Abstract
The Quorum-sensing system in Pseudomonas aeruginosa 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, 39–40 and 44, showed higher bacterial quorum-sensing inhibitory (QSI) activity against P. aeruginosa 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.
Highlights
Pseudomonas aeruginosa regulates its pathogenicity through an intercellular densitydependent communication system mediated by the binding of signaling molecules to quorum-sensing (QS) receptors such as LasR, which, upon its activation, modulates the expression of multiple genes responsible for the production of various virulence factors, biofilm formation, the swarming motility, and antibiotic resistance
We previously reported the design, synthesis, and evaluation of fimbrolide–nitric oxide donor hybrids as antimicrobial agents [7]
We investigated the introduction of acetylene substituents via the Sonogashira reaction of brominated
Summary
Pseudomonas aeruginosa regulates its pathogenicity through an intercellular densitydependent communication system mediated by the binding of signaling molecules to quorum-sensing (QS) receptors such as LasR, which, upon its activation, modulates the expression of multiple genes responsible for the production of various virulence factors (e.g., pyocyanin, rhamnolipids, and pyoverdine), biofilm formation, the swarming motility, and antibiotic resistance. While conventional antibiotics exert increased selective pressure on bacteria, resulting in the development of antibiotic resistance [1,2,3], inhibition of quorum sensing interrupts the cell-to-cell coordination without exerting a selective pressure on bacteria. We previously reported the design, synthesis, and evaluation of fimbrolide–nitric oxide donor hybrids as antimicrobial agents [7] Their therapeutic use is limited by their instability, ease of hydrolysis, and toxicity [8]. Fimbrolides or 5-dibrominated furnaones can Antibiotics 2022, 11, 151 as antimicrobial agents [7] Fimbrolides or 5-dibrominated furnaones can be utilized as a starting template for chemical manipulation into 1,5dihydropyrrol-2-ones such compound
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