Nonquaternary Cholinesterase Reactivators.
Annual rept. Oct 81-Aug 82,
SRI INTERNATIONAL MENLO PARK CA
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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 RC0CNOHSCH2n NR2.HCl, alpha-ketothiohydroximates, type 1 R-CNOHH, alpha-heteroaromatic aldoximes R oxadiazole, thiadiazole, or triazole, type 2 and R-CNOHS CH2CH2NC2H52.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.