Design and Synthesis of 4-Fluorophenyl-5-methylene-2(5H)-furanone Derivatives as Potent Quorum Sensing Inhibitors

摘要

Quorum sensing inhibitors (QSIs) are a class of compoundsthatcan reduce the pathogenicity of bacteria without affecting bacterialgrowth. In this study, we designed and synthesized four series of4-fluorophenyl-5-methylene-2(5H)-furanone derivativesand evaluated their QSI activities. Among them, compound 23e not only showed excellent inhibitory activity against various virulencefactors but also significantly enhanced the inhibitory activity ofantibiotics ciprofloxacin and clarithromycin against two strains of Pseudomonas aeruginosa in vitro. What iseven more exciting is that it remarkably increased the antibacterialeffect in vivo in combination with ciprofloxacinin the bacteremia model infected with P. aeruginosa PAO1. Moreover, 23e had little hemolytic activity tomouse erythrocytes. Further, the results of GFP reporter fluorescencestrain inhibition and beta-galactosidase activity inhibition experimentsdemonstrated that 23e simultaneously targeted the threequorum sensing systems in P. aeruginosa. As a result,compound 23e could be used as an effective QSI for furtherdevelopment against bacterial infections.