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Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2006 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 8, no 5, 935-938 p.Article in journal (Refereed) Published
Abstract [en]

Polycyclic ring-fused 2-pyridones (5a−e and 9a−e) have been prepared via a microwave-assisted acyl-ketene imine cyclocondensation. Starting from 3,4-dihydroisoquinolines (4a−b) or 3,4-dihydroharman (8), fused 2-pyridones could be prepared in a one-step procedure. By using either Meldrum's acid derivatives (1a−d) or 1,3-dioxine-4-ones (7a−b) as acyl-ketene sources, mono- or disubstitution of the fused 2-pyridone ring could be accomplished. As an application of the method, a formal synthesis of the indole alkaloid sempervilam was performed.

Place, publisher, year, edition, pages
Washington, D.C.: American Chemical Society , 2006. Vol. 8, no 5, 935-938 p.
Identifiers
URN: urn:nbn:se:umu:diva-2714DOI: 10.1021/ol052998eOAI: oai:DiVA.org:umu-2714DiVA: diva2:140963
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-03-14Bibliographically 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.
Keyword
2-pyridone, acylketene, antibacterial, biofilm inhibitor, Mannich, Micro-wave-assisted chemistry, peptidomimetic, virulence.
National Category
Organic Chemistry
Identifiers
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
Opponent
Supervisors
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-03-15Bibliographically approved

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