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

Bioorg Med Chem Lett. 2019 Jul 1;29(13):1609-1613. 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 ⁴

Affiliations

1 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
3 Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China.
4 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: ysylilinli@sina.com.cn.

PMID: 31053507 DOI: 10.1016/j.bmcl.2019.04.042

Abstract

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 K_D 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.

Keywords

Influenza A virus; PB2; Small molecule inhibitor; Structure-activity relationship.

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