2. Academic Validation
  3. Identification of C5-NH2 Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability

Identification of C5-NH2 Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability

  • J Med Chem. 2021 Dec 23;64(24):17992-18009. doi: 10.1021/acs.jmedchem.1c01366.
Han Ju 1,  N Arul Murugan 2,  Lingxin Hou 1,  Ping Li 3,  Laura Guizzo 4,  Ying Zhang 1,  Chiara Bertagnin 4,  Xiujie Kong 1,  Dongwei Kang 1,  Ruifang Jia 1,  Xiuli Ma 5,  Ruikun Du 3,  Vasanthanathan Poongavanam 6,  Arianna Loregian 4,  Bing Huang 5,  Xinyong Liu 1,  Peng Zhan 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P.R. China.
  • 2 Department of Computer Science, School of Electrical Engineering and Computer Science, KTH Royal Institute of Technology, Stockholm SE-10044 , Sweden.
  • 3 College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
  • 4 Department of Molecular Medicine, University of Padova, Via Gabelli 63, Padova 35121, Italy.
  • 5 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 202 North Gongye Road, Jinan, Shandong 250100, China.
  • 6 Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M DK-5230, Denmark.
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-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.

Figures
Products