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Functionalization of bicyclic 2-pyridones targeting pilus biogenesis in uropathogenic Escherichia coli
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2007 (German)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1873-3581, Vol. 48, no 26, 4543-4546 p.Article in journal (Refereed) Published
Abstract [en]

Substituted bicyclic 2-pyridones, termed pilicides, prevent pilus assembly in uropathogenic Escherichia coli. Based on the bioactive methyl ester protected 2-pyridone 4, further functionalization at C-6 has yielded a set of new compounds, which have been evaluated for their ability to inhibit pilus formation in uropathogenic E. coli. The key intermediate in the synthesis was formylated 2-pyridone 5, which could be obtained via a Vilsmeier reaction. This versatile intermediate was converted into secondary and tertiary amines via reductive amination and could also be converted to other interesting functionalities using simple chemical transformations.

Place, publisher, year, edition, pages
Oxford: Pergamon Press , 2007. Vol. 48, no 26, 4543-4546 p.
Keyword [en]
2-Pyridone, Formylation, Antibacterial agent, Pilicide, Biofilm inhibitor
URN: urn:nbn:se:umu:diva-2713DOI: 10.1016/j.tetlet.2007.04.142OAI: diva2:140962
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-03-22Bibliographically approved
In thesis
1. Synthesis and functionalization of ring-fused 2-pyridones: Targeting pili formation in E. coli
Open this publication in new window or tab >>Synthesis and functionalization of ring-fused 2-pyridones: Targeting pili formation in E. coli
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bicyclic dihydrothiazolo fused 2-pyridones have been studied as a new class of antibacterial agents, termed pilicides, that target the formation of adhesive bacterial surface organelles (pili) in pathogenic bacteria. Synthetic methods to further functionalize the bicyclic 2-pyridone scaffold have been developed in order to increase water-solubility and thereby facilitate biological evalua-tions. This was accomplished by introducing aminomethylenes at the open position C-6. Tertiary amines were introduced via a microwave–assisted Mannich reaction and a synthetic route based on a formyl intermediate gave access to primary, secondary and tertiary amines, but also to other interesting functionalities. Biological evaluation confirmed that several of the function-alized compounds inhibited pili formation in uropathogenic E. coli., as dem-onstrated by assays of hemagglutination, biofilm formation and adherence to bladder cells. Co-crystallizing one of the pilicides with the target protein gave information about the binding site and based on this a mechanism of action was proposed, which was supported experimentally by surface plas-mon resonance and single point mutations in the protein.

Furthermore, the previously developed acylketene imine reaction used to prepare bicyclic thiazolo fused 2-pyridone pilicides has been developed to allow preparation of other ring-fused 2-pyridone systems. Benzo[a]quinolizine-4-ones and indolo[2,3-a]quinolizine-4-ones could be prepared in a fast and simple manner starting from dihydroisoquinolines and a β-carboline. Finally, this method could also be applied for the preparation of heteroatom analogs of the previously studied sulfur containing pilicides. Biological evaluations established that the sulfur atom can be replaced by oxygen and still maintain the ability to prevent pili assembly.

Place, publisher, year, edition, pages
Umeå: Kemi, 2007. 72 p.
2-pyridone, acylketene, antibacterial, biofilm inhibitor, Mannich, Micro-wave-assisted chemistry, peptidomimetic, virulence.
National Category
Organic Chemistry
urn:nbn:se:umu:diva-1416 (URN)978-91-7264-438-0 (ISBN)
Public defence
2007-11-23, hörsal ALI, fd arbetslivsinstitutet, Umeå, 10:00
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-03-15Bibliographically approved

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Pemberton, NilsJakobsson, LottaAlmqvist, Fredrik
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