).