Bedford C D, Harris R N, Howd R A, Miller A, Nolen H W, Kenley R A
J Med Chem. 1984 Nov;27(11):1431-8. 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 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.
制备了一系列1,3 - 二取代 - 2 - [(羟基亚氨基)甲基]咪唑鎓卤化物，并对其在体外重新激活被对硝基苯基甲基膦酸乙酯（EPMP）和3,3 - 二甲基 - 2 - 丁基甲基膦酰氟（GD）抑制的乙酰胆碱酯酶的能力进行了评估。这些化合物符合通式N(CH3)C(CHNOH)N(CH2OR)CHCH+ X Cl-，其中R = CH3、(CH2)3CH3、(CH2)7CH3、CH2C6H5、CH2C10H7、(CH2)3C6H5、CH(CH3)2、CH2C(CH3)3和CH(CH3)C(CH3)3。为作比较，我们还评估了三种已知的吡啶鎓复活剂，即2 - PAM、HI - 6和氯磷定。咪唑鎓醛肟的肟酸解离常数（pKa）在7.9 - 8.1范围内，以8.0这个被认为对乙酰胆碱酯酶复活最为理想的值为界。当咪唑鎓化合物过量于受抑制的酶时，对于被EPMP抑制的乙酰胆碱酯酶，复活动力学表现良好，且取决于烷基醚基团R的性质。对于被GD抑制的乙酰胆碱酯酶，由于磷酰化酶的快速脱烷基化和酶的再次抑制使动力学常数的解释变得复杂，因此使用最大复活率来比较化合物。
