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Harrison, G. A., Wang, E. R., Cho, K., Mreyoud, Y., Sarkar, S., Almqvist, F., . . . Stallings, C. L. (2024). Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant Mycobacterium tuberculosis. mBio, 15(3)
Åpne denne publikasjonen i ny fane eller vindu >>Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant Mycobacterium tuberculosis
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2024 (engelsk)Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 15, nr 3Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Of the approximately 10 million cases of Mycobacterium tuberculosis (Mtb) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates the conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of Mtb respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for the growth of Mtb in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the Mtb electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing Mtb to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in Mtb that can be exploited to render Mtb sensitive to otherwise subinhibitory concentrations of InhA inhibitor. IMPORTANCE Isoniazid (INH) is a critical frontline antibiotic to treat Mycobacterium tuberculosis (Mtb) infections. INH efficacy is limited by its suboptimal penetration of the Mtb-containing lesion and by the prevalence of clinical INH resistance. We previously discovered a compound, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a set of INH-resistant mutants to INH. Resistance is typically mediated by katG mutations that decrease the activation of INH, which is required for INH to inhibit the essential enzyme InhA. Our current work demonstrates that C10 re-sensitizes INH-resistant katG-hypomorphs without enhancing the activation of INH. We furthermore show that C10 causes Mtb to become particularly vulnerable to InhA inhibition without compromising InhA activity on its own. Therefore, C10 represents a novel strategy to curtail the development of INH resistance and to sensitize Mtb to sub-lethal doses of INH, such as those achieved at the infection site.

sted, utgiver, år, opplag, sider
American Society for Microbiology, 2024
Emneord
antibiotic resistance, isoniazid, KatG, Mycobacterium tuberculosis, mycolic acids
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-222574 (URN)10.1128/mbio.02968-23 (DOI)001155076400001 ()38294237 (PubMedID)2-s2.0-85187690531 (Scopus ID)
Forskningsfinansiär
NIH (National Institutes of Health), T32AI007172NIH (National Institutes of Health), R01 AI134847NIH (National Institutes of Health), R35 ES028365The Kempe Foundations, MK-1755Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JFamiljen Erling-Perssons Stiftelse
Tilgjengelig fra: 2024-04-08 Laget: 2024-04-08 Sist oppdatert: 2024-04-08bibliografisk kontrollert
Sarkar, S., Singh, P., Edin, S., Wendt, O. F. & Almqvist, F. (2024). Synthesis of three-dimensional ring fused heterocycles by a selective [4 + 2] cycloaddition between bicyclic thiazolo 2-pyridones and arynes. Journal of Organic Chemistry, 89(1), 731-739
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis of three-dimensional ring fused heterocycles by a selective [4 + 2] cycloaddition between bicyclic thiazolo 2-pyridones and arynes
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2024 (engelsk)Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 89, nr 1, s. 731-739Artikkel i tidsskrift (Fagfellevurdert) Published
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.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2024
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-219753 (URN)10.1021/acs.joc.3c01957 (DOI)001137559200001 ()38093677 (PubMedID)2-s2.0-85180992605 (Scopus ID)
Forskningsfinansiär
NIH (National Institutes of Health), R01AI134847-01A1NIH (National Institutes of Health), 1U19AI157797-01Familjen Erling-Perssons Stiftelse, P20-00473Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JThe Kempe Foundations, SMK-1755
Tilgjengelig fra: 2024-01-22 Laget: 2024-01-22 Sist oppdatert: 2024-01-22bibliografisk kontrollert
Tükenmez, H., Singh, P., Sarkar, S., Çakır, M., Oliveira, A. H., Lindgren, C., . . . Johansson, J. (2023). A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes [Letter to the editor]. mBio, 14(3), Article ID e0044923.
Åpne denne publikasjonen i ny fane eller vindu >>A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes
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2023 (engelsk)Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, nr 3, artikkel-id e0044923Artikkel i tidsskrift, Letter (Fagfellevurdert) Published
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.

sted, utgiver, år, opplag, sider
American Society for Microbiology, 2023
Emneord
2-pyridones, BrtA, Listeria monocytogenes, PrfA, antibacterial, antibiotic
HSV kategori
Forskningsprogram
molekylär cellbiologi
Identifikatorer
urn:nbn:se:umu:diva-214132 (URN)10.1128/mbio.00449-23 (DOI)000975886700001 ()37120759 (PubMedID)2-s2.0-85172894238 (Scopus ID)
Forskningsfinansiär
Familjen Erling-Perssons StiftelseNIH (National Institutes of Health), RO1AI134847-01A1NIH (National Institutes of Health), 1IU19AI157797-01Olle Engkvists stiftelseVinnova, 2019-05491Swedish Research Council, 2020-02005Swedish Research Council, 2018-04589Swedish Research Council, 202105040J
Tilgjengelig fra: 2023-09-05 Laget: 2023-09-05 Sist oppdatert: 2023-10-13bibliografisk kontrollert
Sarkar, S., Mayer Bridwell, A. E., Good, J. A. D., Wang, E. R., McKee, S. R., Valenta, J., . . . Almqvist, F. (2023). Design, synthesis, and evaluation of novel Δ2-thiazolino 2-pyridone derivatives that potentiate isoniazid activity in an isoniazid-resistant mycobacterium tuberculosis mutant. Journal of Medicinal Chemistry, 66(16), 11056-11077
Åpne denne publikasjonen i ny fane eller vindu >>Design, synthesis, and evaluation of novel Δ2-thiazolino 2-pyridone derivatives that potentiate isoniazid activity in an isoniazid-resistant mycobacterium tuberculosis mutant
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2023 (engelsk)Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, nr 16, s. 11056-11077Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Mycobacterium tuberculosis (Mtb) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10. The (−)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2023
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-213417 (URN)10.1021/acs.jmedchem.3c00358 (DOI)001034973300001 ()37485869 (PubMedID)2-s2.0-85167784865 (Scopus ID)
Forskningsfinansiär
NIH (National Institutes of Health), R01 AI134847NIH (National Institutes of Health), T32AI007172Familjen Erling-Perssons Stiftelse, P20-00473The Kempe Foundations, SMK-1755Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JSwedish Research Council, VR C114766193The Research Council of Norway, 234506The Research Council of Norway, 261669The Research Council of Norway, 309592
Tilgjengelig fra: 2023-08-25 Laget: 2023-08-25 Sist oppdatert: 2023-08-25bibliografisk kontrollert
Hainzl, T., Bonde, M., Almqvist, F., Johansson, J. & Sauer-Eriksson, A. E. (2023). Structural insights into CodY activation and DNA recognition [Letter to the editor]. Nucleic Acids Research, 51(14), 7631-7648
Åpne denne publikasjonen i ny fane eller vindu >>Structural insights into CodY activation and DNA recognition
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2023 (engelsk)Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, nr 14, s. 7631-7648Artikkel i tidsskrift, Letter (Fagfellevurdert) Published
Abstract [en]

Virulence factors enable pathogenic bacteria to infect host cells, establish infection, and contribute to disease progressions. In Gram-positive pathogens such as Staphylococcus aureus (Sa) and Enterococcus faecalis (Ef), the pleiotropic transcription factor CodY plays a key role in integrating metabolism and virulence factor expression. However, to date, the structural mechanisms of CodY activation and DNA recognition are not understood. Here, we report the crystal structures of CodY from Sa and Ef in their ligand-free form and their ligand-bound form complexed with DNA. Binding of the ligands - branched chain amino acids and GTP - induces conformational changes in the form of helical shifts that propagate to the homodimer interface and reorient the linker helices and DNA binding domains. DNA binding is mediated by a non-canonical recognition mechanism dictated by DNA shape readout. Furthermore, two CodY dimers bind to two overlapping binding sites in a highly cooperative manner facilitated by cross-dimer interactions and minor groove deformation. Our structural and biochemical data explain how CodY can bind a wide range of substrates, a hallmark of many pleiotropic transcription factors. These data contribute to a better understanding of the mechanisms underlying virulence activation in important human pathogens.

sted, utgiver, år, opplag, sider
Oxford University Press, 2023
Emneord
CodY, virulence, protein-DNA complex structure
HSV kategori
Forskningsprogram
biokemi
Identifikatorer
urn:nbn:se:umu:diva-214131 (URN)10.1093/nar/gkad512 (DOI)001008706900001 ()2-s2.0-85168963845 (Scopus ID)
Prosjekter
CodY
Forskningsfinansiär
Swedish Research Council, ID 2019-03771Swedish Research Council, 2020-02005_3 toSwedish Research Council, 2018-04589Swedish Research Council, 2021-05040J
Tilgjengelig fra: 2023-09-05 Laget: 2023-09-05 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Tükenmez, H., Nye, T. M., Bonde, M., Caparon, M. G., Almqvist, F., Hultgren, S. J. & Johansson, J. (2022). Complete Genome Sequence of the Uropathogenic Methicillin-Resistant Staphylococcus aureus Strain MRSA-1369. Microbiology Resource Announcements, 11(10)
Åpne denne publikasjonen i ny fane eller vindu >>Complete Genome Sequence of the Uropathogenic Methicillin-Resistant Staphylococcus aureus Strain MRSA-1369
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2022 (engelsk)Inngår i: Microbiology Resource Announcements, E-ISSN 2576-098X, Vol. 11, nr 10Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

MRSA-1369 is a uropathogenic methicillin-resistant Staphylococcus aureus (MRSA) strain. Here, we present the complete genome sequence of MRSA-1369, which consists of one chromosome (2.87 Mb) and two plasmids (16.68 kb and 3.13 kb). This will serve as a reference genome for future Staphylococcus aureus pathogenesis and multiomic studies.

sted, utgiver, år, opplag, sider
American Society for Microbiology, 2022
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-200828 (URN)10.1128/mra.00981-22 (DOI)000868643800002 ()36173194 (PubMedID)2-s2.0-85140455359 (Scopus ID)
Tilgjengelig fra: 2022-11-14 Laget: 2022-11-14 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Nye, T. M., Tükenmez, H., Singh, P., Flores-Mireles, A. L., Obernuefemann, C. L. .., Pinkner, J. S., . . . Hultgren, S. J. (2022). Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics. Proceedings of the National Academy of Sciences of the United States of America, 119(43), Article ID e2210912119.
Åpne denne publikasjonen i ny fane eller vindu >>Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
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2022 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, nr 43, artikkel-id e2210912119Artikkel i tidsskrift (Fagfellevurdert) Published
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.

sted, utgiver, år, opplag, sider
PNAS, 2022
Emneord
antibiotic resistance, antibiotic synergy, multidrug-resistant pathogens, VRE
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-201191 (URN)10.1073/pnas.2210912119 (DOI)36252016 (PubMedID)2-s2.0-85141283133 (Scopus ID)
Forskningsfinansiär
NIH (National Institutes of Health), 1U19AI157797-01NIH (National Institutes of Health), R01AI134847-01A1NIH (National Institutes of Health), R01DK128805NIH (National Institutes of Health), RO1DK51406NIH (National Institutes of Health), T32AI007172Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JThe Kempe Foundations, SMK-1755
Tilgjengelig fra: 2023-01-05 Laget: 2023-01-05 Sist oppdatert: 2023-08-25bibliografisk kontrollert
Núñez-Otero, C., Bahnan, W., Vielfort, K., Silver, J., Singh, P., Elbir, H., . . . Gylfe, Å. (2021). A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis. Antimicrobial Agents and Chemotherapy, 65(5), Article ID e01826-20.
Åpne denne publikasjonen i ny fane eller vindu >>A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis
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2021 (engelsk)Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, nr 5, artikkel-id e01826-20Artikkel i tidsskrift (Fagfellevurdert) Published
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.

sted, utgiver, år, opplag, sider
American Society for Microbiology, 2021
Emneord
Chlamydia trachomatis, antibacterial agents, intracellular bacteria, mode of action, virulence inhibitors
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-174665 (URN)10.1128/AAC.01826-20 (DOI)000641612600035 ()2-s2.0-85105036198 (Scopus ID)
Merknad

Originally included in thesis in manuscript form.

Tilgjengelig fra: 2020-08-31 Laget: 2020-08-31 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Cairns, A. G., Sarkar, S., Singh, P., Larsson, A. & Almqvist, F. (2021). An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry. ARKIVOC, 2020(7), 365-378
Åpne denne publikasjonen i ny fane eller vindu >>An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry
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2021 (engelsk)Inngår i: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, Vol. 2020, nr 7, s. 365-378Artikkel i tidsskrift (Fagfellevurdert) Published
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.

sted, utgiver, år, opplag, sider
Arkat, 2021
Emneord
Acyl ketene, Design of experiments, Flow chemistry, Heterocycle, Pyridone, Thiazolo
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-181828 (URN)10.24820/ARK.5550190.P011.445 (DOI)000746840700002 ()2-s2.0-85102694748 (Scopus ID)
Tilgjengelig fra: 2021-04-06 Laget: 2021-04-06 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Bharate, J. B., Ådén, J., Gharibyan, A., Adolfsson, D. E., Jayaweera, S. W., Singh, P., . . . Almqvist, F. (2021). K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones. Organic and biomolecular chemistry, 19(44), 9758-9772
Åpne denne publikasjonen i ny fane eller vindu >>K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
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2021 (engelsk)Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 19, nr 44, s. 9758-9772Artikkel i tidsskrift (Fagfellevurdert) Published
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.

sted, utgiver, år, opplag, sider
The Royal Society of Chemistry, 2021
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-189516 (URN)10.1039/D1OB01580J (DOI)000714122800001 ()34730163 (PubMedID)2-s2.0-85120001225 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2017-02339; 2017-00695; 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Foundation for Strategic Research, SB12-0070NIH (National Institutes of Health), (R01AI134847-01A1
Tilgjengelig fra: 2021-11-15 Laget: 2021-11-15 Sist oppdatert: 2023-08-09bibliografisk kontrollert
Prosjekter
Molekyler för framtiden [2008-03990_Vinnova]; Umeå universitet
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0003-4646-0216