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Discovery of N-substituted oseltamivir derivatives as novel neuraminidase inhibitors with improved drug resistance profiles and favorable drug-like properties

文献类型： 外文期刊

作者： Jia, Ruifang 1 ; Zhang, Jiwei 1 ; Shi, Fangyuan 1 ; Bonomini, Anna 2 ; Lucca, Camilla 2 ; Bertagnin, Chiara 2 ; Zhang, Jian 3 ; Liu, Chuanfeng 1 ; Jia, Huinan 1 ; Jiang, Yuanmin 1 ; Ma, Xiuli 4 ; Loregian, Arianna 2 ; 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, Shandong, Peoples R China

2.Shandong Univ, Qilu Hosp, Dept Pharm, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China

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

4.Shandong Univ, Hosp 2, Inst Med Sci, 247 Beiyuan St, Jinan 250033, Shandong, Peoples R China

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

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

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

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：6.7； 五年影响因子：6.5 ）

ISSN： 0223-5234

年卷期： 2023 年 252 卷

页码：

收录情况： SCI

摘要： To yield potent neuraminidase inhibitors with improved drug resistance and favorable drug-like properties, two series of novel oseltamivir derivatives targeting the 150-cavity of neuraminidase were designed, synthesized, and biologically evaluated. Among the synthesized compounds, the most potent compound 43b bearing 3-floro-4-cyclopentenylphenzyl moiety exhibited weaker or slightly improved inhibitory activity against wild-type neur-aminidases (NAs) of H1N1, H5N1, and H5N8 compared to oseltamivir carboxylate (OSC). Encouragingly, 43b displayed 62.70-and 5.03-fold more potent activity than OSC against mutant NAs of H5N1-H274Y and H1N1-H274Y, respectively. In cellular antiviral assays, 43b exerted equivalent or more potent activities against H1N1, H5N1, and H5N8 compared to OSC with no significant cytotoxicity up to 200 mu M. Notably, 43b displayed potent antiviral efficacy in the embryonated egg model, in which achieved a protective effect against H5N1 and H5N8 similar to OSC. Molecular docking studies were implemented to reveal the binding mode of 43b in the binding pocket. Moreover, 43b possessed improved physicochemical properties and ADMET properties compared to OSC by in silico prediction. Taken together, 43b appeared to be a promising lead compound for further investigation.

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