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J Enzyme Inhib Med Chem
. 2023 Dec;38(1):2277135.
doi: 10.1080/14756366.2023.2277135. Epub 2023 Nov 13. A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation
Jiwei Zhang 1 , Chuanfeng Liu 1 2 , Ruifang Jia 1 , Xujie Zhang 1 , Jian Zhang 3 , Chiara Bertagnin 4 , Anna Bonomini 4 , Laura Guizzo 4 , Yuanmin Jiang 1 , Huinan Jia 1 , Shuzhen Jia 1 , Xiuli Ma 5 , Arianna Loregian 4 , Bing Huang 5 , Peng Zhan 1 6 , Xinyong Liu 1 6
Affiliations
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.
Keywords: 150-cavity; Influenza virus; drug design; neuraminidase inhibitors; oseltamivir.
. 2023 Dec;38(1):2277135.
doi: 10.1080/14756366.2023.2277135. Epub 2023 Nov 13. A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation
Jiwei Zhang 1 , Chuanfeng Liu 1 2 , Ruifang Jia 1 , Xujie Zhang 1 , Jian Zhang 3 , Chiara Bertagnin 4 , Anna Bonomini 4 , Laura Guizzo 4 , Yuanmin Jiang 1 , Huinan Jia 1 , Shuzhen Jia 1 , Xiuli Ma 5 , Arianna Loregian 4 , Bing Huang 5 , Peng Zhan 1 6 , Xinyong Liu 1 6
Affiliations
- PMID: 37955306
- DOI: 10.1080/14756366.2023.2277135
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.
Keywords: 150-cavity; Influenza virus; drug design; neuraminidase inhibitors; oseltamivir.