Intermediates in the reduction of the antituberculosis drug PA-824, (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine, in aqueous solution.
The reduction chemistry of the new anti-tuberculosis drug PA-824, together with a more water-soluble analogue, have been investigated using pulse and steady-state radiolysis in aqueous solution. Stepwise reduction of these nitroimidazo-dihydrooxazine compounds through electron transfer from the CO(2) (-) species revealed that, unlike related nitroimidazoles, 2-electron addition resulted in the reduction of the imidazole ring in preference to the nitro group. In mildly acidic solution a nitrodihydroimidazo intermediate was formed, which was reduced further to the amine product. In both alkaline and neutral solution, an intermediate produced on 2-electron reduction was resistant to further reduction and reverted to parent compound on extraction or mass spectrometric analysis of the solution. The unusual reduction chemistry of these nitroimidazole compounds, exhibiting ring over nitro group reduction, is associated with alkoxy substitution in the 2-position of a 4-nitroimidazole. The unique properties of the intermediates formed on the reduction of PA-824 need to be considered as playing a possible role in its bactericidal action.
Anderson
Robert F
RF
Department of Chemistry, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. r.anderson@auckland.ac.nz
Shinde
Sujata S
SS
Maroz
Andrej
A
Boyd
Maruta
M
Palmer
Brian D
BD
Denny
William A
WA
D000995:Antitubercular Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009593:Nitroimidazoles / Q000737:chemistry*; D010084:Oxidation-Reduction; D012996:Solutions; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D014867:Water / Q000737:chemistry
D000995:Antitubercular Agents; D009593:Nitroimidazoles; D012996:Solutions; C410767:pretomanid; D014867:Water