Discovery of 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one derivatives as new potent PB2 inhibitors.,Bioorganic & Medicinal Chemistry Letters

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Discovery of 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one derivatives as new potent PB2 inhibitors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2019-04-26 , DOI: 10.1016/j.bmcl.2019.04.042
Jianhong Yang ₁ , Jiatian Du ₁ , Chong Huang ₂ , Tianqi Wang ₃ , Luyi Huang ₂ , Shengyong Yang ₂ , Linli Li ₁

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PB2 is an important subunit of influenza RNA-dependent RNA polymerase (RdRP) and has been recognized as a promising target for the treatment of influenza. We herein report the discovery of a new series of PB2 inhibitors containing the skeleton 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one. Compound 12b is the most potent one, which showed KD values of 0.11 μM and 0.19 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In antiviral activity and cellular cytotoxicity assays, compound 12b showed an EC50 value of 1.025 μM and a CC50 value greater than 100 μM. Molecular docking was also used to predict the binding mode of 12b with PB2. Collectively, this study provides a promising lead compound for subsequent anti-influenza drug discovery targeting PB2.

中文翻译：

发现5-（5-氟-1H-吡咯并[2,3-b]吡啶-3-基）吡嗪-2（1H）-一衍生物作为新型有效的PB2抑制剂。

PB2是流感依赖RNA的RNA聚合酶（RdRP）的重要亚基，并且已被认为是治疗流感的有希望的靶标。我们在此报告发现了一系列新的PB2抑制剂，这些抑制剂包含骨架5-（5-氟-1H-吡咯并[2,3-b]吡啶-3-基）吡嗪-2（1H）-。化合物12b是最有效的化合物，在表面等离振子共振（SPR）和等温滴定量热（ITC）分析中，其KD值分别为0.11μM和0.19μM。在抗病毒活性和细胞毒性试验中，化合物12b的EC50值为1.025μM，CC50值大于100μM。分子对接还用于预测12b与PB2的结合模式。总的来说，这项研究为随后针对PB2的抗流感药物发现提供了有希望的先导化合物。

更新日期：2019-04-26

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