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Design, synthesis and evaluation of triazole functionalized Ring-fused 2-pyridones as antibacterial agents
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. (Laboratories for Chemical Biology Umeå LCBU)
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Laboratories for Chemical Biology Umeå LCBU, Umeå Center for Microbial Research UCMR)
2012 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 54, 637-646 p.Article in journal (Refereed) Published
Abstract [en]

Antibacterial resistance is today a worldwide problem and the demand for new classes of antibacterial agents with new mode of action is enormous. In the strive for new antibacterial agents that inhibit pilus assembly, an important virulence factor, routes to introduce triazoles in position 8 and 2 of ring-fused bicyclic 2-pyridones have been developed. This was made via Sonogashira couplings followed by Huisgen 1,3-dipolar cycloadditions. The method development made it possible to introduce a diverse series of substituted triazoles and their antibacterial properties were tested in a whole cell pili-dependent biofilm assay. Most of the twenty four candidates tested showed low to no activity but interestingly three compounds, one 8-substituted and two 2-substituted, showed promising activities with EC50’s between 9-50 μM.

Place, publisher, year, edition, pages
Elsevier, 2012. Vol. 54, 637-646 p.
Keyword [en]
Pilicide, 2-Pyridone, Triazole, Huisgen 1, 3-dipolar cycloaddition, Antibacterial
National Category
Chemical Sciences
URN: urn:nbn:se:umu:diva-56739DOI: 10.1016/j.ejmech.2012.06.018OAI: diva2:537218
Available from: 2012-06-26 Created: 2012-06-26 Last updated: 2013-04-26Bibliographically approved
In thesis
1. Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
Open this publication in new window or tab >>Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections.

Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent.

The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.   

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 85 p.
Synthesis, 2-pyridone, 2-thiazoline, cross coupling, pili, curli, antibacterial
National Category
Natural Sciences
Research subject
Organic Chemistry
urn:nbn:se:umu:diva-68709 (URN)978-91-7459-552-9 (ISBN)
Public defence
2013-05-24, KBC-Huset, KB3B1, Umeå universitet, Umeå, 10:00 (English)
Available from: 2013-05-03 Created: 2013-04-23 Last updated: 2013-05-03Bibliographically approved

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Bengtsson, ChristofferLindgren, Anders EGUvell, HannaAlmqvist, Fredrik
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