Discovery and optimization of thiazole-based quorum sensing inhibitors as potent blockers of Pseudomonas aeruginosa pathogenicity

Pseudomonas aeruginosa causes life-threatening infections especially in hospitalized patients and shows an increasing resistance to established antibiotics. A process known as quorum sensing (QS) enables the pathogen to collectively adapt to various environmental conditions. Disrupting this cell-to-cell communication machinery by small-molecular entities leads to a blockade of bacterial pathogenicity. We aim to devise QS inhibitors acting on the PA-specific PQS QS system via the signal-molecule receptor and transcriptional regulator PqsR (MvfR). In this manuscript, we describe the further optimization of PqsR inverse agonists by broadening the structural space of a previously described triazole-bearing lead compound and arriving at highly potent thiazole derivatives with activities against P. aeruginosa virulence factor pyocyanin in the nanomolar range. All new derivatives were profiled regarding biological activity as well as in vitro ADMET parameters. Additionally, we assessed safety-pharmacology characteristics of the two most promising compounds both bearing a 3-chloro-4-isopropoxyphenyl motive. Demonstrating an overall favorable profile, our new PqsR inverse agonists represent a valuable addition as optimized lead compounds, enabling preclinical development of P. aeruginosa-specific pathoblockers. [Display omitted] •Design and synthesis of novel Quorum Sensing inhibitors (QSI).•High potency of frontrunner compounds 27 and 35 on the bacterial target PqsR in the single-digit nanomolar range.•Nanomolar inhibition of virulence factor pyocyanin and alkylquinolone biosynthesis in Pseudomonas aeruginosa.•Novel QSI show favorable in vitro DMPK and safety pharmacology.•Co–crystallization of a QSI in complex with target protein.