Structure-activity relationships for reactivators of organophosphorus-inhibited acetylcholinesterase: quaternary salts of 2-[(hydroxyimino)methyl]imidazole.
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 N(CH3)C(CHNOH)N(CH2OR)CHCH+ X 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 (pKa) 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 because rapid phosphonyl enzyme dealkylation and enzyme reinhibition complicate interpretation of kinetic constants.
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004524:Eels; D006898:Hydroxylamines / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008433:Mathematics; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012999:Soman / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D006898:Hydroxylamines; D007093:Imidazoles; D009943:Organophosphorus Compounds; C042896:ethyl 4-nitrophenyl methylphosphonate; C042895:3,3-dimethyl-2-butyl methylphosphonofluoridate; D012999:Soman; D000110:Acetylcholinesterase