Identification of C5-NH2 Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability

文献类型： 外文期刊

第一作者： Ju, Han

作者： Ju, Han;Hou, Lingxin;Zhang, Ying;Kong, Xiujie;Kang, Dongwei;Jia, Ruifang;Liu, Xinyong;Zhan, Peng;Murugan, N. Arul;Li, Ping;Du, Ruikun;Guizzo, Laura;Bertagnin, Chiara;Loregian, Arianna;Ma, Xiuli;Huang, Bing;Poongavanam, Vasanthanathan

作者机构：

期刊名称：JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：7.446； 五年影响因子：7.319 ）

ISSN： 0022-2623

年卷期： 2021 年 64 卷 24 期

页码：

收录情况： SCI

摘要： Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achievemore potent and more selective inhibitors. In this work, foursubseries of C5-NH2modified oseltamivir derivatives weredesigned and synthesized to explore every region inside the 150-cavity. Among them, compound23dwas exceptionally potentagainst the whole panel of Group-1 NAs with IC50values rangingfrom 0.26 to 0.73 nM, being 15 & minus;53 times better than oseltamivircarboxylate (OSC) and 7 & minus;11 times better than zanamivir. Incellular assays,23dshowed more potent or equipotent antiviralactivities against corresponding virus strains compared to OSCwith no cytotoxicity. Furthermore,23dexhibited high metabolicstability in human liver microsomes (HLM) and low inhibitoryeffect on main cytochrome P450 enzymes. Notably,23ddisplayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall,23dappears to be a promising candidate for the treatment of influenza virus infection.

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