Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase
Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase
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发现含酰肼的奥司他韦类似物作为甲型流感神经氨酸酶的有效抑制剂
DOI：
10.1016/j.ejmech.2021.113567
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发表时间：
2021
影响因子：
6.7
通讯作者：
Tian Yongshou
中科院分区：
文献类型：
--
作者：
Zhao Hongqian;Jiang Siyuan;Ye Zhifan;Zhu Hongxi;Hu Baichun;Meng Peipei;Hu Yanmei;Zhang Huicong;Wang Kuanglei;Wang Jun;Tian Yongshou
神经氨酸酶（NA）抑制剂在治疗流感中起主要作用。然而，多种含有变异NA的病毒对NA抑制剂产生了严重的耐药性，因此解决这一问题具有重要意义。受本实验室公开的含脲化合物12的启发，我们设计了一系列以150空腔为靶点的含酰肼片段的奥司他韦衍生物。其中化合物17对H5 N1、H1N1、H5 N1-H274 Y、H1N1-H274 Y四种亚型的NA的活性分别是奥司他韦羧酸酯的8.77倍、4.12倍、203倍和6.23倍。同时，最佳化合物17 a在体外具有良好的代谢稳定性。本研究为奥司他韦的结构优化提供了重要参考。
Neuraminidase (NA) inhibitors play a prime role in treating influenza. However, a variety of viruses containing mutant NAs have developed severe drug resistance towards NA inhibitors, so it is of crucial significance to solve this problem. Encouraged by urea-containing compound12disclosed by our lab, we designed a series of oseltamivir derivatives bearing hydrazide fragment for targeting the 150 cavity. Among the synthesized compounds, compound17ashowed 8.77-fold, 4.12-fold, 203-fold and 6.23-fold more potent activity than oseltamivir carboxylate against NAs from H5N1, H1N1, H5N1–H274Y, H1N1–H274Y, respectively. Meanwhile, the best compound 17a exhibited satisfactory metabolic stabilityin vitro. This study offers an important reference for the structural optimization of oseltamivir aiming at potent inhibition against H274Y mutant of NAs.