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

Eur J Med Chem. 2015 Dec 1:106:144-56. doi: 10.1016/j.ejmech.2015.10.008.

Pearly Shuyi Ng ¹, Ujjini H Manjunatha ¹, Srinivasa P S Rao ¹, Luis R Camacho ¹, Ngai Ling Ma ¹, Maxime Herve ¹, Christian G Noble ¹, Anne Goh ¹, Stefan Peukert ¹, Thierry T Diagana ¹, Paul W Smith ¹, Ravinder Reddy Kondreddi ²

Affiliations

1 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
2 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore. Electronic address: [email protected].

PMID: 26544629 DOI: 10.1016/j.ejmech.2015.10.008

Abstract

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.

Keywords

4-Hydroxy-2-pyridones; Antituberculosis agents; Phenotypic screen; Structure activity relations; Tuberculosis.

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