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.
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Authors | S Kaleem Ahmed, Yamina Belabassi, Lakshmi Sankaranarayanan, Chih-Kai Chao, John M Gerdes, Charles M Thompson |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 23
Issue 7
Pg. 2048-51
(Apr 01 2013)
ISSN: 1464-3405 [Electronic] England |
PMID | 23453838
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2013 Elsevier Ltd. All rights reserved. |
Chemical References |
- Cholinesterase Inhibitors
- Organophosphonates
- Recombinant Proteins
- Acetylcholinesterase
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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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