title: [O,O-dialkyl-S-bromomethylthiophosphates--inhibitors of mammalian choline- and carboxyl esterases: structure-activity relationship].
abstract: The interaction kinetics of potential pesticides, O,O-dialkyl S-bromomethylthiophosphates (RO)2P(O) SCH2Br (R = Et, i-Pr, n-Pr, n-Bu, or n-Am) with acetylcholinesterase, butyryl cholinesterase, and carboxyl esterase from warm-blooded animals was studied. All the compounds irreversibly inhibit these esterases, with k1 (M-1 min-1) being 1.8 x 10(4) - 1.9 x 10(6) for acetylcholinesterase, 2.0 x 10(6) - 4.1 x 10(7) for the more sensitive butyryl cholinesterase, and 2.3 x 10(7) - 2.3 x 10(8) and higher for the most sensitive carboxyl esterase. By using the Hansch and Kubinyi technique of multiple regression analysis, we quantitatively analyzed the relationship between the structure and inhibiting activity of these substances toward acetylcholinesterase and butyryl cholinesterase. Hydrophobic interactions were found to be important for the inhibition of both enzymes but are more pronounced in the case of butyryl cholinesterase. On the other hand, steric factors were much more significant in the inhibition of acetylcholinesterase. For both enzymes, the steric hindrances affect the phosphorylation stage of the enzyme.
authors.affiliation: Institute of Physiologically Active Substances, Russian Academy of Sciences, Moscow oblast, Russia. makh@pharm.unicon.msk.su
authors.forename: G F
authors.initials: GF
authors.lastname: Makhaeva
authors.forename: V L
authors.initials: VL
authors.lastname: Iankovskaia
authors.forename: N V
authors.initials: NV
authors.lastname: Kovaleva
authors.forename: V I
authors.initials: VI
authors.lastname: Fetisov
authors.forename: V V
authors.initials: VV
authors.lastname: Malygin
authors.forename: N A
authors.initials: NA
authors.lastname: Torgasheva
authors.forename: B A
authors.initials: BA
authors.lastname: Khaskin
mesh_terms: D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006736:Horses; D006801:Humans; D007306:Insecticides / Q000737:chemistry*; D007700:Kinetics; D009946:Organothiophosphorus Compounds; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D007306:Insecticides; D009946:Organothiophosphorus Compounds; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase