Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents

Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB. [Display omitted] •Hit pyridone 1 inhibited growth of Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis.•SAR on 6-position of pyridone 1 significantly improved potency and lead compound 30j displayed 50 nM activity against Mtb.•Lead 30j showed favorable oral PK and demonstrated in vivo efficacy in mouse model.•Mechanism of action studies indicated thatpyridones are direct inhibitors of InhA.