Grossman, S. orcid.org/0000-0002-2742-567X, Soukarieh, F., Richardson, W. et al. (6 more authors) (2020) Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR. European Journal of Medicinal Chemistry, 208. 112778. ISSN 0223-5234
Abstract
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 (IC<sub>50</sub> < 300 nM) in a whole-cell assay, using a mCTX:P<sub>pqsA</sub>-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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/). |
Keywords: | Pseudomonas aeruginosa; Quorum sensing; Inhibitors; X-ray crystal structure; PqsR |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 26 Jul 2024 15:29 |
Last Modified: | 26 Jul 2024 15:29 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.ejmech.2020.112778 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:215212 |