Abstract
A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) were designed, synthesized, and tested. These compounds represent a novel group of oximes with enhanced capabilities of crossing the blood-brain barrier. Lack of brain penetration is a major limitation for currently used oximes as antidotes of OP poisoning. The concept described herein relies on a combination of an amidine residue and oxime functionality whereby the amidine increases the binding affinity to the ChE and the oxime is responsible for reactivation. Amidine-oximes were tested in vitro and reactivation rates for OP-BuChE were greater than pralidoxime (2-PAM) or monoisonitrosoacetone (MINA). Amidine-oxime reactivation rates for OP-AChE were lower compared to 2-PAM but greater compared with MINA. After pretreatment for 30 min with oximes 15c and 15d (145 μmol/kg, ip) mice were challenged with a soman model compound. In addition, 15d was tested in a post-treatment experiment (145 μmol/kg, ip, administration 5 min after sarin model compound exposure). In both cases, amidine-oximes afforded 100% 24 h survival in an animal model of OP exposure.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylcholinesterase / chemistry
-
Acetylcholinesterase / metabolism
-
Amidines / chemical synthesis*
-
Amidines / chemistry
-
Amidines / pharmacology
-
Animals
-
Blood-Brain Barrier / metabolism
-
Butyrylcholinesterase / chemistry
-
Butyrylcholinesterase / metabolism
-
Chemical Warfare Agents / poisoning
-
Cholinesterase Inhibitors / poisoning*
-
Cholinesterases / chemistry
-
Cholinesterases / metabolism*
-
Enzyme Reactivators / chemical synthesis*
-
Enzyme Reactivators / chemistry
-
Enzyme Reactivators / pharmacology
-
Female
-
Humans
-
Mice
-
Organophosphate Poisoning*
-
Organophosphorus Compounds
-
Oximes / chemical synthesis*
-
Oximes / chemistry
-
Oximes / pharmacology
-
Permeability
-
Recombinant Proteins / chemistry
-
Sarin / poisoning
-
Soman / poisoning
-
Structure-Activity Relationship
Substances
-
2-(hydroxyimino)-N,N-dimethyl-N'-propylacetimidamide
-
Amidines
-
Chemical Warfare Agents
-
Cholinesterase Inhibitors
-
Enzyme Reactivators
-
N'-ethyl-2-(hydroxyimino)-N,N-dimethylacetimidamide
-
Organophosphorus Compounds
-
Oximes
-
Recombinant Proteins
-
Soman
-
Sarin
-
Acetylcholinesterase
-
Butyrylcholinesterase
-
Cholinesterases
-
cyclohexyl methylphosphonofluoridate