title: Nonquaternary cholinesterase reactivators. 4. Dialkylaminoalkyl thioesters of alpha-keto thiohydroximic acids as reactivators of ethyl methylphosphonyl- and 1,2,2-trimethylpropyl methylphosphonyl-acetylcholinesterase in vitro.
abstract: In the search for improved lipophilic centrally active acetylcholinesterase (AChE) antidotes, a series of alpha-keto thiohydroximates were prepared and evaluated for their ability to reactivate AChEs inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and soman (GD). The compounds conformed to the general structure 4-RC6H5C-(O)C(NOH)S(CH2)nN+R'R''.X- where R = H, CH3, F, Br, Cl, OCH3, CN;R' = CH3, C2H5, i-C3H7; R'' = H, CH3; X = Cl, I; and n = 2, 3. In this series, varying R substituents on the aryl ring produced compounds with oxime pKa values from 6.8 to 8.0, optimum for an AChE reactivator. Increasing lipophilicity of the amine segment correlated with reactivator potency, as did electron-withdrawing groups on the aryl moiety, presumably due to increased binding to hydrophobic sites surrounding the AChE active site. The in vitro reactivation potency of the alpha-keto thiohydroximates approaches and even surpasses that of 2-PAM and toxogonin for GD-inhibited AChE. These initial findings point to additional structure-activity relationships to assist in the design of improved antidotal compounds.
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood*; D055598:Chemical Phenomena; D002621:Chemistry; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D063086:Organothiophosphates / Q000138:chemical synthesis / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D012999:Soman / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; C042896:ethyl 4-nitrophenyl methylphosphonate; D012999:Soman; D000110:Acetylcholinesterase