Divergent synthesis and biological evaluation of 2-(trifluoromethyl)pyridines as virulence-attenuating inverse agonists targeting PqsR

Towards Translation of PqsR Inverse Agonists: From In Vitro Efficacy Optimization to In Vivo Proof‐of‐Principle

“…Overall, the observed binding mode was in accordance with previously reported QSI bearing the trifluoromethylpyridine headgroup. [ 20,21,23 ] Notably, the detected electron density confirmed a more planar conformation of the bi‐aryl ring system in 24 . Upon binding to PqsR, both rings tilted about 24° as observed by the corresponding dihedral angle (see the inset in Figure 3A).…”

“…This compound demonstrates antivirulence activity (pyocyanin inhibition) in the same potency range as other reported frontrunner molecules combined with promising PK properties and clean safety pharmacology profile. [ 20 , 21 , 22 , 36 ] The molecule is well‐tolerated in mice and achieves high exposures in the lung via various routes of application. It enhances the effect of the aminoglycoside antibiotic tobramycin on PA biofilms and, importantly, synergizes with backbone antibiosis in a neutropenic thigh‐infection model in mice.…”

“…[16] We and others have demonstrated the utility of PqsR as an attractive antivirulence target. [15,17,[18][19][20][21][22][23] Previously, we have reported the first PqsR antagonists developed from the natural ligand HHQ, [18,19] but also the discovery of a structurally divergent hit scaffold as well as first successful lead-generation efforts. [20,21,23] Herein, we describe the rational hit-to-lead-to-candidate optimization of a new chemical class of potent PqsR antagonists, starting from the previously published optimized hit 1.…”

“…[15,17,[18][19][20][21][22][23] Previously, we have reported the first PqsR antagonists developed from the natural ligand HHQ, [18,19] but also the discovery of a structurally divergent hit scaffold as well as first successful lead-generation efforts. [20,21,23] Herein, we describe the rational hit-to-lead-to-candidate optimization of a new chemical class of potent PqsR antagonists, starting from the previously published optimized hit 1. [23] The frontrunner compound reported in this study potently impairs pyocyanin production in typical lab strains as well as clinical isolates from noncystic fibrosis bronchiectasis patients and enhances the eradication efficacy of SoC antibiotic tobramycin against PA biofilms.…”

“…[ 16 ] We and others have demonstrated the utility of PqsR as an attractive antivirulence target. [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]…”