Nonquaternary Cholinesterase Reactivators. Annual Report October 1981 - August 1982

摘要

We prepared three general classes of compounds and evaluated them in vitro as reactivators of organophosphonate-inhibited acetylcholinesterase (AChE). The compounds conformed to the following general structures: RC(:0)C(:NOH)S(CH2)n N(R')2.HCl, alpha-ketothiohydroximates, type 1; R''-C(:NOH)H, alpha-heteroaromatic aldoximes (R''= oxadiazole, thiadiazole, or triazole), type 2; and R''-C(:NOH)S CH2CH2N(C2H5)2.HCl, alpha-hetero-aromatic thiohydroximates (R'' as above), type 3. In all cases, the objective was to develop nonquaternary compounds that can restore activity to phosphonylated-AChE and that can penetrate in vivo into the central nervous system. All the compounds reactivate inhibited AChE via pre-equilibrium binding to phosphonylated enzyme followed by nucleophilic attack on phosphorus to liberate active enzyme. We characterized each of the type 1,2, and 3 compounds with respect to acidity, nucleophilicity, reversible anticholinesterase activity, and effective bimolecular rate constants (K sub eff) for reactivation of ethyl methylphosphonyl-AChE. Compound 3a is a powerful reversible competitive inhibitor of AChE (K sub i = 0.98 micrometers). Additionally, 3a protects AChE against inhibition by an organophosphonate and simultaneously reactivates any phosphonyl-AChE that forms. These characteristics recommend 3a as a pretreatment for organophosphonate poisoning.