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
作者： Ju, Han 1 ; Murugan, N. Arul 2 ; Hou, Lingxin 1 ; Li, Ping 3 ; Guizzo, Laura 4 ; Zhang, Ying 1 ; Bertagnin, Chiara 4 ; Kong, Xiujie 1 ; Kang, Dongwei 1 ; Jia, Ruifang 1 ; Ma, Xiuli 5 ; Du, Ruikun 3 ; Poongavanam, Vasanthanathan 6 ; Loregian, Arianna 4 ; Huang, Bing 5 ; Liu, Xinyong 1 ; Zhan, Peng 1 ;
作者机构： 1.Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan 250012, Shandong, Peoples R China
2.KTH Royal Inst Technol, Sch Elect Engn & Comp Sci, Dept Comp Sci, SE-10044 Stockholm, Sweden
3.Shandong Univ Tradit Chinese Med, Coll Pharm, Jinan 250355, Peoples R China
4.Univ Padua, Dept Mol Med, I-35121 Padua, Italy
5.Shandong Acad Agr Sci, Inst Poultry Sci, Jinan 250100, Shandong, Peoples R China
6.Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark
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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