A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation

文献类型： 外文期刊

第一作者： Zhang, Jiwei

作者： Zhang, Jiwei;Liu, Chuanfeng;Jia, Ruifang;Zhang, Xujie;Jiang, Yuanmin;Jia, Huinan;Jia, Shuzhen;Zhan, Peng;Liu, Xinyong;Liu, Chuanfeng;Zhang, Jian;Bertagnin, Chiara;Bonomini, Anna;Guizzo, Laura;Loregian, Arianna;Ma, Xiuli;Huang, Bing;Zhan, Peng;Liu, Xinyong;Huang, Bing;Zhan, Peng;Liu, Xinyong

作者机构：

关键词： Influenza virus; neuraminidase inhibitors; 150-cavity; oseltamivir; drug design

期刊名称：JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY （ 影响因子：5.6； 五年影响因子：5.2 ）

ISSN： 1475-6366

年卷期： 2023 年 38 卷 1 期

页码：

收录情况： SCI

摘要： Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

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