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

Mycobacteriumtuberculosis (Mtb) drug resistanceposes an alarming threat to globaltuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activityof the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INHresistance. Expanding upon this strategy, we identified C10 analogueswith improved potency and drug-like properties. By exploring threeheterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) onthe ring-fused thiazolo-2-pyridone scaffold, we identified two novelisoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respirationand 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 enantiomerand the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development againstdrug-resistant Mtb.