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.
Quaternary salts of 3,3'-bis-pyridinium monooximes: synthesis and biological activity.
Two new series of asymetrically substituted 3,3'-bis-pyridinium monooximes bridged by oxopropane and propane groups were synthesized and characterized by spectral data and acid dissociation constants (pKas). Both the in vitro reactivation potency, in experiments with lyophilized electric eel acetylcholinesterase (AChE) inhibited by diisopropylfluorophosphate, and in vivo protection efficacy against diisopropylfluorophosphate intoxication in mice of these compounds were evaluated and compared with those of trimedoxime and 2-pyridine-aldoxime methiodide. The compounds were also evaluated for in vitro inhibition of AChE. The compounds with the oxopropane link were stronger inhibitors and weaker reactivators than the corresponding propane derivatives. No significant correlation was observed among pKa, oxime inhibition of AChE, reactivation of inhibited AChE, and protection index. Changing substituents in pyridine rings or altering linking groups between pyridine rings did not improve antidotal efficacy compared with trimedoxime and 2-pyridine-aldoxime methiodide.
Phloroglucinol derivatives from Hypericum japonicum.
The isolation and identification of a new phloroglucinol derivative (2), a diterpenol (4), together with the known compounds flavesone (1) and sarothralen B (3), from the aerial parts of Hypericum japonicum are reported. Their structures were established by extensive spectral analysis and the structure of (3) has also been confirmed by a single crystal X-ray determination.