Design, synthesis and evaluation of N-aryl-glyoxamide derivatives as structurally novel bacterial quorum sensing inhibitors

Nizalapur, S; Kimyon, Ö; Biswas, NN; Gardner, CR; Griffith, R; Rice, SA; Manefield, M; Willcox, M; Black, DSC; Kumar, N

Design, synthesis and evaluation of N-aryl-glyoxamide derivatives as structurally novel bacterial quorum sensing inhibitors

Nizalapur, S Kimyon, Ö Biswas, NN Gardner, CR Griffith, R Rice, SA

Manefield, M Willcox, M Black, DSC Kumar, N

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Publication Type:: Journal Article
Citation:: Organic and Biomolecular Chemistry, 2016, 14 (2), pp. 680 - 693
Issue Date:: 2016-01-01

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Field	Value	Language
dc.contributor.author	Nizalapur, S	en_US
dc.contributor.author	Kimyon, Ö	en_US
dc.contributor.author	Biswas, NN	en_US
dc.contributor.author	Gardner, CR	en_US
dc.contributor.author	Griffith, R	en_US
dc.contributor.author	Rice, SA https://orcid.org/0000-0002-9486-2343	en_US
dc.contributor.author	Manefield, M	en_US
dc.contributor.author	Willcox, M	en_US
dc.contributor.author	Black, DSC	en_US
dc.contributor.author	Kumar, N	en_US
dc.date.issued	2016-01-01	en_US
dc.identifier.citation	Organic and Biomolecular Chemistry, 2016, 14 (2), pp. 680 - 693	en_US
dc.identifier.issn	1477-0520	en_US
dc.identifier.uri	http://hdl.handle.net/10453/101424
dc.description.abstract	© 2016 The Royal Society of Chemistry. Bacteria cooperatively regulate the expression of many phenotypes through a mechanism called quorum sensing (QS). Many Gram-negative bacteria use an N-acyl homoserine lactone (AHL)-mediated QS system to control biofilm formation and virulence factor production. In recent years, quorum sensing inhibitors (QSIs) have become attractive tools to overcome antimicrobial resistance exhibited by various pathogenic bacteria. In the present study, we report the design and synthesis of novel N-arylisatin-based glyoxamide derivatives via the ring-opening reaction of N-aryl isatins with cyclic and acylic amines, and amino acid esters. The QSI activity of the synthesized compounds was determined in the LasR-expressing Pseudomonas aeruginosa MH602 and LuxR-expressing Escherichia coli MT102 reporter strains. Compounds 31 and 32 exhibited the greatest QSI activity in P. aeruginosa MH602, with 48.7% and 42.7% reduction in QS activity at 250 μM, respectively, while compounds 31 and 34 showed 73.6% and 43.7% QSI activity in E. coli MT102. In addition, the ability of these compounds to inhibit the production of pyocyanin in P. aeruginosa (PA14) was also determined, with compound 28 showing 47% inhibition at 250 μM. Furthermore, computational docking studies were performed on the LasR receptor protein of P. aeruginosa, which showed that formation of a hydrogen bonding network played a major role in influencing the QS inhibitory activity. We envisage that these novel non-AHL glyoxamide derivatives could become a new tool for the study of QS and potentially for the treatment of bacterial infections.	en_US
dc.relation.ispartof	Organic and Biomolecular Chemistry	en_US
dc.relation.isbasedon	10.1039/c5ob01973g	en_US
dc.subject.classification	Organic Chemistry	en_US
dc.subject.mesh	Pseudomonas aeruginosa	en_US
dc.subject.mesh	Escherichia coli	en_US
dc.subject.mesh	Sulfonylurea Compounds	en_US
dc.subject.mesh	Anti-Bacterial Agents	en_US
dc.subject.mesh	Microbial Sensitivity Tests	en_US
dc.subject.mesh	Molecular Structure	en_US
dc.subject.mesh	Structure-Activity Relationship	en_US
dc.subject.mesh	Dose-Response Relationship, Drug	en_US
dc.subject.mesh	Drug Design	en_US
dc.subject.mesh	Quorum Sensing	en_US
dc.subject.mesh	Molecular Docking Simulation	en_US
dc.title	Design, synthesis and evaluation of N-aryl-glyoxamide derivatives as structurally novel bacterial quorum sensing inhibitors	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	14	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0305 Organic Chemistry	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	14	en_US

Abstract:

© 2016 The Royal Society of Chemistry. Bacteria cooperatively regulate the expression of many phenotypes through a mechanism called quorum sensing (QS). Many Gram-negative bacteria use an N-acyl homoserine lactone (AHL)-mediated QS system to control biofilm formation and virulence factor production. In recent years, quorum sensing inhibitors (QSIs) have become attractive tools to overcome antimicrobial resistance exhibited by various pathogenic bacteria. In the present study, we report the design and synthesis of novel N-arylisatin-based glyoxamide derivatives via the ring-opening reaction of N-aryl isatins with cyclic and acylic amines, and amino acid esters. The QSI activity of the synthesized compounds was determined in the LasR-expressing Pseudomonas aeruginosa MH602 and LuxR-expressing Escherichia coli MT102 reporter strains. Compounds 31 and 32 exhibited the greatest QSI activity in P. aeruginosa MH602, with 48.7% and 42.7% reduction in QS activity at 250 μM, respectively, while compounds 31 and 34 showed 73.6% and 43.7% QSI activity in E. coli MT102. In addition, the ability of these compounds to inhibit the production of pyocyanin in P. aeruginosa (PA14) was also determined, with compound 28 showing 47% inhibition at 250 μM. Furthermore, computational docking studies were performed on the LasR receptor protein of P. aeruginosa, which showed that formation of a hydrogen bonding network played a major role in influencing the QS inhibitory activity. We envisage that these novel non-AHL glyoxamide derivatives could become a new tool for the study of QS and potentially for the treatment of bacterial infections.

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http://hdl.handle.net/10453/101424