Synthesis and biological properties of conjugates between fluoroquinolones and a N3''-functionalized pyochelin

Pyochelin is a siderophore common to Pseudomonas aeruginosa and several other pathogenic bacteria. A pyochelin functionalized at the N3'' position with a propyl-amine extension was previously synthesized. In the present work we proved that this analog binds FptA, the pyochelin outer membra...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2011-12, Vol.9 (24), p.8288-8300
Main Authors: Noël, Sabrina, Gasser, Véronique, Pesset, Bénédicte, Hoegy, Françoise, Rognan, Didier, Schalk, Isabelle J, Mislin, Gaëtan L A
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Chemical Sciences
Fluoroquinolones - chemical synthesis
Fluoroquinolones - chemistry
Fluoroquinolones - pharmacology
Medicinal Chemistry
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Phenols - chemical synthesis
Phenols - chemistry
Phenols - pharmacology
Pseudomonas aeruginosa - drug effects
Solubility
Structure-Activity Relationship
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
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Summary:Pyochelin is a siderophore common to Pseudomonas aeruginosa and several other pathogenic bacteria. A pyochelin functionalized at the N3'' position with a propyl-amine extension was previously synthesized. In the present work we proved that this analog binds FptA, the pyochelin outer membrane receptor, and transports iron(III) efficiently into bacteria. This functionalized pyochelin seemed to be a good candidate for antibiotic vectorization in the framework of a Trojan horse prodrug strategy. In this context, conjugates between pyochelin and three fluoroquinolones (norfloxacin, ciprofloxacin and N-desmethyl-ofloxacin) were synthesized with a spacer arm that was either stable or hydrolyzable in vivo. Some pyochelin-fluoroquinolone conjugates had antibacterial activities in growth inhibition experiments on several P. aeruginosa strains. However, these activities were weaker than those of the antibiotic alone. These properties appeared to be related to both the solubility and bioavailability of conjugates and to the stability of the spacer arm used.
ISSN:1477-0520
1477-0539
DOI:10.1039/c1ob06250f