Design, Synthesis, and Evaluation of Novel Δ 2 -Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant.

Autor:	Sarkar S; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden., Mayer Bridwell AE; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., Good JAD; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden., Wang ER; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., McKee SR; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., Valenta J; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., Harrison GA; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., Flentie KN; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., Henry FL; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., Wixe T; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden., Demirel P; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden., Vagolu SK; Department of Microbiology, University of Oslo, N-0316 Oslo, Norway., Chatagnon J; University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France., Machelart A; University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France., Brodin P; University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France., Tønjum T; Department of Microbiology, University of Oslo, N-0316 Oslo, Norway.; Oslo University Hospital, N-0424 Oslo, Norway., Stallings CL; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States., Almqvist F; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Aug 24; Vol. 66 (16), pp. 11056-11077. Date of Electronic Publication: 2023 Jul 24.
DOI:	10.1021/acs.jmedchem.3c00358
Abstrakt:	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 .
Databáze:	MEDLINE
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