2. Academic Validation
  3. Design, Synthesis, and Evaluation of Novel Δ2-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant

Design, Synthesis, and Evaluation of Novel Δ2-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant

  • J Med Chem. 2023 Aug 24;66(16):11056-11077. doi: 10.1021/acs.jmedchem.3c00358.
Souvik Sarkar 1,  Anne E Mayer Bridwell 2,  James A D Good 1,  Erin R Wang 2,  Samuel R McKee 2,  Joy Valenta 2,  Gregory A Harrison 2,  Kelly N Flentie 2,  Frederick L Henry 2,  Torbjörn Wixe 1,  Peter Demirel 1,  Siva K Vagolu 3,  Jonathan Chatagnon 4,  Arnaud Machelart 4,  Priscille Brodin 4,  Tone Tønjum 3 5,  Christina L Stallings 2,  Fredrik Almqvist 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • 2 Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States.
  • 3 Department of Microbiology, University of Oslo, N-0316 Oslo, Norway.
  • 4 University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France.
  • 5 Oslo University Hospital, N-0424 Oslo, Norway.
PMID: 37485869 DOI: 10.1021/acs.jmedchem.3c00358
Abstract

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.

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