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

被引：10

作者：

Ai, Wei ^{[2
]}

Zhang, Jian ^{[2
]}

Zalloum, Waleed A. ^{[4
]}

Jia, Ruifang ^{[1
]}

Cherukupalli, Srinivasulu ^{[1
]}

Ding, Xiao ^{[1
]}

Sun, Zhuosen ^{[1
]}

Sun, Lin ^{[1
]}

Jiang, Xiangyi ^{[1
]}

Ma, Xiuli ^{[3
]}

Li, Zhong ^{[1
]}

Wang, Defeng ^{[1
]}

Huang, Bing ^{[3
]}

Zhan, Peng ^{[1
]}

Liu, Xinyong ^{[1
]}

机构：

[1] Shandong Univ, 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, 247 Beiyuan Ave, Jinan 250033, Shandong, Peoples R China

[3] Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China

[4] Amer Univ Madaba, Dept Pharm, Fac Hlth Sci, POB 2882, Amman 11821, Jordan

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 191卷

基金：

中国国家自然科学基金;

关键词：

Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives; 150-cavity; Active site; POLYMERASE; RESISTANCE;

D O I：

10.1016/j.ejmech.2020.112147

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页数：23

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