Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack...

In this work, the ability of four newly synthesized oximes--K005 (1,3-bis(2-hydroxyiminomethylpyridinium) propane dibromide), K027 (1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide), K033 (1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide) and K048 (1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide) to reactivate acetylcholinester...

The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the formation of irreversibly inhibited acetylcholinesterase (AChE; EC 3.1.1.7) that could be followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic drug (atropine mostly) to counteract the accumulation of ac...

The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the irreversible inhibition of acetylcholinesterase that is followed by an accumulation of acetylcholine at peripheral and central cholinergic synapses, which in turn leads to the clinical manifestation of various signs and symptoms summarized as acute cholinergic crisis. Nerve agent ...

Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, ...

Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetyl...

Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxim...

Three potential reactivators of nerve agents-inhibited acetylcholinesterase: 2-[(hydroxyimino)phenylmethyl]-1-methylpyridinium iodide 3a, 2-[(hydroxyimino)pyridin-2ylmethyl]-1-methylpyridinium iodide 3b and 2-[(1-hydroxyimino) ethyl]-1-methylpyridinium iodide 3c were synthesized. Their reactivation potency was examined using a standard in vitro reactivation test. A rat brain homogenate was used...

Owing to the threat of organophosphate exposures, not only to pesticides but also to nerve agents, it is very important to know the whole process of organophosphates-inhibited acetylcholinesterase (AChE, EC 3.1.1.7) reactivation. Although current antidotes against organophosphorus intoxications consist also of prophylactics, AChE reactivators are still needed especially in the case of intoxicat...

We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular ...