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

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

  • J Med Chem. 2024 Jan 25;67(2):1008-1023. doi: 10.1021/acs.jmedchem.3c00973.
Fadi Soukarieh 1 2,  Alaa Mashabi 3,  William Richardson 3,  Eduard Vico Oton 1,  Manuel Romero 1 2,  Jean-Frédéric Dubern 1,  Shaun N Robertson 1 2,  Simone Lucanto 1 2,  Zoe Markham-Lee 3,  Tomás Sou 4,  Irena Kukavica-Ibrulj 5,  Roger C Levesque 5,  Christel A S Bergstrom 4,  Nigel Halliday 1,  Barrie Kellam 3,  Jonas Emsley 3 2,  Stephan Heeb 1,  Paul Williams 1 2,  Michael J Stocks 3 2,  Miguel Cámara 1 2
Affiliations

Affiliations

  • 1 School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K.
  • 2 The National Biofilms Innovation Centre, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K.
  • 3 School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, U.K.
  • 4 Department of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden.
  • 5 Institut de Biologie Intégrative et des SystèmesUniversité Laval, Quebec G1V 0A6, Canada.
PMID: 38170170 DOI: 10.1021/acs.jmedchem.3c00973
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.

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