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

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.

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