Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies

Jiqing Ye; Xiao Yang; Min Xu; Paul Kay-Sheung Chan; Cong Ma

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

Eur J Med Chem. 2019 Nov 15:182:111635. doi: 10.1016/j.ejmech.2019.111635. Epub 2019 Aug 22.

Authors

Jiqing Ye¹, Xiao Yang², Min Xu³, Paul Kay-Sheung Chan⁴, Cong Ma⁵

Affiliations

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: [email protected].
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: [email protected].

PMID: 31493744
DOI: 10.1016/j.ejmech.2019.111635

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.

Keywords: 150-cavity; Derivative; Influenza virus; Neuraminidase; Oseltamivir.

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Computer Simulation
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Microbial Sensitivity Tests
Molecular Docking Simulation*
Molecular Structure
Neuraminidase / antagonists & inhibitors*
Neuraminidase / metabolism
Orthomyxoviridae / drug effects*
Orthomyxoviridae / enzymology
Oseltamivir / chemical synthesis
Oseltamivir / chemistry
Oseltamivir / pharmacology*
Structure-Activity Relationship

Substances

Antiviral Agents
Enzyme Inhibitors
Oseltamivir
Neuraminidase