Design, Synthesis, and Evaluation of Novel Δ2-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant
Year: 2023
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide 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 .
Source: Journal of Medicinal Chemistry
Authors: Souvik Sarkar, Anne E. Mayer Bridwell, James A. D. Good, Erin R. Wang, Samuel R. McKee, Joy Valenta, Gregory A. Harrison, Kelly N. Flentie, Frederick L. Henry, Torbjörn Wixe, Peter Demirel, Siva K. Vagolu, Jonathan Chatagnon, Arnaud Machelart, Priscille Brodin, Tone Tønjum, Christina L. Stallings, Fredrik Almqvist
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: National Science Foundation, Burroughs Wellcome Fund, Familjen Erling-Perssons Stiftelse, Joint Programming Initiative on Antimicrobial Resistance, Kempe Foundation, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Vetenskapsrådet, Centre National de la Recherche Scientifique, Umeå Universitet, Universitetet i Oslo, Norges Forskningsråd, Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Uppsala Universitet, Science for Life Laboratory, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute on Minority Health and Health Disparities
Awards: G1255777443, Graduate Research Fellowship Program (GRFP), G1391118055, G157330531, G1672595135, G2042909553, G2914121010, G3021407172, A soft glue to close wounds and relieve pain, G4314642315, G4656594441, G4677157743, Training Program in Cellular and Molecular Biology, G5929604515, Development of novel Mycobacterial Tolerance Inhibitors (MTIs) against MDR/XDR tuberculosis, G652029124, G659425685, G712881263, G7388009323, G776579799, Chemical disarming of drug resistance in Mycobacterium tuberculosis, Design, synthesis and evaluation of new heterocycles targeting bacterial and human amyloid proteins, Development of polymeric-??cyclodextrins with drug nanocarrier and host directed properties against Tuberculosis., Development of Novel Mycobacterial Tolerance Inhibitors (MTIs) against MDR/XDR tuberculosis, G8620077603, Infectious Disease/Basic Microbial Pathogenic Mechanisms
OpenAlex ID: W4385185976