Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections

• Inhibition of PqsD as a novel option to treat bacterial infections.
• Disturbing cell-to-cell communication by PqsD inhibition to avoid selective pressure.
• Turning RNAP inhibition into PqsD inhibition by structural modifications.
• Discovery of selective PqsD inhibitors in the class of benzamidobenzoic acids.

Targeting PqsD is a promising novel approach to disrupt bacterial cell-to-cell-communication in Pseudomonas aeruginosa. In search of selective PqsD inhibitors, two series of benzamidobenzoic acids – one published as RNAP inhibitors and the other as PqsD inhibitors – were investigated for inhibitory activity toward the respective other enzyme. Additionally, novel derivatives were synthesized and biologically evaluated. By this means, the structural features needed for benzamidobenzoic acids to be potent and, most notably, selective PqsD inhibitors were identified. The most interesting compound of this study was the 3-Cl substituted compound 5 which strongly inhibits PqsD (IC50 6.2 μM) while exhibiting no inhibition of RNAP.

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