Alkyne-Substituted Dihydropyrolones as Bacterial Quorum Sensing Inhibitors

Bacteria regulate their virulence factor production and biofilm formation through an intercellular communication system mediated by the binding of signaling molecules to QS receptors such as LasR. A range of natural and synthetic brominated furanones known as fimbrolides and their dihydropyrolones counterparts have been found to act as inhibitors of QS-dependent bacterial phenotypes. In this study, a range of dihydropyrrolone (DHP) analogues were synthesized via the lactone-lactam conversion of lactone intermediates followed by the formation of novel acetylene analogues of dihydropyrrolones. Fifteen novel alkyne analogues of DHPs with various substitution patterns and aliphatic chain lengths were successfully synthesised via lactamisation and Sonogashira coupling reactions in moderate to high yields. The Sonogashira reaction was carried out with DHPs and alkynes in the presence of CuI, palladium catalyst PdCl₂(PPh₃)₂ and TEA. Biological testing demonstrated that several compounds showed low to moderate activity against the P. aeruginosa MH602 reporter strain with little bactericidal effect. The present study represents the first application of the Sonogashira reaction to DHP scaffolds for the synthesis of novel bacterial QS inhibitors.