Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones-targeting virulence of uropathogenic E. coli
2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 22, 7563-7581 p.Article in journal (Refereed) Published
Substituted bicyclic 2-pyridones, termed pilicides, are dipeptide mimetics that prevent pilus assembly in uropathogenic Escherichia coli. Here, we apply rational design to produce four classes of extended peptidomimetics based on two bioactive 2-pyridones. The key intermediate in the synthesis was an amino-functionalised 2-pyridone scaffold, which could be obtained via a mild and selective nitration and subsequent reduction. Procedures were then developed to further derivatize this amino-substituted core and a total of 24 extended peptidomimetics were synthesised and evaluated for chaperone affinity and in vivo antivirulence activity in P pili producing E. coli. Enhanced affinities for the target protein were observed within the generated set of compounds, while the ability to prevent pilus assembly in vivo was significantly decreased compared to the parent lead compounds. The results suggest that the limited in vivo potencies of the analogues are either uptake/distribution related or due to loss in binding specificity.
Place, publisher, year, edition, pages
Oxford: Pergamon Press , 2006. Vol. 14, no 22, 7563-7581 p.
Bicyclo Compounds; Heterocyclic/*chemical synthesis/chemistry/*pharmacology, Biomimetics, Crystallography; X-Ray, Drug Design, Escherichia coli/*drug effects/*pathogenicity, Magnetic Resonance Spectroscopy, Molecular Chaperones/chemistry/metabolism, Molecular Structure, Peptides/*chemistry, Pyridones/*chemistry, Structure-Activity Relationship, Urinary Tract/microbiology
IdentifiersURN: urn:nbn:se:umu:diva-12343DOI: 10.1016/j.bmc.2006.07.017PubMedID: 16904898OAI: oai:DiVA.org:umu-12343DiVA: diva2:152014