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
  • 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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