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

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

Abstract

Pseudomonas aeruginosa 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 pqs system, one of three QS systems in P. aeruginosa, 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 1 (IC50 3.2 μM in P. aeruginosa PAO1-L), which led to the discovery of 2-(4-(3-((6-chloro-1-isopropyl-1H-benzo[d]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile (6f) as a potent PqsR antagonist. Compound 6f inhibited the PqsR-controlled PpqsA-lux transcriptional reporter fusion in P. aeruginosa at low submicromolar concentrations. Moreover, 6f showed improved efficacy against P. aeruginosa CF isolates with significant inhibition of pyocyanin, 2-alkyl-4(1H)-quinolones production.

Citation

Soukarieh, F., Mashabi, A., Richardson, W., Oton, E. V., Romero, M., Dubern, J., …Cámara, M. (2024). Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections. Journal of Medicinal Chemistry, 67(2), 1008-1023. https://doi.org/10.1021/acs.jmedchem.3c00973

• Journal Article Type: Article
• Acceptance Date: Dec 12, 2023
• Online Publication Date: Jan 3, 2024
• Publication Date: Jan 25, 2024
• Deposit Date: Dec 14, 2023
• Publicly Available Date: Jan 4, 2025
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 2
• Pages: 1008-1023
• DOI: https://doi.org/10.1021/acs.jmedchem.3c00973
• Keywords: Drug Discovery; Molecular Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/28429121
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00973