Nonquaternary cholinesterase reactivators. Dialkylaminoalkyl thioesters of .alpha.-ketothiohydroximic acids as reactivators of diisopropyl phosphorofluoridate-inhibited acetylcholinesterase
| Autor: | John S. Winterle, Robert A. Howd, Richard A. Kenley, Carol W. Mosher |
|---|---|
| Rok vydání: | 1981 |
| Předmět: |
chemistry.chemical_classification
Isoflurophate biology Sulfides Hydroxamic Acids Oxime Medicinal chemistry Acetylcholinesterase Enzyme assay Acid dissociation constant Kinetics chemistry.chemical_compound Enzyme Reactivators Enzyme Reaction rate constant chemistry Nucleophile Drug Discovery biology.protein Molecular Medicine Cholinesterase Inhibitors Equilibrium constant |
| Zdroj: | Journal of Medicinal Chemistry. 24:1124-1133 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00142a003 |
| Popis: | We have prepared a series of alpha-ketothiohydroximic acid thioesters and evaluated them in vitro with respect to their ability to reactivate (diisopropylphosphoryl)acetylcholinesterase. The compounds conform to the general formula RC(=O)C(=NOH)S(CH2)nNR2'.HCl, where R = CH3, C6H5, 4-CH3OC6H4, 4-NO2C6H4; n = 2, 3; and R' = CH3, C2H5, or i-C3h7. We also prepared 4-BrC6H4C(=NOH)S(CH2)2N(C2H5)2.HCl and 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.CH3I for comparison. The alpha-ketothiohydroximates exhibit oxime acid dissociation constants (pKa) in the range 6.9 to 8.4, bracketing the value of pKa = 7.9, believed to be optimal for acetylcholinesterase reactivation. The compounds are also good nucleophiles; bimolecular rate constants (kn) for reaction with p-nitrophenyl acetate follow the expression log (kn) = 6.7 - 0.69(14 - pKa = The reactivation of (diisopropylphosphoryl)acetylcholinesterase is highly dependent on the alpha-ketothiohydroximate structure: 4-h incubation of inhibited enzyme at pH 7.6, 25 degrees C, with 1 x 10(-3) M 4-CH3OC6H4C(=O)C(=NOH)S(CH2)3N(CH3)2.HCl gives no detectable restoration of activity, whereas 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.HCl restores inhibited enzyme activity to 58% of control under identical conditions. With alpha-ketothiohydroximate in excess over inhibited enzyme, the kinetics of reactivation are governed by an equilibrium constant (Kr) for binding alpha-ketothiohydroximate to the inhibited enzyme and a nucleophilic displacement rate constant (kr) for attack on phosphorus. |
| Databáze: | OpenAIRE |
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