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

Abstract

Quorum sensing inhibitors (QSIs) are a class of compounds that can reduce the pathogenicity of bacteria without affecting bacterial growth. In this study, we designed and synthesized four series of 4fluorophenyl-5-methylene-2(5H)-furanone derivatives and evaluated their QSI activities. Among them, compound 23e not only showed excellent inhibitory activity against various virulence factors but also significantly enhanced the inhibitory activity of antibiotics ciprofloxacin and clarithromycin against two strains of Pseudomonas aeruginosa in vitro. What is even more exciting is that it remarkably increased the antibacterial effect in vivo in combination with ciprofloxacin in the bacteremia model infected with P. aeruginosa PAO1. Moreover, 23e had little hemolytic activity to mouse erythrocytes. Further, the results of GFP reporter fluorescence strain inhibition and β-galactosidase activity inhibition experiments demonstrated that 23e simultaneously targeted the three quorum sensing systems in P. aeruginosa. As a result, compound 23e could be used as an effective QSI for further development against bacterial infections.

A hybrid energy-based and AI-based screening approach for the discovery of novel inhibitors of JAK3

“…For the discovery of new backbone JAK3 inhibitors, we employed computer-aided drug design approaches. Computational methods have been applied in the drug development process for screening and discovery of compounds with novel sketches in recent years ( 15 , 16 ). Among them, virtual screening tools could significantly reduce the time and cost of drug discovery and increase development efficiency ( 17 ).…”