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 methyl-phosphonofluoridate (
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
aldoximes. Selected compounds were also evaluated for their inhibition of AChE phosphorylation by GD and
antimuscarinic and antinicotinic receptor blocking effects.