Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 17; pp. 3650 - 3653
• Main Authors: Kang, Young-Goo, Park, Chan-Yong, Shin, Hongsuk, Singh, Ramandeep, Arora, Garima, Yu, Chan-mo, Lee, Ill Young
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2015; Elsevier
• Subjects: 2-Nitrodihydro-5H-imidazo[2,1-b][1,3]oxazine; 2-Nitroimidazooxazine; Antibacterial activity; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Mycobacterium tuberculosis - drug effects; Nitroimidazoles - chemistry; PA-824; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Tuberculosis; 2-Nitroimidazooxazine; Antibacterial activity; PA-824; 2-Nitrodihydro-5H-imidazo[2,1-b][1,3]oxazine; Tuberculosis; ANTITUBERCULAR DRUG
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.06.060

[Display omitted] 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=0.078μM) with trifluoromethoxy benzyl group was 5-fold more potent than PA-824 (MIC=0.390μM) in the in vitro assays against the wild-type Mtb, and the phenyl ether compound 9g-R (MIC=0.050μM) exhibited the most potent antimycobacterial activity.