一系列新型喹啉衍生物作为抗呼吸道合胞病毒或抗甲型流感病毒药物的合成及抗病毒活性
Synthesis and antiviral activity of a series of novel quinoline derivatives as anti-RSV or anti-IAV agents.
作者信息
Wang Minghua, Zhang Guoning, Zhao Jianyuan, Cheng Ningning, Wang Yujia, Fu Yuanhui, Zheng Yanpeng, Wang Juxian, Zhu Mei, Cen Shan, He Jinsheng, Wang Yucheng
机构信息
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044, China.
出版信息
Eur J Med Chem. 2021 Mar 15;214:113208. doi: 10.1016/j.ejmech.2021.113208. Epub 2021 Jan 27.
We report herein the synthesis of a series of novel quinoline derivatives, based on the lead compound 1a, identified from a rRSV-mGFP high-throughput screening assay. Our results revealed that target compounds 1b, 1g-h, 1af and 1ah (IC = 3.10-6.93 μM) had good in vitro activity against RSV, which were better than 1a and ribavirin. In addition, we found that compound 1g displayed the lower cytotoxicity (CC: 2490.33 μM) and the highest selective index (SI = 673.06), suggesting its promising potential as a candidate for further development. On the other hand, compounds 1a, 1m, 1v, 1ad-1af and 1ah-1ai (ICs: 1.87-14.28 μM) were more active against IAV than or comparable to ribavirin (IC: 15.36 ± 0.93 μM). Particularly, the most active compound 1ae (IC: 1.87 ± 0.58 μM) was found to be 8.2-fold more potent than the reference drug, which could inhibit the virus transcription and replication cycle at an early stage.
我们在此报告基于从呼吸道合胞病毒（rRSV）-修饰绿色荧光蛋白（mGFP）高通量筛选试验中鉴定出的先导化合物1a合成的一系列新型喹啉衍生物。我们的结果表明，目标化合物1b、1g - h、1af和1ah（IC₅₀ = 3.10 - 6.93 μM）对呼吸道合胞病毒具有良好的体外活性，优于1a和利巴韦林。此外，我们发现化合物1g表现出较低的细胞毒性（CC₅₀：2490.33 μM）和最高的选择性指数（SI = 673.06），表明其作为进一步开发候选物具有广阔的潜力。另一方面，化合物1a、1m、1v、1ad - 1af和1ah - 1ai（IC₅₀：1.87 - 14.28 μM）对甲型流感病毒（IAV）的活性比利巴韦林（IC₅₀：15.36 ± 0.93 μM）更强或与之相当。特别地，发现活性最强的化合物1ae（IC₅₀：1.87 ± 0.58 μM）的效力是参考药物的8.2倍，它可以在早期抑制病毒转录和复制周期。
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