Cu-Catalyzed Synthesis of Alkylaminotroponyl Sulfones as Pseudomonas Aeruginosa Quorum Sensing Inhibitors Targeting lasI/R QS Circuitry.

Abstract

The scarcity of novel bioactive molecules against multidrug-resistant (MDR) bacterial strains like Pseudomonas aeruginosa is alarming. This bacterial virulence is regulated via Quorum sensing (QS), a cell-cell communication process. Disabling QS circuits (las, pqs, rhl) with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. This strategy focuses on interruption of bacterial virulence, rather than killing them to tackle the drug resistance problem. Herein, we describe the synthesis of rationally designed Alklyamionotroponyl Sulfone (ATS) derivatives by Cu-catalyzed C(sp2 )-H functionalization at tropone ring and the screening of their anti-QS activity against P. aeruginosa. Importantly, two sulfones (∼20 μM) remarkably exhibit the down regulation of the lasI/R QS genes. These molecules also inhibit swarming motility, biofilm formation and pyocyanin production, which reduce P. aeruginosa virulence in cells. Hence, ATS derivatives could be considered as potential therapeutic candidates for the treatment of P. aeruginosa infections.