Design, Synthesis, and Evaluation of New 1 H -Benzo[ d ]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections

• Published in: Journal of medicinal chemistry 2024-01, Vol.67 (2), p.1008-1023
• Main Authors: Soukarieh, Fadi, Mashabi, Alaa, Richardson, William, Oton, Eduard Vico, Romero, Manuel, Dubern, Jean-Frédéric, Robertson, Shaun N, Lucanto, Simone, Markham-Lee, Zoe, Sou, Tomás, Kukavica-Ibrulj, Irena, Levesque, Roger C, Bergstrom, Christel A S, Halliday, Nigel, Kellam, Barrie, Emsley, Jonas, Heeb, Stephan, Williams, Paul, Stocks, Michael J, Cámara, Miguel
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00973

is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to cell signaling system controlling virulence, has emerged as a promising approach as an antibiotic adjuvant therapy. Interference with the system, one of three QS systems in , results in reduction of bacterial virulence gene expression and biofilm maturation. Herein, we report a hit to lead process to fine-tune the potency of our previously reported inhibitor (IC 3.2 μM in PAO1-L), which led to the discovery of 2-(4-(3-((6-chloro-1-isopropyl-1 -benzo[ ]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile ( ) as a potent PqsR antagonist. Compound inhibited the PqsR-controlled P - transcriptional reporter fusion in at low submicromolar concentrations. Moreover, showed improved efficacy against CF isolates with significant inhibition of pyocyanin, 2-alkyl-4(1 )-quinolones production.