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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.
    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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  • 4. 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.

  • 5.
    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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  • 6.
    Kulén, Martina
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Núñez-Otero, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Cairns, Andrew G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Silver, Jim
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Andersson, Emma K.
    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. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    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).
    Bahnan, Wael
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Good, James A. D.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Svensson, Richard
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors2019In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 11, p. 1966-1987Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg(-1) showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.

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  • 7.
    Nye, Taylor M.
    et al.
    Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States.
    Tükenmez, Hasan
    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, Department of Molecular Biology (Faculty of Medicine).
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Flores-Mireles, Ana L.
    Department of Biological Sciences, University of Notre Dame, Notre Dame, India.
    Obernuefemann, Chloe L.P.
    Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States.
    Pinkner, Jerome S.
    Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States.
    Sarkar, Souvik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bonde, Mari
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Dodson, Karen W.
    Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Caparon, Michael G.
    Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States.
    Hultgren, Scott J.
    Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States.
    Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics2022In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 43, article id e2210912119Article in journal (Refereed)
    Abstract [en]

    The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

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  • 8.
    Núñez-Otero, Carlos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bahnan, Wael
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vielfort, Katarina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elbir, Haitham
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 5, article id e01826-20Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to lifelong sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-Pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first-generation compound KSK120 inhibits the developmental cycle of Chlamydia, resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis, and the effect was only observable upon reinfection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen Chlamydia muridarum and in Chlamydia caviae. The molecular target of KSK213 may thus be different in C. trachomatis or nonessential in C. muridarum and C. caviae. Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNase III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-Pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.

  • 9.
    Oelker, Melanie
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    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).
    Lindgren, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kiss, Anita
    Lindgren, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. 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).
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Kulén, Martina
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nagel, Nadja
    van der Lingen, Ingeborg
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Tyagi, Mohit
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Begum, Afshan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Hall, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Lindgren, Anders E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    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).
    Sauer-Eriksson, A. Elisabeth
    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).
    Discovery of three new binding sites and modes of ring-fused 2-pyridones to PrfA: How can they contribute to drug design?Manuscript (preprint) (Other academic)
  • 10. Petzold, Daniel
    et al.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    König, Burkhard
    Visible light mediated synthesis of β chloro ketones from aryl cyclopropanes2019In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, p. 8577-8580Article in journal (Refereed)
    Abstract [en]

    We report the visible light mediated synthesis of β chloro ketones from aryl cyclopropanes, oxygen, hydrochloric acid and nitric acid. The operationally simple and catalyst free method uses cheap standard lab reagents and displays a broad functional group tolerance. Moreover, scale up of the reaction and late stage functionalization of bioactive compounds is possible, providing the opportunity to utilize the cyclopropane ring as a masked β chloro ketone in a reaction sequence. We propose a light‐driven radical chain reaction initiated by the reaction of diluted hydrochloric and nitric acid producing small quantities of molecular chlorine. The mechanistic hypothesis is supported by 18O labelling and UV‐VIS experiments, cyclovoltammetry and several control reactions.

  • 11.
    Sarkar, Souvik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Edin, Simon
    Centre for Analysis and Synthesis, Lund University, Lund, Sweden.
    Wendt, Ola F.
    Centre for Analysis and Synthesis, Lund University, Lund, Sweden.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of three-dimensional ring fused heterocycles by a selective [4 + 2] cycloaddition between bicyclic thiazolo 2-pyridones and arynes2024In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 89, no 1, p. 731-739Article in journal (Refereed)
    Abstract [en]

    A selective [4 + 2] cycloaddition reaction of thiazolo-2-pyridones with arynes has been demonstrated. The developed protocol allows rapid access to highly functionalized, structurally complex thiazolo-fused bridged isoquinolones in high yields, which are susceptible to further late-stage functionalization.

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  • 12. Singh, Amandeep
    et al.
    Sharma, Bharvi
    Sachdeva, Divya
    Mehra, Vishu
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kumar, Vipan
    β‐Lactam‐Synthon Interceded Diastereoselective Synthesis of 2‐Azido‐γ‐amino Alcohols with Subsequent Transformations to Functionally Enriched Heterocycles2018In: ChemistrySelect, ISSN 2365-6549, Vol. 3, no 17, p. 4764-4767Article in journal (Refereed)
    Abstract [en]

    The present manuscript explicates Boron‐dimethylsulfide‐promoted diastereoselective synthesis of 2‐azido‐γ‐amino alcohols using β‐lactam synthon protocol along with its utilization in the formation of diversely functionalized heterocycles having biological relevance. The developed protocol has the potential to surpass the typical drawbacks of conventional protocols.

  • 13.
    Singh, Pardeep
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Adolfsson, Dan E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cairns, Andrew G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bartens, Christian
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    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.
    Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding2019In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 7, p. 3887-3903Article in journal (Refereed)
    Abstract [en]

    We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

  • 14.
    Singh, Pardeep
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cairns, Andrew G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Adolfsson, Dan E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer, Uwe H.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones2019In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 21, p. 6946-6950Article in journal (Refereed)
    Abstract [en]

    We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

  • 15.
    Singh, Pardeep
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Krishnan, K Syam
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kindahl, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    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.
    Synthesis of multiring fused 2‑pyridones via a nitrene insertion reaction: fluorescent modulators of α‑synuclein amyloid formation2015In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, no 24, p. 6194-6197Article in journal (Refereed)
    Abstract [en]

    An efficient, straightforward method for the synthesis of thiazolo-2-pyridone embedded peptidomimetic polyheterocycles via a catalyst-free, microwave-assisted, intramolecular C−H amination reaction is reported. All the synthesized polyheterocycles were evaluated for their fluorescent properties and effect on α-synuclein amyloid formation.

  • 16.
    Tyagi, Mohit
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Adolfsson, Dan E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jayaweera, Sanduni Wasana
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gharibyan, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bharate, Jaideep B.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kiss, Anita
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sarkar, Souvik
    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.
    Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones2021In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 86, no 23, p. 16582-16592Article in journal (Refereed)
    Abstract [en]

    Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

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  • 17. Tyagi, Mohit
    et al.
    Adolfsson, Dan E.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sarkar, Souvik
    Kiss, Anita
    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).
    Functionalization of Thiazolino fused 2-Pyridones by thiazoline ring opening and closing: Identification of new Amyloid Binding HeterocyclesManuscript (preprint) (Other academic)
    Abstract [en]

    Reaction of thiazolino fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generate N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via an intramolecular [2 + 2] cycloaddition between in situ generated allene and the α,β-unsaturated carbonyl moiety. This method enabled the synthesis of a variety of cyclobutane and thiazolino fused 2-pyridones, which were tested for α-synuclein binding activity. Most of the bioactive thiazolino fused 2-pyridones tolerated this transformation and in addition provided an exocyclic alkene as a handle for tuning bioactivity.

  • 18.
    Tükenmez, Hasan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). 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). QureTech Bio, Umeå, Sweden.
    Singh, Pardeep
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sarkar, Souvik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Çakır, Melike
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Oliveira, Ana H.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lindgren, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vaitkevicius, Karolis
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bonde, Mari
    QureTech Bio, Umeå, Sweden.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes2023In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 3, article id e0044923Article in journal (Refereed)
    Abstract [en]

    Listeria monocytogenes is a facultative Gram-positive bacterium that causes listeriosis, a severe foodborne disease. We previously discovered that ring-fused 2-pyridone compounds can decrease virulence factor expression in Listeria by binding and inactivating the PrfA virulence activator. In this study, we tested PS900, a highly substituted 2-pyridone that was recently discovered to be bactericidal to other Gram-positive pathogenic bacteria, such as Staphylococcus aureus and Enterococcus faecalis. We show that PS900 can interact with PrfA and reduce the expression of virulence factors. Unlike previous ring-fused 2-pyridones shown to inactivate PrfA, PS900 had an additional antibacterial activity and was found to potentiate sensitivity toward cholic acid. Two PS900-tolerant mutants able to grow in the presence of PS900 carried mutations in the brtA gene, encoding the BrtA repressor. In wild-type (WT) bacteria, cholic acid binds and inactivates BrtA, thereby alleviating the expression of the multidrug transporter MdrT. Interestingly, we found that PS900 also binds to BrtA and that this interaction causes BrtA to dissociate from its binding site in front of the mdrT gene. In addition, we observed that PS900 potentiated the effect of different osmolytes. We suggest that the increased potency of cholic acid and osmolytes to kill bacteria in the presence of PS900 is due to the ability of the latter to inhibit general efflux, through a yet-unknown mechanism. Our data indicate that thiazolino 2-pyridones constitute an attractive scaffold when designing new types of antibacterial agents.

    IMPORTANCE: Bacteria resistant to one or several antibiotics are a very large problem, threatening not only treatment of infections but also surgery and cancer treatments. Thus, new types of antibacterial drugs are desperately needed. In this work, we show that a new generation of substituted ring-fused 2-pyridones not only inhibit Listeria monocytogenes virulence gene expression, presumably by inactivating the PrfA virulence regulator, but also potentiate the bactericidal effects of cholic acid and different osmolytes. We identified a multidrug repressor as a second target of 2-pyridones. The repressor–2-pyridone interaction displaces the repressor from DNA, thus increasing the expression of a multidrug transporter. In addition, our data suggest that the new class of ring-fused 2-pyridones are efficient efflux inhibitors, possibly explaining why the simultaneous addition of 2-pyridones together with cholic acid or osmolytes is detrimental for the bacterium. This work proves conclusively that 2-pyridones constitute a promising scaffold to build on for future antibacterial drug design.

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