2. Academic Validation
  3. Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

  • J Med Chem. 2018 Nov 21;61(22):9976-9999. doi: 10.1021/acs.jmedchem.8b01065.
Jian Zhang 1,  Natarajan Arul Murugan 2,  Ye Tian 1 3,  Chiara Bertagnin 4,  Zengjun Fang 1 5,  Dongwei Kang 1,  Xiujie Kong 1,  Haiyong Jia 1,  Zhuosen Sun 1,  Ruifang Jia 1,  Ping Gao 1,  Vasanthanathan Poongavanam 6,  Arianna Loregian 4,  Wenfang Xu 1,  Xiuli Ma 7,  Xiao Ding 1,  Bing Huang 7,  Peng Zhan 1,  Xinyong Liu 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 , 250012 Jinan , Shandong , P. R. China.
  • 2 Division of Theoretical Chemistry and Biology, School of Biotechnology , KTH Royal Institute of Technology , S-106 91 Stockholm , Sweden.
  • 3 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences , Shandong University , 44 West Culture Road , 250012 Jinan , Shandong P. R. China.
  • 4 Department of Molecular Medicine , University of Padova , Via Gabelli 63 , 35121 Padova , Italy.
  • 5 The Second Hospital of Shandong University , No. 247 Beiyuan Avenue , 250033 Jinan , China.
  • 6 Department of Physics, Chemistry, and Pharmacy , University of Southern Denmark , DK-5230 Odense M, Denmark.
  • 7 Institute of Poultry Science , Shandong Academy of Agricultural Sciences , 1, Jiaoxiao Road , 250023 Jinan , Shandong , P. R. China.
PMID: 30365885 DOI: 10.1021/acs.jmedchem.8b01065
Abstract

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited Antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent Antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of Influenza Virus infection.

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