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Eur J Med Chem. 2019 Aug 22;182:111635. doi: 10.1016/j.ejmech.2019.111635. [Epub ahead of print]
Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies.
Ye J1, Yang X2, Xu M3, Chan PK4, Ma C5.
Author information
1 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong Special Administrative Region. 2 Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region. 3 School of Electrical and Data Engineering, Faculty of Engineering and IT, University of Technology Sydney, Sydney, Australia. 4 Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region; Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region. Electronic address: paulkschan@cuhk.edu.hk. 5 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong Special Administrative Region. Electronic address: cong.ma@polyu.edu.hk.
Abstract
The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
150-cavity; Derivative; Influenza virus; Neuraminidase; Oseltamivir
PMID: 31493744 DOI: 10.1016/j.ejmech.2019.111635
Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies.
Ye J1, Yang X2, Xu M3, Chan PK4, Ma C5.
Author information
1 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong Special Administrative Region. 2 Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region. 3 School of Electrical and Data Engineering, Faculty of Engineering and IT, University of Technology Sydney, Sydney, Australia. 4 Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region; Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region. Electronic address: paulkschan@cuhk.edu.hk. 5 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong Special Administrative Region. Electronic address: cong.ma@polyu.edu.hk.
Abstract
The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
150-cavity; Derivative; Influenza virus; Neuraminidase; Oseltamivir
PMID: 31493744 DOI: 10.1016/j.ejmech.2019.111635