Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2023)

A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation

  • Jiwei Zhang,
  • Chuanfeng Liu,
  • Ruifang Jia,
  • Xujie Zhang,
  • Jian Zhang,
  • Chiara Bertagnin,
  • Anna Bonomini,
  • Laura Guizzo,
  • Yuanmin Jiang,
  • Huinan Jia,
  • Shuzhen Jia,
  • Xiuli Ma,
  • Arianna Loregian,
  • Bing Huang,
  • Peng Zhan,
  • Xinyong Liu

DOI
https://doi.org/10.1080/14756366.2023.2277135
Journal volume & issue
Vol. 38, no. 1

Abstract

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Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

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