Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships.

2.50
Hdl Handle:
http://hdl.handle.net/10033/325005
Title:
Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships.
Authors:
Lu, Cenbin; Kirsch, Benjamin; Maurer, Christine K; de Jong, Johannes C; Braunshausen, Andrea; Steinbach, Anke; Hartmann, Rolf W
Abstract:
Increasing antibiotic resistance urgently requires novel therapeutic options to combat bacterial infections. The anti-virulence therapy selectively intervening with pathogenicity without affecting bacterial viability is such a strategy to overcome resistance. We consider the virulence regulator PqsR as an attractive target in the human pathogen Pseudomonas aeruginosa, and recently discovered the first PqsR antagonists, which, however, suffered from poor aqueous solubility. In this work, the antagonists were structurally modified to become more soluble, and their structure-activity as well as structure-property relationships were studied. A novel promising compound with improved solubility and enhanced anti-virulence activity was discovered (IC50: 3.8 μM, pyocyanin). Our findings emphasize the crucial role of substituents at the 3-position and the carbonyl group at the 4-position for ligand-receptor interactions, and illuminate the way for further optimization of PqsR antagonists as anti-virulence agents.
Affiliation:
Helmholtz-Institut für Pharmazeutische Forschung Saarland Campus, Geb. C2.3 Universität des Saarlandes, D-66123 Saarbrücken, Germany.
Citation:
Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships. 2014, 79:173-83 Eur J Med Chem
Journal:
European journal of medicinal chemistry
Issue Date:
22-May-2014
URI:
http://hdl.handle.net/10033/325005
DOI:
10.1016/j.ejmech.2014.04.016
PubMed ID:
24735643
Type:
Article
Language:
en
ISSN:
1768-3254
Appears in Collections:
publications of the department drug design and optimization (HIPS]DDOP)

Full metadata record

DC FieldValue Language
dc.contributor.authorLu, Cenbinen
dc.contributor.authorKirsch, Benjaminen
dc.contributor.authorMaurer, Christine Ken
dc.contributor.authorde Jong, Johannes Cen
dc.contributor.authorBraunshausen, Andreaen
dc.contributor.authorSteinbach, Ankeen
dc.contributor.authorHartmann, Rolf Wen
dc.date.accessioned2014-08-20T09:16:05Z-
dc.date.available2014-08-20T09:16:05Z-
dc.date.issued2014-05-22-
dc.identifier.citationOptimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships. 2014, 79:173-83 Eur J Med Chemen
dc.identifier.issn1768-3254-
dc.identifier.pmid24735643-
dc.identifier.doi10.1016/j.ejmech.2014.04.016-
dc.identifier.urihttp://hdl.handle.net/10033/325005-
dc.description.abstractIncreasing antibiotic resistance urgently requires novel therapeutic options to combat bacterial infections. The anti-virulence therapy selectively intervening with pathogenicity without affecting bacterial viability is such a strategy to overcome resistance. We consider the virulence regulator PqsR as an attractive target in the human pathogen Pseudomonas aeruginosa, and recently discovered the first PqsR antagonists, which, however, suffered from poor aqueous solubility. In this work, the antagonists were structurally modified to become more soluble, and their structure-activity as well as structure-property relationships were studied. A novel promising compound with improved solubility and enhanced anti-virulence activity was discovered (IC50: 3.8 μM, pyocyanin). Our findings emphasize the crucial role of substituents at the 3-position and the carbonyl group at the 4-position for ligand-receptor interactions, and illuminate the way for further optimization of PqsR antagonists as anti-virulence agents.en
dc.language.isoenen
dc.rightsArchived with thanks to European journal of medicinal chemistryen
dc.titleOptimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Institut für Pharmazeutische Forschung Saarland Campus, Geb. C2.3 Universität des Saarlandes, D-66123 Saarbrücken, Germany.en
dc.identifier.journalEuropean journal of medicinal chemistryen

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