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Structure–Activity Relationships of 2‐Sufonylpyrimidines as Quorum‐Sensing Inhibitors to Tackle Biofilm Formation and eDNA Release of Pseudomonas aeruginosa
Authors:Andreas Thomann  Christian Brengel  Dr. Carsten Börger  Dr. Dagmar Kail  Dr. Anke Steinbach  Dr. Martin Empting  Prof. Dr. Rolf W. Hartmann
Affiliation:1. Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Saarbrücken, Germany;2. PharmBioTec GmbH, Saarbrücken, Germany;3. Saarland University, Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarbrücken, Germany
Abstract: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.
Keywords:biofilms  drug design  Hansch analysis  medicinal chemistry  nitrogen heterocycles  P.   aeruginosa
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