Design and synthesis of lactams derived from mucochloric and mucobromic acids as pseudomonas aeruginosa quorum sensing inhibitors

Almohaywi, B; Taunk, A; Wenholz, DS; Nizalapur, S; Biswas, NN; Ho, KKK; Rice, SA; Iskander, G; Black, DSC; Griffith, R; Kumar, N

Design and synthesis of lactams derived from mucochloric and mucobromic acids as pseudomonas aeruginosa quorum sensing inhibitors

Almohaywi, B Taunk, A Wenholz, DS Nizalapur, S Biswas, NN Ho, KKK Rice, SA

Iskander, G Black, DSC Griffith, R Kumar, N

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Publication Type:: Journal Article
Citation:: Molecules, 2018, 23 (5)
Issue Date:: 2018-01-01

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Field	Value	Language
dc.contributor.author	Almohaywi, B	en_US
dc.contributor.author	Taunk, A	en_US
dc.contributor.author	Wenholz, DS	en_US
dc.contributor.author	Nizalapur, S	en_US
dc.contributor.author	Biswas, NN	en_US
dc.contributor.author	Ho, KKK	en_US
dc.contributor.author	Rice, SA https://orcid.org/0000-0002-9486-2343	en_US
dc.contributor.author	Iskander, G	en_US
dc.contributor.author	Black, DSC	en_US
dc.contributor.author	Griffith, R	en_US
dc.contributor.author	Kumar, N	en_US
dc.date.available	2018-05-05	en_US
dc.date.issued	2018-01-01	en_US
dc.identifier.citation	Molecules, 2018, 23 (5)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/127777
dc.description.abstract	© 2018 by the authors. Bacterial infections, particularly hospital-acquired infections caused by Pseudomonas aeruginosa, have become a global threat with a high mortality rate. Gram-negative bacteria including P. aeruginosa employ N-acyl homoserine lactones (AHLs) as chemical signals to regulate the expression of pathogenic phenotypes through a mechanism called quorum sensing (QS). Recently, strategies targeting bacterial behaviour or QS have received great attention due to their ability to disarm rather than kill pathogenic bacteria, which lowers the evolutionary burden on bacteria and the risk of resistance development. In the present study, we report the design and synthesis of N-alkyl- and N-aryl 3,4 dichloro- and 3,4-dibromopyrrole-2-one derivatives through the reductive amination of mucochloric and mucobromic acid with aliphatic and aromatic amines. The quorum sensing inhibition (QSI) activity of the synthesized compounds was determined against a P. aeruginosa MH602 reporter strain. The phenolic compounds exhibited the best activity with 80% and 75% QSI at 250 µM and were comparable in activity to the positive control compound Fu-30. Computational docking studies performed using the LasR receptor protein of P. aeruginosa suggested the importance of hydrogen bonding and hydrophobic interactions for QSI.	en_US
dc.relation.ispartof	Molecules	en_US
dc.relation.isbasedon	10.3390/molecules23051106	en_US
dc.subject.classification	Organic Chemistry	en_US
dc.subject.mesh	Pseudomonas aeruginosa	en_US
dc.subject.mesh	Lactams	en_US
dc.subject.mesh	Furans	en_US
dc.subject.mesh	Pyrroles	en_US
dc.subject.mesh	Bacterial Proteins	en_US
dc.subject.mesh	Trans-Activators	en_US
dc.subject.mesh	Anti-Bacterial Agents	en_US
dc.subject.mesh	Microbial Sensitivity Tests	en_US
dc.subject.mesh	Gene Expression	en_US
dc.subject.mesh	Protein Structure, Secondary	en_US
dc.subject.mesh	Protein Binding	en_US
dc.subject.mesh	Structure-Activity Relationship	en_US
dc.subject.mesh	Amination	en_US
dc.subject.mesh	Oxidation-Reduction	en_US
dc.subject.mesh	Drug Design	en_US
dc.subject.mesh	Quorum Sensing	en_US
dc.subject.mesh	Protein Interaction Domains and Motifs	en_US
dc.subject.mesh	Acyl-Butyrolactones	en_US
dc.subject.mesh	Molecular Docking Simulation	en_US
dc.title	Design and synthesis of lactams derived from mucochloric and mucobromic acids as pseudomonas aeruginosa quorum sensing inhibitors	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	23	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0307 Theoretical and Computational 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	open_access
pubs.issue	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	23	en_US

Abstract:

© 2018 by the authors. Bacterial infections, particularly hospital-acquired infections caused by Pseudomonas aeruginosa, have become a global threat with a high mortality rate. Gram-negative bacteria including P. aeruginosa employ N-acyl homoserine lactones (AHLs) as chemical signals to regulate the expression of pathogenic phenotypes through a mechanism called quorum sensing (QS). Recently, strategies targeting bacterial behaviour or QS have received great attention due to their ability to disarm rather than kill pathogenic bacteria, which lowers the evolutionary burden on bacteria and the risk of resistance development. In the present study, we report the design and synthesis of N-alkyl- and N-aryl 3,4 dichloro- and 3,4-dibromopyrrole-2-one derivatives through the reductive amination of mucochloric and mucobromic acid with aliphatic and aromatic amines. The quorum sensing inhibition (QSI) activity of the synthesized compounds was determined against a P. aeruginosa MH602 reporter strain. The phenolic compounds exhibited the best activity with 80% and 75% QSI at 250 µM and were comparable in activity to the positive control compound Fu-30. Computational docking studies performed using the LasR receptor protein of P. aeruginosa suggested the importance of hydrogen bonding and hydrophobic interactions for QSI.

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http://hdl.handle.net/10453/127777