Identification of C5-NH2Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability

Han Ju, N. Arul Murugan, Lingxin Hou, Ping Li, Laura Guizzo, Ying Zhang, Chiara Bertagnin, Xiujie Kong, Dongwei Kang, Ruifang Jia, Xiuli Ma, Ruikun Du, Vasanthanathan Poongavanam, Arianna Loregian*, Bing Huang*, Xinyong Liu*, Peng Zhan*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH2 modified oseltamivir derivatives were designed and synthesized to explore every region inside the 150-cavity. Among them, compound 23d was exceptionally potent against the whole panel of Group-1 NAs with IC50 values ranging from 0.26 to 0.73 nM, being 15-53 times better than oseltamivir carboxylate (OSC) and 7-11 times better than zanamivir. In cellular assays, 23d showed more potent or equipotent antiviral activities against corresponding virus strains compared to OSC with no cytotoxicity. Furthermore, 23d exhibited high metabolic stability in human liver microsomes (HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, 23d displayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall, 23d appears to be a promising candidate for the treatment of influenza virus infection.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume64
Issue number24
Pages (from-to)17992-18009
ISSN0022-2623
DOIs
Publication statusPublished - 23. Dec 2021

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