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.