Design, synthesis and biological evaluation of "Multi-Site"-binding influenza virus neuraminidase inhibitors
文献类型： 外文期刊
作者： Jia, Ruifang 1 ; Zhang, Jian 1 ; Ai, Wei 1 ; Ding, Xiao 1 ; Desta, Samuel 1 ; Sun, Lin 1 ; Sun, Zhuosen 1 ; Ma, Xiuli 2 ; Li 1 ;
作者机构： 1.Shandong Univ, Dept Med Chem, Key Lab Chem Biol, Sch Pharmaceut Sci,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China
2.Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China
关键词： Influenza virus; Neuraminidase inhibitors; 430-Cavity; 150-Cavity; Oseltamivir derivatives
期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：6.514； 五年影响因子：6.099 ）
ISSN： 0223-5234
年卷期： 2019 年 178 卷
页码：
收录情况： SCI
摘要： Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 mu M. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-l-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents. (C) 2019 Elsevier Masson SAS. All rights reserved.
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