Journal
CHEMMEDCHEM
Volume 11, Issue 22, Pages 2522-2533Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201600419
Keywords
biofilms; drug design; Hansch analysis; medicinal chemistry; nitrogen heterocycles; P; aeruginosa
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Funding
- European Regional Development Fund
- Saarland State Ministry [C/4-PBT-400-4/2010]
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Drug-resistant Pseudomonas aeruginosa (PA) strains are on the rise, making treatment with current antibiotics ineffective. Hence, circumventing resistance or restoring the activity of antibiotics by novel approaches is of high demand. Targeting the Pseudomonas quinolone signal quorum sensing (PQS-QS) system is an intriguing strategy to abolish PA pathogenicity without affecting the viability of the pathogen. Herein we report the structure-activity relationships of 2-sulfonylpyrimidines, which were previously identified as dual-target inhibitors of the PQS receptor PqsR and the PQS synthase PqsD. The SAR elucidation was guided by a combined approach using ligand efficiency and ligand lipophilicity efficiency to select the most promising compounds. In addition, the most effective inhibitors were rationally modified by the guidance of QSAR using Hansch analyses. Finally, these inhibitors showed the capacity to decrease biofilm mass and extracellular DNA, which are important determinants for antibiotic resistance.
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