Structure鈥揂ctivity Relationships of Antitubercular Nitroimidazoles. 3. Exploration of the Linker and Lipophilic Tail of ((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)

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• 作者：Joseph Cherian ; Inhee Choi ; Amit Nayyar ; Ujjini H. Manjunatha ; Tathagata Mukherjee ; Yong Sok Lee ; Helena I. Boshoff ; Ramandeep Singh ; Young Hwan Ha ; Michael Goodwin ; Suresh B. Lakshminarayana ; Pornwaratt Niyomrattanakit ; Jan Jiricek ; Sindhu Ravindran ; Thomas Dick ; Thomas H. Keller ; Veronique Dartois ; Clifton E. Barry ; III
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5639-5659
• 全文大小：1362K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

The (S)-2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine named PA-824 (1) has demonstrated antitubercular activity in vitro and in animal models and is currently in clinical trials. We synthesized derivatives at three positions of the 4-(trifluoromethoxy)benzylamino tail, and these were tested for whole-cell activity against both replicating and nonreplicating Mycobacterium tuberculosis (Mtb). In addition, we determined their kinetic parameters as substrates of the deazaflavin-dependent nitroreductase (Ddn) from Mtb that reductively activates these pro-drugs. These studies yielded multiple compounds with 40 nM aerobic whole cell activity and 1.6 渭M anaerobic whole cell activity: 10-fold improvements over both characteristics from the parent molecule. Some of these compounds exhibited enhanced solubility with acceptable stability to microsomal and in vivo metabolism. Analysis of the conformational preferences of these analogues using quantum chemistry suggests a preference for a pseudoequatorial orientation of the linker and lipophilic tail.