Synthesis of Novel Quinazolinone Analogues for Quorum Sensing Inhibition
As bacteria continue to develop resistance mechanisms against antimicrobials, an alternative method to tackle this global concern must be developed. As the <i>pqs</i> system is the most well-known and responsible for biofilm and pyocyanin production, quinazolinone inhibitors of the <i...
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| Main Authors: | , , , , |
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| Format: | Book |
| Published: |
MDPI AG,
2023-07-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | As bacteria continue to develop resistance mechanisms against antimicrobials, an alternative method to tackle this global concern must be developed. As the <i>pqs</i> system is the most well-known and responsible for biofilm and pyocyanin production, quinazolinone inhibitors of the <i>pqs</i> system in <i>P. aeruginosa</i> were developed. Molecular docking following a rationalised medicinal chemistry approach was adopted to design these analogues. An analysis of docking data suggested that compound <b>6b</b> could bind with the key residues in the ligand binding domain of PqsR in a similar fashion to the known antagonist M64. The modification of cyclic groups at the 3-position of the quinazolinone core, the introduction of a halogen at the aromatic core and the modification of the terminal group with aromatic and aliphatic chains were investigated to guide the synthesis of a library of 16 quinazolinone analogues. All quinazolinone analogues were tested in vitro for <i>pqs</i> inhibition, with the most active compounds <b>6b</b> and <b>6e</b> being tested for biofilm and growth inhibition in <i>P. aeruginosa</i> (PAO1). Compound <b>6b</b> displayed the highest <i>pqs</i> inhibitory activity (73.4%, 72.1% and 53.7% at 100, 50 and 25 µM, respectively) with no bacterial growth inhibition. However, compounds <b>6b</b> and <b>6e</b> only inhibited biofilm formation by 10% and 5%, respectively. |
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| Item Description: | 10.3390/antibiotics12071227 2079-6382 |