期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 10, 期 10, 页码 1462-1466出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00308
关键词
Deuterium isotope effect; Meisenheimer complex; nitrobenzothiazinone; nitroso; antituberculosis
资金
- NIH [R01 AI054193, R37 AI054193]
- University of Notre Dame (George & Winifred Clark professorship)
Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphosphoryl-beta-D-ribose-2'-oxidase (DprE1) of Mycobacterium tuberculosis (Mtb). The resulting cell wall synthesis inhibition is lethal to Mtb, leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex. Herein we demonstrate that chemical reduction of BTZ043 with NaBD4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.
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