title: Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa employs a quorum sensing (QS) communication system that makes use of small diffusible molecules. Among other effects, the QS system coordinates the formation of biofilm which decisively contributes to difficulties in the therapy of Pseudomonas infections. The present work deals with the structure-activity exploration of ureidothiophene-2-carboxylic acids as inhibitors of PqsD, a key enzyme in the biosynthetic pathway of signal molecules in the Pseudomonas QS system. We describe an improvement of the inhibitory activity by successfully combining features from two different PqsD inhibitor classes. Furthermore the functional groups, which are responsible for the inhibitory potency, were identified. Moreover, the inability of the new inhibitors, to prevent signal molecule formation in whole cell assays, is discussed.
authors: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany.
authors: J Henning
authors: JH
authors: Sahner
authors: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany.
authors: Martin
authors: M
authors: Empting
authors: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany.
authors: Ahmed
authors: A
authors: Kamal
authors: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany.
authors: Elisabeth
authors: E
authors: Weidel
authors: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany.
authors: Matthias
authors: M
authors: Groh
authors: PharmBioTec GmbH, Science Park 1, 66123 Saarbrücken, Germany.
authors: Carsten
authors: C
authors: Börger
authors: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany. Electronic address: rolf.hartmann@helmholtz-hzi.de.
authors: Rolf W
authors: RW
authors: Hartmann
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D053038:Quorum Sensing / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013876:Thiophenes; D014508:Urea
keywords: Antibacterial agents; Bacterial cell-to-cell communication; Pseudomonas aeruginosa; Quorum sensing; Ureidothiophene-2-carboxylic acids