Structure-activity relationships for reactivators of organophosphorus-inhibited acetylcholinesterase: quaternary salts of 2[(hydroxyimino)methyl]imidazoles

Publisher Website
Google Scholar
Abstract
A series of 1,3-disubstituted-2-[(hydroxyimino)methyl]imidazolium halides [2-[(hydroxyimino)methyl]-1-(methoxy-methyl)-3-methylimidazolium chloride, 2-[(hydroximino)methyl]-1-(isopropoxy-methyl)-3-methylimidazolium chloride, 1-[(2,2-dimethylpropoxy)methyl]-2-[(hydroxyimino)-methyl]-3-methylimidazolium chloride, 2-[(hydroxyimino)methyl]-3-methyl-1-[(3,3-dimethyl-2-butoxy)methyl]imidazolium chloride, 1-(-butoxy-methyl)-2-[(hydroxyimino)methyl]-3-methyl-imidazolium chloride, 2-[(hydroxyimino)methyl]-3-methyl-1-(1-octoxy methyl)-imidazolium chloride 1-[(benzyloxy)methyl]-2-[(hydroxyimino)methyl]-3-methylimidazolium chloride, 2-[(hydroxyimino)methyl]-3-methyl-1-[(3-phenylpropoxy)methyl]imidazolium chloride and 2-[(hydroxyimino)methyl]-1-[(1-naphthylmethoxy)methyl]imidazolium chloride] 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 methylphosphonofluroide (GD). The compounds conform to the general formula N(CH3)C(CHNOH)N(CH2OR)CHCH+.cntdot.Cl-, where R = CH3, (CH2)3CH3, (CH2)7CH3, CH2C6H5, CH2C10H7, (C-H2)3C6H5, CH(CH3)2, CH2C(CH3)3 and CH(CH3)C(CH3)3. For comparison, 3 known pyridinium reactivators, 2-PAM [2-[(hydroxyimino)methyl]-1-methylpyridinium halide], HI-6 [4-carbamoyl-2''-(hydroxyiminomethyl)-1,1(oxydimethylene)bis(pyridinium) salt], and toxogonin were evaluated. The imidazolium aldoximes exhibited oxime 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 were well behaved for EPMP-inhibited AChE and depended 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.