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Discovery of Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant

文献类型： 外文期刊

作者： Jia, Ruifang 1 ; Zhang, Jiwei 1 ; Zhang, Jian 2 ; Bertagnin, Chiara 3 ; Bonomini, Anna 3 ; Guizzo, Laura 3 ; Gao, Zhen 1 ; Ji, Xiangkai 1 ; Li, Zhuo 1 ; Liu, Chuanfeng 1 ; Ju, Han 1 ; Ma, Xiuli 4 ; Loregian, Arianna 3 ; Huang, Bing 4 ; Zhan, Peng 1 ; Liu, Xinyong 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, Peoples R China

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

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

关键词： influenza; neuraminidase inhibitors; oseltamivir derivatives; 150-cavity; boronic acid

期刊名称：MOLECULES （ 影响因子：4.927； 五年影响因子：5.11 ）

ISSN：

年卷期： 2022 年 27 卷 19 期

页码：

收录情况： SCI

摘要： To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization.

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