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Design, synthesis, and evaluation of novel Δ2-thiazolino 2-pyridone derivatives that potentiate isoniazid activity in an isoniazid-resistant mycobacterium tuberculosis mutant
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0003-1803-2708
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, MO, St. Louis, United States.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0003-2377-030X
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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2023 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, no 16, p. 11056-11077Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023. Vol. 66, no 16, p. 11056-11077
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-213417DOI: 10.1021/acs.jmedchem.3c00358ISI: 001034973300001PubMedID: 37485869Scopus ID: 2-s2.0-85167784865OAI: oai:DiVA.org:umu-213417DiVA, id: diva2:1791535
Funder
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, 309592Available from: 2023-08-25 Created: 2023-08-25 Last updated: 2023-08-25Bibliographically approved

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Sarkar, SouvikGood, James A. D.Wixe, TorbjörnDemirel, PeterAlmqvist, Fredrik

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