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  • 1.
    Adolfsson, Dan E.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tyagi, Mohit
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Deuschmann, Adrian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gharibyan, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Jayaweera, Sanduni Wasana
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils2020In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 85, no 21, p. 14174-14189Article in journal (Other academic)
    Abstract [en]

    A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

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  • 2.
    Adolfsson, Dan E.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tyagi, Mohit
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kaur, Amandeep
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bharate, Jaideep B.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Enhanement of amyloid fibril binding by ring expansion of thiazolino fused 2-pyridone peptidomimeticsManuscript (preprint) (Other academic)
    Abstract [en]

    Thiazolino fused 2-pyridones undergo thiazoline ring opening by reaction with 2-nitrobenzyl bromide through thi- oether attack, and base promoted fragmentation of the resulting sulfonium ions. Subsequent deprotonation of the benzylic carbon and intramolecular 1,4-addition leads to ring closure, generating dihydrothiazine fused 2-pyridones by net ring expansion of the thiazoline ring. Application of the ring expansion procedure to the pyridine and pyrimidine fused thiazolino 2-pyridones provided compounds with enhanced fibril binding activity.

  • 3.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    SESSION 3, Chemical neuroscience and selected short talks: Pilicides & curlicides –antibacterial agents targeting bacterial virulence2011Conference paper (Other academic)
  • 4.
    Almqvist, Fredrik
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Manner, Sophie
    Thornqvist, Viveca
    Berg, Ulf
    Wallin, Margareta
    Frejd, Torbjörn
    Umeå University, Faculty of Science and Technology, Chemistry.
    Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)2004In: ORGANIC & BIOMOLECULAR CHEMISTRY, ISSN 1477-0520, Vol. 2, no 21, p. 3085-90Article in journal (Refereed)
    Abstract [en]

    The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.

  • 5.
    Andersson, Emma K.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bengtsson, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Evans, Margery L.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sellstedt, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Lindgren, Anders E.G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hufnagel, David A.
    Bhattacharya, Moumita
    Tessier, Peter M.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chapman, Matthew R.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). University of Michigan, USA.
    Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones2013In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 20, no 10, p. 1245-1254Article in journal (Refereed)
    Abstract [en]

    Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."

  • 6.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Olsson, Roger
    Synthesis of 2-Substituted Pyridines via a Regiospecific Alkylation, Alkynylation, and Arylation of Pyridine N-Oxides2007In: Organic Letters, Vol. 9, no 7, p. 1335-7Article in journal (Refereed)
    Abstract [en]

    Sequential addition of Grignard reagents to pyridine N-oxides in THF at room temperature followed by treatment with acetic anhydride at 120 C afforded 2-substituted pyridines in good to high yields. Furthermore, by exchanging acetic anhydride for DMF in the second step, 2-substituted pyridine N-oxides were obtained, as intermediates suitable for addition of a second Grignard reagent for the synthesis of 2,6-disubstituted pyridines.

  • 7.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Banchelin, Thomas Sainte-Luce
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Pralay
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gustafsson, Magnus
    Acadia Pharmaceuticals AB, Medeon Science Park S-20512, Malmö, Sweden.
    Olsson, Roger
    Acadia Pharmaceuticals AB, Medeon Science Park S-20512, Malmö, Sweden.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Complete regioselective addition of grignard reagents to pyrazine N-oxides, toward an efficient enantioselective synthesis of substituted piperazines2010In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 12, no 2, p. 284-6Article in journal (Refereed)
    Abstract [en]

    A conceptually new one-pot strategy for the synthesis of protected substituted piperazines via the addition of Grignard reagents to pyrazine N-oxides is presented. This strategy is high yielding (33-91% over three steps), step-efficient, and fast. The synthesized N,N-diprotected piperazines are convenient to handle and allow for orthogonal deprotection at either nitrogen for selective transformations. In addition, this is a synthetic route to enantiomerically enriched piperazines by using a combination of phenyl magnesium chloride and (-)-sparteine, which resulted in enantiomeric excesses up to 83%.

  • 8.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Sajal
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gustafsson, Magnus
    Olsson, Roger
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of substituted 4-pyridones and 4-aminopyridinium salts via a one-pot pyridine synthesis2010In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 32, p. 4218-4220Article in journal (Refereed)
    Abstract [en]

    Synthesis of substituted 4-benzyloxypyridinium salts by the addition of Grignard reagents to pyridine N-oxides provides an efficient route for obtaining substituted 4-pyridones or 4-aminopyridinium salts.

  • 9.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gustafsson, Magnus
    Boström, Dan
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Olsson, Roger
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The Regio- and Stereoselective Synthesis of trans-2,3-Dihydropyridine N-oxides and Piperidines2009In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 48, no 18, p. 3288-3291Article in journal (Refereed)
    Abstract [en]

    No Abstract

  • 10.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gustafsson, Magnus
    Olsson, Roger
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents2008In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 48, p. 6901-3Article in journal (Refereed)
    Abstract [en]

    Addition of i-PrMgCl to pyridine N-oxides in THF at −78 °C generates selectively an ortho-metallated species, which can be trapped with various electrophiles to generate 2-substituted pyridine N-oxides. Furthermore, by applying a double metal-catalyzed cross-coupling, direct arylation of the pyridine N-oxides is achieved.

  • 11.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olsson, Roger
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Reactions between Grignard reagents and heterocyclic N-oxides: stereoselective synthesis of substituted pyridines, piperidines, and piperazines2011In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, p. 337-346Article in journal (Refereed)
    Abstract [en]

    In this perspective we discuss the recent developments of stereoselective synthesis of substituted pyridines, piperidines, and piperazines from cheap and commercially readily available starting materials. Pyridine N-oxides and pyrazine N-oxides are reacted with alkyl, aryl, alkynyl and vinyl Grignard reagents to give a diverse set of heterocycles in high yields. Optically active substituted piperazines are obtained by an asymmetric reaction from pyrazine N-oxides using sparteine as chiral ligand. In addition, a stereoselective synthesis of dienal-oximes from the reaction between pyridine N-oxides and Grignard reagents is presented, which results in a useful intermediate for the synthesis of a diverse set of compounds.

  • 12.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sainte-Luce Banchelin, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Sajal
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olsson, Roger
    Institutionen för kemi och molekylärbiologi, Göteborgs universitet, Göteborg, Sverige .
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Efficient, mild and completely regioselective synthesis of substituted pyridines2010In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 46, no 19, p. 3384-3386Article in journal (Refereed)
    Abstract [en]

    Addition of Grignard reagents to pyridine N-oxides in THF at low temperature (-78 to -20 °C) and treatment with TFAA provides an efficient general procedure for synthesis of substituted pyridines. The method is compatible with a range of functional groups such as esters, halogens and nitriles.

  • 13.
    Andersson, Hans
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Wang, Xiaoyang
    Umeå University, Faculty of Science and Technology, Chemistry.
    Björklund, Mikael
    Umeå University, Faculty of Science and Technology, Chemistry.
    Olsson, Roger
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Reaction of pyridine N-oxides with Grignard reagents: a stereodefined synthesis of substituted dienal oximes2007In: Tetrahedron Letters, Vol. 48, p. 6941-4Article in journal (Refereed)
    Abstract [en]

    Rapid addition of Grignard reagents to pyridine N-oxides under mild conditions gave stereodefined dienal oximes in good to excellent yields. This reaction provides an efficient access to substituted olefins with defined stereochemistry that are potentially of interest as bioactives themselves or as versatile synthetic intermediates.

  • 14.
    Andersson, Magnus
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Axner, Ove
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fällman, Erik
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Physical Properties of Biopolymers Assessed by Optical Tweezers: Analysis of folding and refolding of bacterial pili2008In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 9, no 2, p. 221-235Article in journal (Refereed)
    Abstract [en]

    Bacterial adhesion to surfaces mediated by specific adhesion organelles that promote infections, as exemplified by the pili of uropathogenic E. coli, is studied mostly at the level of cell-cell interactions and thereby reflects the averaged behavior of multiple pili. The role of pilus rod structure has therefore only been estimated from the outcome of experiments involving large numbers of organelles at the same time. It has, however, lately become clear that the biomechanical behavior of the pilus shafts play an important, albeit hitherto rather unrecognized, role in the adhesion process. For example, it has been observed that shafts from two different strains, even though they are similar in structure, result in large differences in the ability of the bacteria to adhere to their host tissue. However, in order to identify all properties of pilus structures that are of importance in the adhesion process, the biomechanical properties of pili must be assessed at the single-molecule level. Due to the low range of forces of these structures, until recently it was not possible to obtain such information. However, with the development of force-measuring optical tweezers (FMOT) with force resolution in the low piconewton range, it has lately become possible to assess forces mediated by individual pili on single living bacteria in real time. FMOT allows for a more or less detailed mapping of the biomechanical properties of individual pilus shafts, in particular those that are associated with their elongation and contraction under stress. This Mi- nireview presents the FMOT technique, the biological model system, and results from assessment of the biomechanical properties of bacterial pili. The information retrieved is also compared with that obtained by atomic force microscopy.

  • 15.
    Barange, Deepak Kumar
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johnson, Magnus T.
    Cairns, Andrew G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olsson, Roger
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines2016In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 18, no 24, p. 6228-6231Article in journal (Refereed)
    Abstract [en]

    Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times.

  • 16.
    Basu, Basudeb
    et al.
    Department of Chemistry, University of North Bengal, Darjeeling 734013, India.
    Das, Sajal
    Department of Chemistry, University of North Bengal, Darjeeling 734013, India.
    Das, Pralay
    Department of Chemistry, University of North Bengal, Darjeeling 734013, India.
    Mandal, Bablee
    Department of Chemistry, University of North Bengal, Darjeeling 734013, India.
    Banerjee, Dipanjan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Palladium supported on a Polyionic Resin as an efficient, ligand-free, and recyclable catalyst for Heck, Suzuki-Miyaura, and Sonogashira reactions2009In: Synthesis (Stuttgart), ISSN 0039-7881, E-ISSN 1437-210X, no 7, p. 1137-1146Article in journal (Refereed)
    Abstract [en]

    Polyionic Amberlite resin formate (ARF), derived from commercially available Amberlite resin chloride by simple rinsing with aqueous formic acid, could be soaked with palladium(0) from palladium salts, the formate counteranion being the reducing source. The resulting Amberlite resin formate supported with palladium(0), ARF-Pd, showed excellent catalytic activity in Heck, Suzuki­-Miyaura, and Sonogashira couplings with a range of substrates. The catalyst may be recovered easily and quantitatively without leaching and recycled; it was tested for five runs without any significant loss of activity.

  • 17. Basu, Basudeb
    et al.
    Paul, Susmita
    Kundu, Samir
    Byström, Emil
    Irgum, Knut
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Organic Polymeric Resins Embedded with Pd NPs: Newly Designed, Efficient and Chemoselective Catalyst for Reduction of Nitrobenzenes2017In: Current Organocatalysis, ISSN 2213-3372, Vol. 4, no 1, p. 48-61Article in journal (Refereed)
    Abstract [en]

    Background: Organic polymer supported palladium nanoparticles (NPs) are important for use as heterogeneous catalyst in various organic reactions. This works describes Pd Nps immobilized on to polystyrene-based ion-exchange resin surface for use as catalyst in the reduction of nitrobenzenes. The heterogeneous catalyst was found useful for hydrogenation of nitro group under both catalytic transfer hydrogenation (CTH) as well as by using molecular hydrogen (H2).

    Methods: The catalyst was prepared from Amberlite IRA 900 Cl after rinsing with formic acid (10%) and subsequent treatment with Na2PdCl4 in DMF. The resulting Pd Nps immobilized resins was designated as VersaCat Pd and used for CTH of nitrobenzenes in the presence of H-donors (sodium formate, formic acid, hydrazine hydrate) and also for hydrogenation with H2 gas. The catalyst was characterized by FT-IR, MAS-NMR, SEM, TEM and XPS and surface morphologies were studied before and after the reaction.

    Results: Hydrogenations of nitrobenzenes under CTH using different H-source and direct use of H2 gas were achieved successfully with good to excellent yields. Reactions were performed under mild conditions and high degree of chemoselectivity was also observed. The catalyst was recyclable, used for six consecutive runs with appreciable conversions and showed higher activity (> 3 times) in terms of metalcontent than commercially available Pd/C (10%) in the hydrogenation of nitrobenzenes using H2 gas. The TEM images showed that Pd Nps are evenly distributed with size 50-200 mm on polymeric matrices and there was no significant changes observed after the first catalytic run. However, considerable rupture of the polymeric surface occurred after six runs, as seen from SEM studies.

    Conclusion: The present study establishes high catalytic efficiency and chemoselectivity of the newly developed organic polystyrene-based resin-soaked Pd NPs (VersaCat Pd) in the reduction of nitrobenzenes. Both CTH and hydrogenation using H2 gas were successfully done. Interestingly, hydrazine hydrate offered excellent control over chemoselectivity under CTH conditions and allowed clean conversion from nitro to amine, while keeping a chloro substitutent unaffected. Hydrogenation using molecular H2 gave maximum TOF. Easy preparation, high efficacy, TOF, chemoselectivity, and versatile applications are notable features for this heterogeneous palladium catalyst (VersaCat Pd). These features are often required in chemical industries.

  • 18.
    Bengtsson, Christoffer
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    A Selective Intramolecular 5-exo-dig or 6-endo-dig Cyclization en Route to 2-Furanone or 2-Pyrone Containing Tricyclic Scaffolds2011In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 23, p. 9817-9825Article in journal (Refereed)
    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.

  • 19.
    Bengtsson, Christoffer
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Regioselective Halogenations and Subsequent Suzuki-Miyaura Coupling onto Bicyclic 2-Pyridones2010In: The Journal of organic chemistry, ISSN 1520-6904, Vol. 75, no 3, p. 972-5Article in journal (Refereed)
    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.

  • 20.
    Bengtsson, Christoffer
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of triazole functionalized bicyclic 2-pyridones2011In: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 242, p. 247-ORGN-Article in journal (Refereed)
  • 21. Bengtsson, Christoffer
    et al.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Krishnan, Syam
    Banchelin, Thomas Sainte-Luce
    Gustafson, Karl
    Das, Pralay
    Sinha, Arun K
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of a bromomethyl substituted bicyclic 2-pyridone scaffold2013In: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 245Article in journal (Refereed)
  • 22.
    Bengtsson, Christoffer
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindgren, Anders EG
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design, synthesis and evaluation of triazole functionalized Ring-fused 2-pyridones as antibacterial agents2012In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 54, p. 637-646Article in journal (Refereed)
    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.

  • 23.
    Bengtsson, Christoffer
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nelander, Hanna
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Asymmetric Synthesis of 2,4,5-Trisubstituted (2)-Thiazolines2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 30, p. 9916-9922Article in journal (Refereed)
    Abstract [en]

    (2)-Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to 2,4,5-trisubstituted (2)-thiazolines. These (2)-thiazolines were synthesized from readily accessible/commercially available ,-unsaturated methyl esters through a Sharpless asymmetric dihydroxylation and an ON acyl migration reaction as key steps. The final products were obtained in good yields with up to 97% enantiomeric excess.

  • 24.
    Bharate, Jaideep B.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gharibyan, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Adolfsson, Dan E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jayaweera, Sanduni Wasana
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vielfort, Katarina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tyagi, Mohit
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bonde, Mari
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones2021In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 19, no 44, p. 9758-9772Article in journal (Refereed)
    Abstract [en]

    We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

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  • 25. Bharate, Jaideep B.
    et al.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gharibyan, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Adolfsson, Dan E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jayaweera, Sanduni Wasana
    Vielfort, Katarina
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tyagi, Mohit
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    K2S2O8-mediated aerobic oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-pyridones with aldehydes: Direct access to highly functionalized pyrimidine fused thiazolino-2-pyridones with amyloid fibril binding activity or inhibitors of Amyloid-β fibril formationManuscript (preprint) (Other academic)
    Abstract [en]

    We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)- thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have the ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature Amyloid-β and α-Synuclein fibrils.

  • 26.
    Cairns, Andrew G.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sarkar, Souvik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Andreas
    FOI, Swedish Defence Research Agency, CBRN Defence & Security, Umeå, Sweden.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry2021In: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, Vol. 2020, no 7, p. 365-378Article in journal (Refereed)
    Abstract [en]

    Thiazolino ring fused 2-pyridones are a valuable scaffold with varied and substitution dependent biological activity, accessed primarily by an acyl ketene-imine cycloaddition and rearrangement. Although powerful, some aspects of this chemistry such as the requirement for excess starting material and the production of gas can make larger scale synthesis challenging. Here we describe the development, application and scaling of a continuous flow process allowing larger scale synthesis, with better handling of hazards and more reliable scaling. Optimisation and control of conditions allows for a more efficient synthesis, with a lower equivalence of the acyl ketene precursor required.

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  • 27.
    Cairns, Andrew G.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vazquez-Romero, Ana
    Mahdi-Moein, Mohammad
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elmore, Charles S.
    Takano, Akihiro
    Arakawa, Ryosuke
    Varrone, Andrea
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schou, Magnus
    Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy2018In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 9, no 11, p. 2542-2547Article in journal (Refereed)
    Abstract [en]

    Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

  • 28.
    Cegelski, Lynette
    et al.
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA..
    Pinkner, Jerome S
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Hammer, Neal D
    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
    Cusumano, Corinne K
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Hung, Chia S
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Åberg, Veronica
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Walker, Jennifer N
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Seed, Patrick C
    Departments of Pediatrics and Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chapman, Matthew R
    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
    Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation2009In: Nature Chemical Biology, ISSN 1552-4450, EISSN 1552-4469, Vol. 5, no 12, p. 913-919Article in journal (Refereed)
    Abstract [en]

    Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type

    1pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1–dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1pili endows unique anti-biofilm and anti-virulence activities on these compounds.

  • 29.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Henrik, Antti
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    A novel animal model for Parkinson's disease based on in vivo effects of small-molecule of alpha-synucleinManuscript (preprint) (Other academic)
    Abstract [en]

    Amyloid fibrils of alpha-synuclein are major constituents of Lewy bodies, the pathological hallmark of Parkinson’s disease. Monomeric α-synuclein is involved in synaptic vesicle trafficking and long-term maintenance of neurons. The underlying mechanisms of Parkinson’s disease are not known but it has been proposed that oligomers of α-synuclein, formed during the aggregation process, are toxic to neurons. To search for a new animal model of Parkinson’s disease, here we capitalized on the in vitro discovery of a small-molecule templator of α-synuclein fibrillization, the 2-pyridone, FN075. FN075 and MS382, another 2-pyridone variant that act as an inhibitor of amyloids in vitro, were injected into the striatum or substantia nigra of normal C57Bl/6 mice. No acute toxicity of the compounds was detected, as there was 100 % survival of the injected mice. At 6 months after the striatal injection, sensorimotor functions were impaired with no reduction in TH-positive neurons in the substantia nigra in mice injected with FN075, whereas mice injected with MS382 or vehicle had no dysfunctions. Injection of FN075 into the substantia nigra revealed a significant loss of TH-positive neurons already at 3 months and TH-negative inclusion-like structures were detected in substantia nigra neurons of these mice. Thus, the results suggest that injection of a templator of α-synuclein aggregation into the brain of normal mice can serve as a novel experimental design for an animal model of Parkinson’s disease.

  • 30.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pokrzywa, Malgorzata
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice2015In: Parkinson's Disease, ISSN 2090-8083, E-ISSN 2042-0080, Vol. 1, article id 15024Article in journal (Refereed)
    Abstract [en]

    The assembly process of a-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson´s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of a-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of a-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and follwed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substansia nigra of normal and a-synuclein knockout mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed singificant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in a-synuclein knock-out mice injected with accelerator intor the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson´s disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.

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  • 31.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Emma
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Evans, Margery L.
    Jain, Neha
    Götheson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Åden, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chapman, Matthew R.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 10, p. 1-11, article id e0140194Article in journal (Refereed)
    Abstract [en]

    Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode the chaperone-like proteins CsgC and CsgE that both can reduce in vitro amyloid formation by CsgA. CsgC was also found to arrest amyloid formation of the human amyloidogenic protein α-synuclein, which is involved in Parkinson’s disease. Here, we report that the inhibitory effects of CsgC arise due to transient interactions that promote the formation of spherical α-synuclein oligomers. We find that CsgE also modulates α-synuclein amyloid formation through transient contacts but, in contrast to CsgC, CsgE accelerates α-synuclein amyloid formation. Our results demonstrate the significance of transient protein interactions in amyloid regulation and emphasize that the same protein may inhibit one type of amyloid while accelerating another.

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  • 32.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bengtsson, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sainte-Luce Banchelin, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Pralay
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sinha, Arun K
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinkner, Jerome S
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity2011In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, no 4, p. 1103-1116Article in journal (Refereed)
    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.

  • 33.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Pralay
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Diverse functionalization of Thiazolo ring-fused 2-Pyridones2007In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 13, p. 4917-4924Article in journal (Refereed)
    Abstract [en]

    Thiazolo ring-fused 2-pyridones have proven to be highly interesting scaffolds for the development of biologically active compounds. Many methods are today available to introduce a variety of substituents in the 2-pyridone part of the heterocycle. Herein we disclose how a diverse set of substituents can be introduced in the thiazolo ring, with possibilities to vary also the spatial arrangement of the substituents. A key intermediate is the oxidized framework 9 for which an effective synthesis is described. The thiazolo part of this system can be substituted either via conjugate additions, resulting in trans selectivity, or via microwave-assisted Heck couplings that result in unsaturated aryl-substituted analogues. The scaffold can also be lithiated followed by the addition of various electrophiles, which increases the diversification potential substantially, as exemplified with the introduction of halogens, alkyl, acyl, and amide substituents.

  • 34.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Edvinsson, Sofie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Improved procedure for the enantioselective synthesis of dihydrooxazolo and dihydrothiazolo ring-fused 2-pyridones2010In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 18, p. 2461-2463Article in journal (Refereed)
    Abstract [en]

    Improved procedures to synthesize enantioselectively analogues of a peptidomimetic scaffold with high biological relevance have been developed. Experimental design led to a general method for the preparation of dihydrooxazolo ring-fused 2-pyridones in good yields and high enantiomeric purity. The knowledge gained from this was also used to improve the microwave-accelerated synthesis of dihydrothiazolo ring-fused 2-pyridones to give complete stereo retention and high yields.

  • 35.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinkner, Jerome S
    Bengtsson, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Banchelin, Thomas Sainte-Luce
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Edvinsson, Sofie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hultgren, Scott J
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study2012In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 20, no 9, p. 3128-3142Article in journal (Refereed)
    Abstract [en]

    Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study of the dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to distinguish active from inactive compounds in which polarity proved to be the most important factor for discrimination. A quantitative SAR (QSAR) partial least squares (PLS) model was calculated on the active compounds for prediction of biofilm inhibition activity. In this model, compounds with high inhibitory activity were generally larger, more lipophilic, more flexible and had a lower HOMO. Overall, this resulted in both highly valuable SAR information and potent inhibitors of type 1 pili dependent biofilm formation. The most potent biofilm inhibitor had an EC(50) of 400nM.

  • 36.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinkner, Jerome S
    Bengtsson, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Edvinsson, Sofie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cusumano, Corinne K
    Rosenbaum, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Lennart B-Å
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hultgren, Scott J
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms2012In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, p. 4522-4532Article in journal (Refereed)
    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.

  • 37.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinkner, Jerome S.
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Bengtsson, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Edvinsson, Sofie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cusumano, Corinne K.
    Rosenbaum, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Lennart B-Å
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hultgren, Scott J.
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanismsManuscript (preprint) (Other academic)
    Abstract [en]

    Pilicides and curlicides block formation of the E. coli virulence factors pili and curli. 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 using a strategy where key pilicide and curlicide substituents were replaced by fluorophores having similar physicochemical properties. The resulting fluorescent compounds had improved anti-virulence activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing both coumarin and 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide scaffold. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated to the bacteria and seem to discriminate between different bacteria in a population.

  • 38.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinkner, Jerome S
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Phan, Gilles
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Edvinsson, Sofie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Buelens, Floris
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Remaut, Han
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Waksman, Gabriel
    Institute of Structural and Molecular Biology, University College London/Birkbeck, Malet Street, London WC1E 7HX, U.K..
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design and synthesis of C-2 substituted Thiazolo and Dihydrothiazolo ring-fused 2-Pyridones: pilicides with increased antivirulence activity2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 15, p. 5690-5695Article in journal (Refereed)
    Abstract [en]

    Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.

  • 39.
    Dang, Hung The
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, USA.
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinkner, Jerome S.
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, USA.
    Hultgren, Scott J.
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, USA.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives: antibacterial agents with antivirulence activity2014In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, no 12, p. 1942-1956Article in journal (Refereed)
    Abstract [en]

    Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17 500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in a uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as the starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E. coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20-23) of E. coli biofilm development without an effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity.

  • 40.
    Drobni, Mirva
    et al.