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

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

  • Eur J Med Chem. 2023 Apr 5;252:115275. doi: 10.1016/j.ejmech.2023.115275.
Ruifang Jia 1,  Jiwei Zhang 1,  Fangyuan Shi 2,  Anna Bonomini 3,  Camilla Lucca 3,  Chiara Bertagnin 3,  Jian Zhang 4,  Chuanfeng Liu 1,  Huinan Jia 1,  Yuanmin Jiang 1,  Xiuli Ma 5,  Arianna Loregian 3,  Bing Huang 6,  Peng Zhan 7,  Xinyong Liu 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 2 Department of Pharmacy, Qilu Hospital, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 3 Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35121, Padova, Italy.
  • 4 Institute of Medical Sciences, The Second Hospital, Shandong University, 247 Beiyuan Street, 250033, Jinan, Shandong, PR China.
  • 5 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan, Shandong, 250023, PR China.
  • 6 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan, Shandong, 250023, PR China. Electronic address: hbind@163.com.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 8 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 36931117 DOI: 10.1016/j.ejmech.2023.115275
Abstract

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 neuraminidases (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 μM. 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.

Keywords

150-Cavity; Drug resistance; Influenza virus; Neuraminidase inhibitors; Oseltamivir.

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