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Synthesis and functionalization of ring-fused 2-pyridones: Targeting pili formation in E. coli
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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 [en]
2-pyridone, acylketene, antibacterial, biofilm inhibitor, Mannich, Micro-wave-assisted chemistry, peptidomimetic, virulence.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-1416ISBN: 978-91-7264-438-0 (print)OAI: oai:DiVA.org:umu-1416DiVA: diva2:140965
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
List of papers
1. Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones
Open this publication in new window or tab >>Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones
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2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 23, 7830-7835 p.Article in journal (Refereed) Published
Abstract [en]

By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene substituents were introduced via a cyanodehalogenation followed by a borane dimethyl sulfide reduction of the afforded nitrile. In both of these transformations, microwave irradiation proved to be superior to traditional conditions and the primary amines were obtained in good overall yields (55-58% over three steps). To incorporate tertiary aminomethylene substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed iminium salts proved to be effective. Thus highly substituted 2-pyridones were obtained in 48-93% yields.

 

Place, publisher, year, edition, pages
Easton, Pa.: American Chemical Society, 2004
Identifiers
urn:nbn:se:umu:diva-5469 (URN)10.1021/jo048554y (DOI)
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2017-12-14Bibliographically approved
2. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria
Open this publication in new window or tab >>Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria
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2006 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 47, 17897-17902 p.Article in journal (Refereed) Published
Abstract [en]

A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone–usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone–subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.

Place, publisher, year, edition, pages
Washtington: National Academy of Sciences, 2006
Keyword
antimicrobials, chaperone–usher pathway, pilicide, urinary tract infection
Identifiers
urn:nbn:se:umu:diva-12796 (URN)doi:10.1073/pnas.0606795103 (DOI)
Available from: 2007-10-03 Created: 2007-10-03 Last updated: 2017-12-14Bibliographically approved
3. Functionalization of bicyclic 2-pyridones targeting pilus biogenesis in uropathogenic Escherichia coli
Open this publication in new window or tab >>Functionalization of bicyclic 2-pyridones targeting pilus biogenesis in uropathogenic Escherichia coli
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2007 (German)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, 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
Keyword
2-Pyridone, Formylation, Antibacterial agent, Pilicide, Biofilm inhibitor
Identifiers
urn:nbn:se:umu:diva-2713 (URN)10.1016/j.tetlet.2007.04.142 (DOI)
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2017-12-14Bibliographically approved
4. Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation
Open this publication in new window or tab >>Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation
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
Identifiers
urn:nbn:se:umu:diva-2714 (URN)10.1021/ol052998e (DOI)
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2017-12-14Bibliographically approved
5. Synthesis and evaluation of dihydroimidazolo and di-hydrooxazolo ring-fused 2-pyridones - Targeting pilus biogenesis in uropathogenic bacteria
Open this publication in new window or tab >>Synthesis and evaluation of dihydroimidazolo and di-hydrooxazolo ring-fused 2-pyridones - Targeting pilus biogenesis in uropathogenic bacteria
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2715 (URN)
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2010-01-13Bibliographically approved

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