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

Ye, J; Yang, X; Xu, M; Chan, PK-S; Ma, C

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

Ye, J Yang, X Xu, M

Chan, PK-S Ma, C

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Publisher:: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Publication Type:: Journal Article
Citation:: European journal of medicinal chemistry, 2019, 182, pp. 111635
Issue Date:: 2019-11

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Field	Value	Language
dc.contributor.author	Ye, J
dc.contributor.author	Yang, X
dc.contributor.author	Xu, M https://orcid.org/0000-0001-9581-8849
dc.contributor.author	Chan, PK-S
dc.contributor.author	Ma, C
dc.date.accessioned	2020-05-04T07:55:53Z
dc.date.available	2019-08-19
dc.date.available	2020-05-04T07:55:53Z
dc.date.issued	2019-11
dc.identifier.citation	European journal of medicinal chemistry, 2019, 182, pp. 111635
dc.identifier.issn	0223-5234
dc.identifier.issn	1768-3254
dc.identifier.uri	http://hdl.handle.net/10453/140470
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
dc.relation.ispartof	European journal of medicinal chemistry
dc.relation.isbasedon	10.1016/j.ejmech.2019.111635
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Medicinal & Biomolecular Chemistry
dc.subject.mesh	Humans
dc.subject.mesh	Orthomyxoviridae
dc.subject.mesh	Neuraminidase
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Antiviral Agents
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Molecular Structure
dc.subject.mesh	Structure-Activity Relationship
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Drug Design
dc.subject.mesh	Computer Simulation
dc.subject.mesh	Oseltamivir
dc.subject.mesh	Molecular Docking Simulation
dc.subject.mesh	Antiviral Agents
dc.subject.mesh	Computer Simulation
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Drug Design
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Humans
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Molecular Docking Simulation
dc.subject.mesh	Molecular Structure
dc.subject.mesh	Neuraminidase
dc.subject.mesh	Orthomyxoviridae
dc.subject.mesh	Oseltamivir
dc.subject.mesh	Structure-Activity Relationship
dc.title	Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies.
dc.type	Journal Article
utslib.citation.volume	182
utslib.location.activity	France
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - INEXT - Innovation in IT Services and Applications
pubs.organisational-group	/University of Technology Sydney/Strength - GBDTC - Global Big Data Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Electrical and Data Engineering
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	closed_access	*
dc.date.updated	2020-05-04T07:55:52Z
pubs.publication-status	Published
pubs.volume	182
utslib.start-page	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.

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http://hdl.handle.net/10453/140470