Ng, Pearly (2015) Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents. European Journal of Medicinal Chemistry, 106. pp. 144-156. ISSN 1768-3254

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.

Item Type:	Article
Keywords:	4-Hydroxy-2-pyridones Antituberculosis agents Phenotypic screen Structure activity relations Tuberculosis
Date Deposited:	25 Nov 2017 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/22292