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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.
AuthorsS Kaleem Ahmed, Yamina Belabassi, Lakshmi Sankaranarayanan, Chih-Kai Chao, John M Gerdes, Charles M Thompson
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 7 Pg. 2048-51 (Apr 01 2013) ISSN: 1464-3405 [Electronic] England
PMID23453838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Cholinesterase Inhibitors
  • Organophosphonates
  • Recombinant Proteins
  • Acetylcholinesterase
Topics
  • Acetylcholinesterase (metabolism)
  • Animals
  • Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Humans
  • Molecular Structure
  • Organophosphonates (chemical synthesis, chemistry, pharmacology)
  • Rats
  • Recombinant Proteins (antagonists & inhibitors, metabolism)
  • Structure-Activity Relationship

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