Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR

Grossman, Scott; Soukarieh, Fadi; Richardson, William; Liu, Ruiling; Mashabi, Alaa; Emsley, Jonas; Williams, Paul; C�mara, Miguel; Stocks, Michael J.

Abstract

© 2020 The Authors Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50 < 300 nM) in a whole-cell assay, using a mCTX:PpqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation.

Citation

Grossman, S., Soukarieh, F., Richardson, W., Liu, R., Mashabi, A., Emsley, J., Williams, P., Cámara, M., & Stocks, M. J. (2020). Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR. European Journal of Medicinal Chemistry, 208, Article 112778. https://doi.org/10.1016/j.ejmech.2020.112778

• Journal Article Type: Article
• Acceptance Date: Aug 20, 2020
• Online Publication Date: Aug 28, 2020
• Publication Date: Dec 15, 2020
• Deposit Date: Sep 8, 2020
• Publicly Available Date: Aug 29, 2021
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Electronic ISSN: 1768-3254
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 208
• Article Number: 112778
• DOI: https://doi.org/10.1016/j.ejmech.2020.112778
• Keywords: Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4890073
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523420307509