| Autor: |
Sarkar, Souvik, Mayer Bridwell, Anne E., Good, James A. D., Wang, Erin R., McKee, Samuel R., Valenta, Joy, Harrison, Gregory A., Flentie, Kelly N., Henry, Frederick L., Wixe, Torbjörn, Demirel, Peter, Vagolu, Siva K., Chatagnon, Jonathan, Machelart, Arnaud, Brodin, Priscille, Tønjum, Tone, Stallings, Christina L., Almqvist, Fredrik |
| Zdroj: |
Journal of Medicinal Chemistry; 20230101, Issue: Preprints |
| 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 Mtbrespiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtbisolates. 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, 17hand 17j. 17hand 17jinhibited Mtbrespiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtbmutant, and more effectively inhibited intracellular Mtbreplication than C10. The (−)17jenantiomer showed further enhanced activity compared to its enantiomer and the 17jracemic mixture. Our potent second-generation C10analogues offer promise for therapeutic development against drug-resistant Mtb. |
| Databáze: |
Supplemental Index |
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