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Identification of C5-NH2 Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability
Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan 250012, Shandong, Peoples R China..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-0185-5724
Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan 250012, Shandong, Peoples R China..
Shandong Univ Tradit Chinese Med, Coll Pharm, Jinan 250355, Peoples R China..
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2021 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 64, no 24, p. 17992-18009Article in journal (Refereed) Published
Abstract [en]

Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achievemore potent and more selective inhibitors. In this work, foursubseries of C5-NH2modified oseltamivir derivatives weredesigned and synthesized to explore every region inside the 150-cavity. Among them, compound23dwas exceptionally potentagainst the whole panel of Group-1 NAs with IC50values rangingfrom 0.26 to 0.73 nM, being 15 & minus;53 times better than oseltamivircarboxylate (OSC) and 7 & minus;11 times better than zanamivir. Incellular assays,23dshowed more potent or equipotent antiviralactivities against corresponding virus strains compared to OSCwith no cytotoxicity. Furthermore,23dexhibited high metabolicstability in human liver microsomes (HLM) and low inhibitoryeffect on main cytochrome P450 enzymes. Notably,23ddisplayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall,23dappears to be a promising candidate for the treatment of influenza virus infection.

Place, publisher, year, edition, pages
American Chemical Society (ACS) , 2021. Vol. 64, no 24, p. 17992-18009
National Category
Microbiology in the medical area
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URN: urn:nbn:se:kth:diva-309277DOI: 10.1021/acs.jmedchem.1c01366ISI: 000749341300025PubMedID: 34735766Scopus ID: 2-s2.0-85119066033OAI: oai:DiVA.org:kth-309277DiVA, id: diva2:1640539
Note

QC 20220224

Available from: 2022-02-24 Created: 2022-02-24 Last updated: 2022-06-25Bibliographically approved

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Natarajan Arul, Murugan

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