title: Synthesis and anti-acetylcholinesterase properties of novel β- and γ-substituted alkoxy organophosphonates.
abstract: Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts. Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs. In this report, we prepared a panel of β-substituted ethoxy and γ-substituted propoxy phosphonoesters of the type p-NO(2)PhO-P(X)(R)[(O(CH(2))(n)Z] (R=Me, Et; X=O, S; n=2, 3; Z=halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel. The β-fluoroethoxy methylphosphonate analog (R=Me, Z=F, n=2) was the most potent anti-AChE compound comparable (ki ∼6 × 10(6)M(-1)min(-1)) to paraoxon against EEAChE. Analogs with Z=Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R=Me) were more potent than the corresponding ethyl phosphonates (R=Et). As expected, analogs with a thionate linkage (PS) were poor inhibitors of the AChEs.
authors: Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59812, USA.
authors: S
authors: S
authors: Kaleem Ahmed
authors: Yamina
authors: Y
authors: Belabassi
authors: Lakshmi
authors: L
authors: Sankaranarayanan
authors: Chih-Kai
authors: CK
authors: Chao
authors: John M
authors: JM
authors: Gerdes
authors: Charles M
authors: CM
authors: Thompson
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004593:Electrophorus; D006801:Humans; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D063065:Organophosphonates; D011994:Recombinant Proteins; D000110:Acetylcholinesterase