Structure-Activity Relationships for Reactivators of Organophosphorus-Inhibited Acetylcholinesterase: Quaternary Salts of 2-imidazole

Article abstract of DOI:10.1021/jm00377a010

A series of 1,3-disubstituted-2-<(hydroxyimino)methyl>imidazolium halides were prepared and evaluated in vitro with respect to their ability to reactivate acetylcholinesterase inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methylphosphonofluoridate (GD).The compounds conform to the general formula ⁺*Cl^-, where R = CH3, (CH2)3CH3, (CH2)7CH3, CH2C6H5, CH2C10H7, (CH2)3C6H5, CH(CH3)2, CH2C(CH3)3, and CH(CH3)C(CH3)3.For comparison we also evaluated three known pyridinium reactivators, 2-PAM, HI-6, and toxogonin.The imidazolium aldoximes exhibit oxime acid dissociation constants (pK_a) in the range 7.9-8.1, bracketing the value of 8.0, believed to be optimal for acetylcholinesterase reactivation.With imidazolium compound in excess over inhibited enzyme, the kinetics of reactivation are well behaved for EPMP-inhibited AChE and depend on the nature of the alkyl ether group R.For GD-inhibited AChE, maximal reactivation was used to compare compounds becouse rapid phosphonyl enzyme dealkylation and enzyme reihibition complicate interpretation of kinetic constants.