Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of Pseudomonas aeruginosa

The Quorum-sensing system in is responsible for the pathogenicity and the production of virulence factors and biofilm formation. Dihydropyrrolones were previously found to act as inhibitors of QS-dependent bacterial phenotypes. In this study, a range of dihydropyrrolone (DHP) analogues was synthesiz...

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Bibliographic Details
Published in:Antibiotics (Basel) 2022-01, Vol.11 (2), p.151
Main Authors: Almohaywi, Basmah, Yu, Tsz Tin, Iskander, George, Sabir, Shekh, Bhadbhade, Mohan, Black, David StC, Kumar, Naresh
Format: Article
Language:English
Subjects:
Acetylene
alkyne synthesis
Alkynes
Amides
Antibiotics
Antimicrobial agents
Bacteria
Biofilms
Bromination
Carbon
Chemical reactions
dihydropyrrolones
Drug resistance
Inhibitors
Intermediates
Palladium
Pathogenicity
Pathogens
Pharmaceutical sciences
Phenotypes
Pseudomonas aeruginosa
quorum sensing
Solvents
Virulence
Virulence factors
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Summary:The Quorum-sensing system in is responsible for the pathogenicity and the production of virulence factors and biofilm formation. Dihydropyrrolones were previously found to act as inhibitors of QS-dependent bacterial phenotypes. In this study, a range of dihydropyrrolone (DHP) analogues was synthesized via the lactone-lactam conversion of lactone intermediates followed by the formation of novel acetylene analogues of dihydropyrrolones from brominated dihydropyrrolones via Sonogashira coupling reactions in moderate to high yields. Upon biological testing, the most potent compounds, - and showed higher bacterial quorum-sensing inhibitory (QSI) activity against reporter strain at 62.5 µM. Structure-activity relationship studies revealed that di-alkynyl substituent at the exocyclic position of DHPs possessed higher QSI activities than those of mono-alkynyl DHPs. Moreover, a hexyl-substituent at C3 of DHPs was beneficial to QSI activity while a phenyl substituent at C4 of DHPs was detrimental to QSI activity of analogues.
ISSN:2079-6382
2079-6382
DOI:10.3390/antibiotics11020151