Nonquaternary cholinesterase reactivators. 4. Dialkylaminoalkyl thioesters of α-keto thiohydroximic acids as reactivators of ethyl methylphosphonyl- and 1,2,2-trimethylpropyl methylphosphonyl-acetylcholinesterase in vitro

Article abstract of DOI:10.1021/jm00159a021

In the search for improved lipophilic centrally active acetylcholinesterase (AChE) antidotes, a series of α-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)(n)N⁺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 pK(a) 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 α-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.