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

Ng, Pearly and Manjunatha, Ujjini Havaldar and Rao, Srinivasa P.S. and Camacho, Luis and Ngai Ling , Ma and Herve, Maxime Marcel and Noble, Christian Guy and Goh, Anne and Peukert, Stefan and Diagana, Thierry Tidiane and Smith, Paul William and Kondreddi, Ravinder Reddy (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 00:45
URI: https://oak.novartis.com/id/eprint/23457

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