Structure-activity relationships in reactivators of organophosphorus-inhibited acetylcholinesterase. V. Quaternary salts of hydroxyiminomethylimidazoles.
The methiodides of (E)-1-methyl-2-hydroxyiminomethylimidazole, (E)-1-benzyl-2-hydroxyiminomethylimidazole, and (Z)-1-methyl-5-hydroxyiminomethylimidazole were tested in vitro as reactivators of phosphorylated acetylcholinesterase. From the hydrolysis rate measurements, it was ascertained that only the compounds derived from 2-hydroxyiminomethylimidazole had an activity comparable with that of methiodide of 2-hydroxyiminomethylpyridine, whereas the methiodide of (Z)-1-methyl-5-hydroxyiminomethylimidazole was inactive. The structure-activity relationships of these reactivators are briefly discussed.
Imidazole Aldoximes Effective in Assisting Butyrylcholinesterase Catalysis of Organophosphate Detoxification
Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP–hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP–hBChE conjugate.
Polarization of Comet Arend–Roland
WHEN, last May, Comet Arend–Roland became a bright naked-eye object in the northern hemisphere, we carried out a series of photoelectric measures of the polarization of its coma at different phase angles. The technique employed utilized a piece of ‘Polaroid’ attached to a rotatable six-position disk contained in the photometer. This enables measurements of intensity to be made as the ‘Polaroid’ is turned through 60 dog. for each position of the disk. Standard B and V filters employed in the UBV system, together with interference filters having peak transmissions centred on 5890 A., 5000 A., 4700 A. and 4300 A. and half-widths of 80 A. were used for isolating the different wave-lengths. Each of the three circular apertures behind the ‘Polaroid’ transmitted 3.7 square minutes of arc of the sky.