tetano
Editor, Senior Moderator
J Med Chem
. 2021 Nov 4.
doi: 10.1021/acs.jmedchem.1c01366. Online ahead of print.
Identification of C5-NH [SUB]2[/SUB] Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability
Han Ju[SUP] 1 [/SUP], N Arul Murugan[SUP] 2 [/SUP], Lingxin Hou[SUP] 1 [/SUP], Ping Li[SUP] 3 [/SUP], Laura Guizzo[SUP] 4 [/SUP], Ying Zhang[SUP] 1 [/SUP], Chiara Bertagnin[SUP] 4 [/SUP], Xiujie Kong[SUP] 1 [/SUP], Dongwei Kang[SUP] 1 [/SUP], Ruifang Jia[SUP] 1 [/SUP], Xiuli Ma[SUP] 5 [/SUP], Ruikun Du[SUP] 3 [/SUP], Vasanthanathan Poongavanam[SUP] 6 [/SUP], Arianna Loregian[SUP] 4 [/SUP], Bing Huang[SUP] 5 [/SUP], Xinyong Liu[SUP] 1 [/SUP], Peng Zhan[SUP] 1 [/SUP]
Affiliations
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-NH[SUB]2[/SUB] 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 IC[SUB]50[/SUB] 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.
. 2021 Nov 4.
doi: 10.1021/acs.jmedchem.1c01366. Online ahead of print.
Identification of C5-NH [SUB]2[/SUB] Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability
Han Ju[SUP] 1 [/SUP], N Arul Murugan[SUP] 2 [/SUP], Lingxin Hou[SUP] 1 [/SUP], Ping Li[SUP] 3 [/SUP], Laura Guizzo[SUP] 4 [/SUP], Ying Zhang[SUP] 1 [/SUP], Chiara Bertagnin[SUP] 4 [/SUP], Xiujie Kong[SUP] 1 [/SUP], Dongwei Kang[SUP] 1 [/SUP], Ruifang Jia[SUP] 1 [/SUP], Xiuli Ma[SUP] 5 [/SUP], Ruikun Du[SUP] 3 [/SUP], Vasanthanathan Poongavanam[SUP] 6 [/SUP], Arianna Loregian[SUP] 4 [/SUP], Bing Huang[SUP] 5 [/SUP], Xinyong Liu[SUP] 1 [/SUP], Peng Zhan[SUP] 1 [/SUP]
Affiliations
- PMID: 34735766
- DOI: 10.1021/acs.jmedchem.1c01366
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-NH[SUB]2[/SUB] 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 IC[SUB]50[/SUB] 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.