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Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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.
Keyword [en]
Synthesis, 2-pyridone, 2-thiazoline, cross coupling, pili, curli, antibacterial
National Category
Natural Sciences
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-68709ISBN: 978-91-7459-552-9 (print)OAI: oai:DiVA.org:umu-68709DiVA: diva2:617583
Public defence
2013-05-24, KBC-Huset, KB3B1, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2013-05-03 Created: 2013-04-23 Last updated: 2013-05-03Bibliographically approved
List of papers
1. Regioselective Halogenations and Subsequent Suzuki-Miyaura Coupling onto Bicyclic 2-Pyridones
Open this publication in new window or tab >>Regioselective Halogenations and Subsequent Suzuki-Miyaura Coupling onto Bicyclic 2-Pyridones
2010 (English)In: The Journal of organic chemistry, ISSN 1520-6904, Vol. 75, no 3, 972-5 p.Article in journal (Refereed) Published
Abstract [en]

A selective synthesis of 6-bromo-8-iodo dihydro thiazolo ring-fused 2-pyridones is described. These halogenated 2-pyridones are selectively arylated by sequential Suzuki-Miyaura couplings. This approach can advantageously be used to synthesize focused libraries of substituted ring-fused 2-pyridones, a class of compounds with novel antibacterial properties.

Place, publisher, year, edition, pages
American Chemical Society, 2010
Identifiers
urn:nbn:se:umu:diva-30482 (URN)10.1021/jo902458g (DOI)000273982900059 ()20025251 (PubMedID)
Available from: 2010-01-04 Created: 2010-01-04 Last updated: 2013-04-26Bibliographically approved
2. Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity
Open this publication in new window or tab >>Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity
Show others...
2011 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, no 4, 1103-1116 p.Article in journal (Refereed) Published
Abstract [en]

Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Aβ aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.

Place, publisher, year, edition, pages
Elsevier Masson SAS, 2011
Keyword
Pilicide, Anti-virulence, 2-Pyridone, peptidomimetic
National Category
Infectious Medicine Organic Chemistry Inorganic Chemistry Medicinal Chemistry Organic Chemistry
Research subject
Biorganic Chemistry; Infectious Diseases; läkemedelskemi; Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-43916 (URN)10.1016/j.ejmech.2011.01.025 (DOI)21316127 (PubMedID)
Available from: 2011-05-16 Created: 2011-05-16 Last updated: 2017-12-11Bibliographically approved
3. Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms
Open this publication in new window or tab >>Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms
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2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, 4522-4532 p.Article in journal (Refereed) Published
Abstract [en]

Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.

Place, publisher, year, edition, pages
Berlin: Wiley-VCH Verlagsgesellschaft, 2012
Keyword
antivirulence, biological activity, coumarin, fluorescence, structure–activity relationships
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-53543 (URN)10.1002/chem.201103936 (DOI)22431310 (PubMedID)
Available from: 2012-04-02 Created: 2012-04-02 Last updated: 2017-12-07Bibliographically approved
4. Design, synthesis and evaluation of triazole functionalized Ring-fused 2-pyridones as antibacterial agents
Open this publication in new window or tab >>Design, synthesis and evaluation of triazole functionalized Ring-fused 2-pyridones as antibacterial agents
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
Keyword
Pilicide, 2-Pyridone, Triazole, Huisgen 1, 3-dipolar cycloaddition, Antibacterial
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-56739 (URN)10.1016/j.ejmech.2012.06.018 (DOI)
Available from: 2012-06-26 Created: 2012-06-26 Last updated: 2017-12-07Bibliographically approved
5. A Selective Intramolecular 5-exo-dig or 6-endo-dig Cyclization en Route to 2-Furanone or 2-Pyrone Containing Tricyclic Scaffolds
Open this publication in new window or tab >>A Selective Intramolecular 5-exo-dig or 6-endo-dig Cyclization en Route to 2-Furanone or 2-Pyrone Containing Tricyclic Scaffolds
2011 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 23, 9817-9825 p.Article in journal (Refereed) Published
Abstract [en]

Ringfused bicyclic 2-pyridones exhibit interesting biological properties against pili assembly in uropathogenic E. coli1 as well as curli formation2. In the strive for new ring-fused central fragments highly selective synthetic routes to the 2-furanone or 2-pyrone containing tricyclic scaffolds 1 and 2 have been developed.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-49167 (URN)10.1021/jo201952p (DOI)22008034 (PubMedID)
Available from: 2011-11-01 Created: 2011-11-01 Last updated: 2017-12-08Bibliographically approved

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