Document Report Card

ID: ALA1123431

Journal: J Med Chem

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.

Authors: Bedford CD, Miura M, Bottaro JC, Howd RA, Nolen HW.

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.

CiteXplore: 3746817

DOI: 10.1021/jm00159a021