1. A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation
- Author
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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, and Xinyong Liu
- Subjects
Influenza virus ,neuraminidase inhibitors ,150-cavity ,oseltamivir ,drug design ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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.
- Published
- 2023
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