| Literature DB >> 26544629 |
Pearly Shuyi Ng1, Ujjini H Manjunatha1, Srinivasa P S Rao1, Luis R Camacho1, Ngai Ling Ma1, Maxime Herve1, Christian G Noble1, Anne Goh1, Stefan Peukert1, Thierry T Diagana1, Paul W Smith1, Ravinder Reddy Kondreddi2.
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.Entities:
Keywords: 4-Hydroxy-2-pyridones; Antituberculosis agents; Phenotypic screen; Structure activity relations; Tuberculosis
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Year: 2015 PMID： 26544629 DOI： 10.1016/j.ejmech.2015.10.008
Source DB: PubMed Journal: Eur J Med Chem ISSN： 0223-5234 Impact factor: 6.514