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Synthesis and biological evaluation of Bicyclic β-Lactams and 2-Pyridinones: Pilicides Targeting Pilus Biogenesis in Pathogenic Bacteria
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

New methods have been developed for the synthesis of bicyclic β-lactams and 2-pyridinones by combining acyl Meldrum’s acids and Δ2-thiazolines. The 2-pyridinones were synthesised both in solution using conventional heating or microwave assisted heating as well as by solid supported chemistry.

The compounds (pilicides) were designed to interfere with the assembly of pili in uropathogenic E. coli by inhibiting the periplasmic chaperones. The affinity of the pilicides to the chaperones was investigated with surface plasmon resonance technique (Biacore) and with relaxation-edited 1H NMR spectroscopy experiments. Finally, the pilicides were investigated for their ability to inhibit pili formation in uropathogenic E. coli in a hemagglutination assay, where members of the 2-pyridinone family proved to be able to cause depiliation.

Place, publisher, year, edition, pages
Umeå: Department of Chemistry, Organic Chemistry, Umeå University , 2003. , 75 p.
Keyword [en]
Organic chemistry, β-lactam, 2-pyridinone, 2-pyridone, Meldrum’s acid, Δ2-thiazoline, solid-phase synthesis, microwave assisted synthesis, antibacterial, pili, pilicide
Keyword [sv]
Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-165ISBN: 91-7305-546-8 (print)OAI: oai:DiVA.org:umu-165DiVA: diva2:141704
Public defence
2003-12-19, Stora Hörsalen, KBC-huset,, Umeå universitet, Umeå, 13:00 (English)
Opponent
Available from: 2003-11-28 Created: 2003-11-28 Last updated: 2012-05-15Bibliographically approved
List of papers
1. Stereoselective Synthesis of Optically Active β-Lactams, Potential Inhibitors of Pilus Assembly in Pathogenic Bacteria
Open this publication in new window or tab >>Stereoselective Synthesis of Optically Active β-Lactams, Potential Inhibitors of Pilus Assembly in Pathogenic Bacteria
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2000 In: Organic Letters, Vol. 2, 2065-2067 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3199 (URN)
Available from: 2003-11-28 Created: 2003-11-28Bibliographically approved
2. Stereoselective Synthesis of Optically Active Bicyclic β-Lactam Carboxylic Acids that Target Pilus Biogenesis in Pathogenic Bacteria
Open this publication in new window or tab >>Stereoselective Synthesis of Optically Active Bicyclic β-Lactam Carboxylic Acids that Target Pilus Biogenesis in Pathogenic Bacteria
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2003 In: Organic & Biomolecular Chemistry, Vol. 1, 1308-1314 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3200 (URN)
Available from: 2003-11-28 Created: 2003-11-28Bibliographically approved
3. An Enantioselective Ketene-Imine Cycloaddition Method for Synthesis of Substituted Ring-Fused 2-Pyridinones
Open this publication in new window or tab >>An Enantioselective Ketene-Imine Cycloaddition Method for Synthesis of Substituted Ring-Fused 2-Pyridinones
2001 (English)In: The Journal of Organic Chemistry, Vol. 66, no 20, 6756-61 p.Article in journal (Refereed) Published
Abstract [en]

Previously, a method for the stereoselective synthesis of -lactams, starting from 2H-2-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-2-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 78 C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 64 C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different 2-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-9584 (URN)doi:10.1021/jo015794u (DOI)
Available from: 2008-04-28 Created: 2008-04-28 Last updated: 2012-05-15Bibliographically approved
4. Design and evaluation of Pilicides: Potential novel antibacterial agents directed against Uropathogenic Escherichia coli
Open this publication in new window or tab >>Design and evaluation of Pilicides: Potential novel antibacterial agents directed against Uropathogenic Escherichia coli
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2001 (English)In: ChemBioChem (Print), ISSN 1439-4227, ChemBioChem (Online), ISSN '1439-7633', Vol. 2, no 12, 915-918 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Wiley InterScience, 2001
Keyword
antibiotics, bioorganic chemistry, chaperone proteins, peptidomimetics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biorganic Chemistry
Identifiers
urn:nbn:se:umu:diva-3202 (URN)
Available from: 2003-11-28 Created: 2003-11-28 Last updated: 2010-03-08Bibliographically approved
5. Design and Parallel Solid Phase Synthesis of Ring Fused 2-Pyridinones that Target Pilus Biogenesis in Pathogenic Bacteria
Open this publication in new window or tab >>Design and Parallel Solid Phase Synthesis of Ring Fused 2-Pyridinones that Target Pilus Biogenesis in Pathogenic Bacteria
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2002 (English)In: Journal of Combinatorial Chemistry, Vol. 4, 630-639 p.Article in journal (Refereed) Published
Abstract [en]

A new method for the solid-phase synthesis of enantiomerically enriched highly substituted ring-fused 2-pyridinones 13 has been developed. The synthesis mediates introduction of substituents at two positions in the 2-pyridinone ring in a diverse manner and is suitable for parallel synthesis. 19F NMR spectroscopy was used as a tool to monitor each of the five steps in the reaction sequence. The optimized conditions thus obtained were then used to prepare a library of 20 2-pyridinones with high yields. The library members were chosen from a statistical multivariate design to ensure diversity and reliable data for structure−activity relationships. Screening of the library against the bacterial periplasmic chaperone PapD was performed using surface plasmon resonance. Three new 2-pyridinones with a higher affinity for the chaperone PapD than the previous best 13{10,1} were found, and important structural features could be deduced.

Identifiers
urn:nbn:se:umu:diva-3203 (URN)10.1021/cc020032d (DOI)
Available from: 2003-11-28 Created: 2003-11-28 Last updated: 2010-02-17Bibliographically approved
6. Efficient Microwave Assisted Synthesis of Optically Active Bicyclic 2-Pyridinones via Δ2-Thiazolines
Open this publication in new window or tab >>Efficient Microwave Assisted Synthesis of Optically Active Bicyclic 2-Pyridinones via Δ2-Thiazolines
2003 (English)In: Molecular diversity, ISSN 1381-1991, E-ISSN 1573-501X, no 2-4, 165-169 p.Article in journal (Refereed) Published
Abstract [en]

A new efficient synthesis of optically active bicyclic 2-pyridiones has been developed using microwave irradiation. The synthesis is a two-step procedure via 2-thiazolines, which only requires a 3 + 2 min reaction time compared to 2 days when using conventional heating. The optimized conditions proved to be suitable for the synthesis of a small library in excellent yields and with limited racemizations.

Place, publisher, year, edition, pages
Springer Netherlands, 2003
Keyword
cycloaddition, Meldrum's acid, microwave, pyridone, thiazoline, 2-pyridinone
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-3204 (URN)10.1023/B:MODI.0000006800.46154.99 (DOI)
Available from: 2003-11-28 Created: 2003-11-28 Last updated: 2012-06-14Bibliographically approved

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