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Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).ORCID-id: 0000-0003-4646-0216
2006 (Engelska)Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 8, nr 5, s. 935-938Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Washington, D.C.: American Chemical Society , 2006. Vol. 8, nr 5, s. 935-938
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-2714DOI: 10.1021/ol052998eOAI: oai:DiVA.org:umu-2714DiVA, id: diva2:140963
Tillgänglig från: 2007-11-01 Skapad: 2007-11-01 Senast uppdaterad: 2019-03-14Bibliografiskt granskad
Ingår i avhandling
1. Synthesis and functionalization of ring-fused 2-pyridones: Targeting pili formation in E. coli
Öppna denna publikation i ny flik eller fönster >>Synthesis and functionalization of ring-fused 2-pyridones: Targeting pili formation in E. coli
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Kemi, 2007. s. 72
Nyckelord
2-pyridone, acylketene, antibacterial, biofilm inhibitor, Mannich, Micro-wave-assisted chemistry, peptidomimetic, virulence.
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-1416 (URN)978-91-7264-438-0 (ISBN)
Disputation
2007-11-23, hörsal ALI, fd arbetslivsinstitutet, Umeå, 10:00
Opponent
Handledare
Tillgänglig från: 2007-11-01 Skapad: 2007-11-01 Senast uppdaterad: 2011-03-15Bibliografiskt granskad

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Förlagets fulltexthttp://dx.doi.org/10.1021/ol052998e

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Almqvist, Fredrik

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Organic Letters
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