title: Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs.
abstract: Tuberculosis (TB) is a major global health problem, and new drug targets and scaffolds need to be identified to combat the emergence of drug resistant TB. The nitroimidazooxazine PA-824 represents a new class of bio-reductive drug to treat TB. In this study we report a 2-nitroimidazooxazine derivative with modification at the C-7 position that exhibited better activity than PA-824 against Mycobacterium tuberculosis (Mtb) H37Rv strain in vitro. From 7a as a key intermediate, we functionalized with benzyl ether (8), phenyl ether (9), benzyl carbonate (10) and benzyl carbamate (11). Among the 23 compounds produced, 8a-R (MIC=0.078 μM) with trifluoromethoxy benzyl group was 5-fold more potent than PA-824 (MIC=0.390 μM) in the in vitro assays against the wild-type Mtb, and the phenyl ether compound 9g-R (MIC=0.050 μM) exhibited the most potent antimycobacterial activity.
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejon 305-600, Republic of Korea; Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Young-Goo
authors.initials: YG
authors.lastname: Kang
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejon 305-600, Republic of Korea; Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Chan-Yong
authors.initials: CY
authors.lastname: Park
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejon 305-600, Republic of Korea.
authors.forename: Hongsuk
authors.initials: H
authors.lastname: Shin
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Haryana, India.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Haryana, India; Symbiosis School of Biomedical Sciences, Symbiosis International University, Lavale, Pune, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Arora
authors.affiliation: Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Chan-mo
authors.initials: CM
authors.lastname: Yu
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejon 305-600, Republic of Korea. Electronic address: iylee@krict.re.kr.
authors.forename: Ill Young
authors.initials: IY
authors.lastname: Lee
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid
keywords: 2-Nitrodihydro-5H-imidazo[2,1-b][1,3]oxazine; 2-Nitroimidazooxazine; Antibacterial activity; PA-824; Tuberculosis