2. Academic Validation
  3. Discovery of novel "Dual-site" binding oseltamivir derivatives as potent influenza virus neuraminidase inhibitors

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

  • Eur J Med Chem. 2020 Apr 1;191:112147. doi: 10.1016/j.ejmech.2020.112147.
Wei Ai 1,  Jian Zhang 1,  Waleed A Zalloum 2,  Ruifang Jia 3,  Srinivasulu Cherukupalli 3,  Xiao Ding 3,  Zhuosen Sun 3,  Lin Sun 3,  Xiangyi Jiang 3,  Xiuli Ma 4,  Zhong Li 3,  Defeng Wang 3,  Bing Huang 5,  Peng Zhan 6,  Xinyong Liu 7
Affiliations

Affiliations

  • 1 The Second Hospital of Shandong University, No. 247 Beiyuan Avenue, 250033, Jinan, Shandong, PR China.
  • 2 Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 4 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan, Shandong, 250023, PR China.
  • 5 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan, Shandong, 250023, PR China. Electronic address: [email protected].
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: [email protected].
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: [email protected].
PMID: 32092589 DOI: 10.1016/j.ejmech.2020.112147
Abstract

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.

Keywords

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

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