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Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavity

文献类型： 外文期刊

作者： Jia, Ruifang 1 ; Zhang, Jian 2 ; Bertagnin, Chiara 3 ; Cherukupalli, Srinivasulu 1 ; Ai, Wei 1 ; Ding, Xiao 1 ; Li, Zh 1 ;

作者机构： 1.Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Med Chem,Key Lab Chem Biol,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China

2.Shandong Univ, Hosp 2, Cheeloo Coll Med, Inst Med Sci, Jinan 250033, Shandong, Peoples R China

3.Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy

4.Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China

5.China Belgium Collaborat Res Ctr Innovat Antivira, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China

关键词： Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives; 150-Cavity

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：5.572； 五年影响因子：5.207 ）

ISSN： 0223-5234

年卷期： 2021 年 212 卷

页码：

收录情况： SCI

摘要： Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C-5-NH2 of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1-H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1-H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1-H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties. (C) 2020 Elsevier Masson SAS. All rights reserved.

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