From in vitroto in cellulo: structure-activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa

• Published in: Organic & biomolecular chemistry Vol. 12; no. 32; pp. 6094 - 6104
• Main Authors: Storz, Michael P, Allegretta, Giuseppe, Kirsch, Benjamin, Empting, Martin, Hartmann, Rolf W
• Format: Journal Article
• Language: English
• Published: 01.07.2014
• Subjects: Pseudomonas aeruginosa
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c4ob00707g

Recent studies have shown that compounds based on a (2-nitrophenyl)methanol scaffold are promising inhibitors of PqsD, a key enzyme of signal molecule biosynthesis in the cell-to-cell communication of Pseudomonas aeruginosa. The most promising molecule displayed anti-biofilm activity and a tight-binding mode of action. Herein, we report on the convenient synthesis and biochemical evaluation of a comprehensive series of (2-nitrophenyl)methanol derivatives. The in vitropotency of these inhibitors against recombinant PqsD as well as the effect of selected compounds on the production of the signal molecules HHQ and PQS in P. aeruginosawere examined. The gathered data allowed the establishment of a structure-activity relationship, which was used to design fluorescent inhibitors, and finally, led to the discovery of (2-nitrophenyl)methanol derivatives with improved in celluloefficacy providing new perspectives towards the application of PqsD inhibitors as anti-infectives.