title: Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents.
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.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Pearly Shuyi
authors.initials: PS
authors.lastname: Ng
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Srinivasa P S
authors.initials: SP
authors.lastname: Rao
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Luis R
authors.initials: LR
authors.lastname: Camacho
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Ngai Ling
authors.initials: NL
authors.lastname: Ma
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Maxime
authors.initials: M
authors.lastname: Herve
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Noble
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore. Electronic address: ravinder.kondreddi@novartis.com.
authors.forename: Ravinder Reddy
authors.initials: RR
authors.lastname: Kondreddi
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: C000610704:6-((4,4-dimethylcyclohexyl)methyl)-4-hydroxy-3-phenylpyridin-2(1H)-one; D000995:Antitubercular Agents; D011728:Pyridones
keywords: 4-Hydroxy-2-pyridones; Antituberculosis agents; Phenotypic screen; Structure activity relations; Tuberculosis