Discovery of novel "Dual-site" binding oseltamivir derivatives as potent influenza virus neuraminidase inhibitors

文献类型： 外文期刊

第一作者： Jia, Ruifang

作者： Jia, Ruifang;Cherukupalli, Srinivasulu;Ding, Xiao;Sun, Zhuosen;Sun, Lin;Jiang, Xiangyi;Li, Zhong;Wang, Defeng;Zhan, Peng;Liu, Xinyong;Ai, Wei;Zhang, Jian;Ma, Xiuli;Huang, Bing;Zalloum, Waleed A.

作者机构：

关键词： Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives; 150-cavity; Active site

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：6.514； 五年影响因子：6.099 ）

ISSN： 0223-5234

年卷期： 2020 年 191 卷

页码：

收录情况： SCI

摘要： From our research group, it was noticed that oseltamivir derivatives targeting 150-cavity of neuraminidase enzyme (NA) could significantly increase antiviral activity. Thus, we further enriched the C5-NH2 position of oseltamivir structure to obtain more potent oseltamivir derivatives. In this article a series of oseltamivir derivatives were synthesized by modifying C5-NH2 position of oseltamivir. All the compounds were evaluated for in vitro antiviral activity against H5N1 and H5N8. Encouragingly, compounds 9a and 11e were exhibited prominent activity, which is similar to oseltamivir carboxylate (OSC) and in NAs inhibitory assay, 11e showed remarkable potency against N1 (H5N1), N2 (H5N2), N6 (H5N6) and N8 (H5N8). In addition, 11e demonstrated low cytotoxicity and no obvious toxicity at the dose of 1500 mg/kg in mice. Molecular docking studies of 9a and 11e provided a plausible rationale for the high potency against group-1 NAs. This work provided new insights to design further neuraminidase inhibitors, which can help to investigate new potent inhibitors for group-1 and group-2 shortly. (c) 2020 Elsevier Masson SAS. All rights reserved.

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