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.

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.

Radiohalodestannylation: synthesis of 125I-labeled 17 alpha-E-iodovinylestradiol.

17 alpha-E-Iodovinylestradiol and its iodine-125-labeled analog were prepared by halodestannylation. The synthesis of the unlabeled compound was achieved from estrone in two steps with an overall yield of 30%. The tributylstannylvinylestradiol intermediate reacted with sodium [125I]iodide (specific activity = 2200 Ci/mmol) in the presence of hydrogen peroxide and acetic acid to give the 17 alpha-E-[125I]iodovinylestradiol in 40-60% yield after isolation by reversed phase column chromatography. The radiochemical purity was greater than 98% and no other u.v. active components could be detected by HPLC. The ease of preparation and isolation of this radioligand suggests that radiohalodestannylation may be the method of choice for this and structurally similar compounds.

New compounds: synthesis of 2-chloromethylbenzo[b]furans.

2-Chloromethylbenzo[b]furans were prepared in high overall yield from the corresponding chloroethylphenyl ethers through chloroepoxide and alpha-chlorophenylacetone intermediates.