117941-64-7Relevant academic research and scientific papers
Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 2. Preparation and in vitro and in vivo evaluation of 1-(alkoxymethyl)-2-[(hydroxyimino)methyl]-3-methylimidazolium halides for reactivation of organophosphorus-inhibited acetylcholinesterases
Bedford,Harris III,Howd,Goff,Koolpe,Petesch,Miller,Nolen III,Musallam,Pick,Jones,Koplovitz,Sultan
, p. 493 - 503 (2007/10/02)
A series of structurally related mono- and bis-1,3-disubstituted 2-[(hydroxyimino)methyl]imidazolium halides were evaluated in vitro for their ability to reactivate electric eel, bovine, and human erythrocyte (RBC) acetylcholinesterases (AChE) inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methylphosphonofluoridate (soman, GD). All new compounds were characterized for (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol-buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivation of EPMP-inhibited AChEs. For GD-inhibited AChEs, maximal reactivation was used to compare compounds since rapid phosphonyl enzyme dealkylation 'aging' complicated interpretation of kinetic constants. For comparison, we also evaluated three known pyridinium therapeutics, 2-PAM, HI-6, and toxogonin. In vivo evaluation in mice revealed that when selected imidazolium compounds were coadministered with atropine sulfate, they were effective in providing lifesaving protection against both GD and EPMP challenges. This was a major accomplishment in the search for effective anticholinesterase therapeutics - the synthesis and preliminary evaluation of the first new monoquaternary soman antidotes with potencies superior to 2-PAM. Significantly, there was an apparent inverse relationship between in vitro and in vivo results; the most potent in vivo compounds proved to be the poorest in vitro reactivators. These results suggested that an alternative and possibly novel antidotal mechanism of protective action may be applicable for the imidazolium aldoxines. Selected compounds were also evaluated for their inhibition of AChE phosphonylation by GD and antimuscarinic and antinicotinic receptor blocking effects.
Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 3. Synthesis and evaluation of (alkenyloxy)-, (alkynyloxy)-, and (aralkyloxy)methyl quaternarized 2[(hydroxyimino)methyl]-1-alkylimidazolium halides as reactivators and therapy for soman intoxication
Bedford,Harris III,Howd,Goff,Koolpe,Petesch,Koplovitz,Sultan,Musallam
, p. 504 - 516 (2007/10/02)
A series of structurally related monosubstituted 1-[(alkenyloxy)methyl]-, 1-[(alkynyloxy)methyl]-, and 1-[(aralkyloxy)methyl]-2-[(hydroxyimino)methyl]-3-methylimidazolium halides were prepared and evaluated. All new compounds were characterized with respect to (hydroxyimino)methyl acid dissocation constant, nucleophilicity, and octanol-buffer partition coefficient. The alkynyloxy-substituted compounds were also evaluated in vitro with respect to reversible inhibition of human erythrocyte (RBC) acetylcholinesterase (AChE) and kinetics of reactivation of human AChE inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP). In vivo evaluation in mice revealed that coadministration of alkynyloxy-substituted imidazolium compounds with atropine sulfate provided significant protection against a 2 x LD50 challenge of GD. For the alkynyloxy-substituted imidazolium drugs there is a direct relationship between in vitro and in vivo activity: the most potent in vivo compounds against GD proved to be potent in vitro reactivators against EPMP-inhibited human AChE. These results differ from the observations made on the sterically hindered imidazolium compounds (see previous article) and suggest that several antidotal mechanisms of protective action may be applicable for the imidazolium aldoxime family of therapeutics. The ability of the alkynyloxy substituents to provide life-saving protection against GD intoxication was not transferable to the pyridinium or triazolium heteroaromatic ring systems.
