Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.

• Keywords
• acetylcholinesterase, computational methods, mechanistic studies, nerve agents, reactivation, trimedoxime,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes pharmacology   MeSH
• Cholinesterase Inhibitors metabolism   pharmacology   MeSH
• Rats MeSH
• Humans MeSH
• Mice MeSH
• Nerve Agents chemistry   MeSH
• Organophosphorus Compounds chemistry   MeSH
• Oximes chemistry   MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• Trimedoxime pharmacology   therapeutic use   MeSH
• Computational Biology methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Cholinesterase Inhibitors MeSH
• Nerve Agents MeSH
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Cholinesterase Reactivators MeSH
• Trimedoxime MeSH

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.

• Keywords
• acetylcholinesterase, new trends in reactivators, organophosphorus compounds, reactivation process, therapeutic potential,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• GPI-Linked Proteins metabolism   MeSH
• Humans MeSH
• Oximes chemistry   therapeutic use   MeSH
• Patents as Topic MeSH
• Cholinesterase Reactivators * chemistry   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• ACHE protein, human MeSH Browser
• GPI-Linked Proteins MeSH
• Oximes MeSH
• Cholinesterase Reactivators * MeSH

The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator's molecule are described.

• Keywords
• acetylcholinesterase, in vitro, molecular docking, organophosphate, oxime, reactivation,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Carbon-13 Magnetic Resonance Spectroscopy MeSH
• Organophosphorus Compounds toxicity   MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Cholinesterase Reactivators chemical synthesis   chemistry   pharmacology   MeSH
• Recombinant Proteins metabolism   MeSH
• Molecular Docking Simulation * MeSH
• In Vitro Techniques MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphorus Compounds MeSH
• Cholinesterase Reactivators MeSH
• Recombinant Proteins MeSH

BACKGROUND: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. METHODS: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). RESULTS: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min- 1. M- 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min- 1. M- 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. DISCUSSION: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

• Keywords
• Antidotes, Chemical warfare agents, Oxime, Poisoning, Reactivator, Treatment,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes metabolism   MeSH
• Cholinesterase Inhibitors metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Brain enzymology   MeSH
• Organophosphates metabolism   MeSH
• Oximes metabolism   MeSH
• Pyridinium Compounds metabolism   MeSH
• Cholinesterase Reactivators metabolism   MeSH
• Molecular Docking Simulation MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Browser
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphates MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

• MeSH
• Acetylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Oximes chemistry   MeSH
• Molecular Docking Simulation MeSH
• Protein Binding MeSH
• Hydrogen Bonding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Oximes MeSH

We have in vitro tested the ability of common, commercially available, cholinesterase reactivators (pralidoxime, obidoxime, methoxime, trimedoxime and HI-6) to reactivate human acetylcholinesterase (AChE), inhibited by five structurally different organophosphate pesticides and inhibitors (paraoxon, dichlorvos, DFP, leptophos-oxon and methamidophos). We also tested reactivation of human butyrylcholinesterase (BChE) with the aim of finding a potent oxime, suitable to serve as a "pseudocatalytic" bioscavenger in combination with this enzyme. Such a combination could allow an increase of prophylactic and therapeutic efficacy of the administered enzyme. According to our results, the best broad-spectrum AChE reactivators were trimedoxime and obidoxime in the case of paraoxon, leptophos-oxon, and methamidophos-inhibited AChE. Methamidophos and leptophos-oxon were quite easily reactivatable by all tested reactivators. In the case of methamidophos-inhibited AChE, the lower oxime concentration (10(-5) M) had higher reactivation ability than the 10(-4) M concentration. Therefore, we evaluated the reactivation ability of obidoxime in a concentration range of 10(-3)-10(-7) M. The reactivation of methamidophos-inhibited AChE with different obidoxime concentrations resulted in a bell shaped curve with maximum reactivation at 10(-5) M. In the case of BChE, no reactivator exceeded 15% reactivation ability and therefore none of the oximes can be recommended as a candidate for "pseudocatalytic" bioscavengers with BChE.

• Keywords
• acetylcholinesterase, butyrylcholinesterase, in vitro, nerve agent, organophosphate, oxime, pesticide, reactivator, scavenger,
• MeSH
• Acetylcholinesterase chemistry   metabolism   MeSH
• Butyrylcholinesterase chemistry   metabolism   MeSH
• Cholinesterase Inhibitors chemistry   metabolism   MeSH
• Erythrocytes enzymology   MeSH
• Humans MeSH
• Organophosphorus Compounds chemistry   metabolism   MeSH
• Oximes chemistry   MeSH
• Pesticides chemistry   metabolism   MeSH
• Cholinesterase Reactivators chemistry   metabolism   MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Pesticides MeSH
• Cholinesterase Reactivators MeSH

• Keywords
• acetylcholinesterase, antidote, nerve agent, organophosphates, prophylaxis, therapy,
• Publication type
• Journal Article MeSH

In this work, two oximes for the treatment of tabun-inhibited acetylcholinesterase (AChE; EC 3.1.1.7), K074 (1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide) and K075 ((E)-1,4-bis(4-hydroxyiminomethylpyridinium)but-2-en dibromide), were tested in vitro as reactivators of AChE. Comparison was made with currently used AChE reactivators (pralidoxime, HI-6, methoxime and obidoxime). Human brain homogenate was taken as an appropriate source of the cholinesterases. As resulted, oxime K074 appears to be the most potent reactivator of tabun-inhibited AChE, with reactivation potency comparable to that of obidoxime. A second AChE reactivator, K075, does not attain as great a reactivation potency as K074, although its maximal reactivation (17%) was achieved at relevant concentrations for humans.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation drug effects   MeSH
• Butanes chemistry   pharmacology   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Humans MeSH
• Caudate Nucleus drug effects   enzymology   MeSH
• Obidoxime Chloride chemistry   pharmacology   MeSH
• Organophosphates toxicity   MeSH
• Oximes chemistry   pharmacology   MeSH
• Pralidoxime Compounds chemistry   pharmacology   MeSH
• Pyridinium Compounds chemistry   pharmacology   MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• In Vitro Techniques MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide MeSH Browser
• Acetylcholinesterase MeSH
• asoxime chloride MeSH Browser
• Butanes MeSH
• Cholinesterase Inhibitors MeSH
• K075 compound MeSH Browser
• N,N'-monomethylenebis(pyridiniumaldoxime) MeSH Browser
• Obidoxime Chloride MeSH
• Organophosphates MeSH
• Oximes MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser

INTRODUCTION: Organophosphorus nerve agents inhibit the enzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE reactivators (also known as oximes) are generally used for the reactivation of an inhibited enzyme. METHODS: Two new AChE reactivators--K033 and K027--were tested for their in vitro reactivation of sarin-inhibited pig-brain AChE. Their reactivation potencies were compared with the commercially available AChE reactivators, pralidoxime, obidoxime, and HI-6. RESULTS: Of the oximes tested, the newly developed oxime K027 achieved the highest reactivation potency (100%; concentration of the oxime -10(-2) M). However, oxime HI-6 (33%) and obidoxime (23%) seem to be the best AChE reactivators for human relevant doses (10(-4) M and lower). CONCLUSION: For human relevant doses, newly developed oximes (K027 and K033) do not surpass the reactivation potency of the most promising oxime, HI-6.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes pharmacology   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Brain drug effects   enzymology   MeSH
• Obidoxime Chloride pharmacology   MeSH
• Oximes pharmacology   MeSH
• Pralidoxime Compounds pharmacology   MeSH
• Swine MeSH
• Pyridinium Compounds pharmacology   MeSH
• Cholinesterase Reactivators pharmacology   MeSH
• Sarin toxicity   MeSH
• In Vitro Techniques MeSH
• Research Design MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
• 1,4-bis(2-hydroxyiminomethylpyridinium)butane MeSH Browser
• Acetylcholinesterase MeSH
• Antidotes MeSH
• asoxime chloride MeSH Browser
• Cholinesterase Inhibitors MeSH
• Obidoxime Chloride MeSH
• Oximes MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• Sarin MeSH

The influence of newly developed oximes, K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide] and K048 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) butane dibromide], or currently used oximes (pralidoxime, obidoxime, trimedoxime, HI-6) and anticholinergic drugs (atropine, benactyzine) on the ability of antidotal treatment to eliminate tabun-induced acute toxic effects was studied in mice. The therapeutical efficacy of trimedoxime and both newly developed oximes (K027, K048) is significantly higher than the potency of pralidoxime (regardless of the choice of anticholinergic drug), obidoxime (in the case of its combination with atropine) and the oxime HI-6 (in the case of its combination with benactyzine). All studied oximes with the exception of pralidoxime and the oxime HI-6, when combined with benactyzine, appear to be more efficacious in the elimination of toxic effects of the lethal dose of tabun than their combination with atropine. The findings support the hypothesis that the choice of acetylcholinesterase reactivators as well as the anticholinergic drug selection are important for the effectiveness of an antidotal mixture in the case of antidotal treatment of tabun-induced acute poisonings.

• MeSH
• Antidotes pharmacology   MeSH
• Chemical Warfare Agents poisoning   MeSH
• Cholinergic Antagonists pharmacology   MeSH
• Drug Evaluation MeSH
• Lethal Dose 50 MeSH
• Drug Interactions MeSH
• Mice MeSH
• Organophosphates antagonists & inhibitors   MeSH
• Organophosphate Poisoning MeSH
• Oximes pharmacology   MeSH
• Cholinesterase Reactivators therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Antidotes MeSH
• Chemical Warfare Agents MeSH
• Cholinergic Antagonists MeSH
• Organophosphates MeSH
• Oximes MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser