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Design, synthesis, ...
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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- Sarkar, Souvik (författare)
- Umeå universitet,Kemiska institutionen
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- Mayer Bridwell, Anne E. (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- Good, James A. D., 1985- (författare)
- Umeå universitet,Kemiska institutionen
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- Wang, Erin R. (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- McKee, Samuel R. (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- Valenta, Joy (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- Harrison, Gregory A. (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- Flentie, Kelly N. (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- Henry, Frederick L. (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- Wixe, Torbjörn (författare)
- Umeå universitet,Kemiska institutionen
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- Demirel, Peter (författare)
- Umeå universitet,Kemiska institutionen
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- Vagolu, Siva K. (författare)
- Department of Microbiology, University of Oslo, Oslo, Norway
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- Chatagnon, Jonathan (författare)
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
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- Machelart, Arnaud (författare)
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
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- Brodin, Priscille (författare)
- University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
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- Tønjum, Tone (författare)
- Department of Microbiology, University of Oslo, Oslo, Norway; Oslo University Hospital, Oslo, Norway
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- Stallings, Christina L. (författare)
- Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States
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- Almqvist, Fredrik (författare)
- Umeå universitet,Kemiska institutionen
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(creator_code:org_t)
- American Chemical Society (ACS), 2023
- 2023
- Engelska.
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:16, s. 11056-11077
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
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- Av författaren/redakt...
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Sarkar, Souvik
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Mayer Bridwell, ...
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Good, James A. D ...
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Wang, Erin R.
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McKee, Samuel R.
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Valenta, Joy
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visa fler...
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Harrison, Gregor ...
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Flentie, Kelly N ...
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Henry, Frederick ...
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Wixe, Torbjörn
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Demirel, Peter
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Vagolu, Siva K.
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Chatagnon, Jonat ...
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Machelart, Arnau ...
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Brodin, Priscill ...
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Tønjum, Tone
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Stallings, Chris ...
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Almqvist, Fredri ...
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Infektionsmedici ...
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Journal of Medic ...
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Umeå universitet