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

Seven new oxime-based acetylcholinesterase reactivators were compared with three currently available ones (obidoxime, trimedoxime, HI-6) for their ability to lessen cholinesterase inhibition in blood and brain of cyclosarin-treated rats. Oximes were given at doses of 5% their LD(50) along with 21 mg/kg atropine five min before the LD(50) of cyclosarin (120 ug/kg) was administered. Blood and brain samples were collected 30 minutes later. The greatest difference between acetylcholinesterase inhibition in blood of cyclosarin-treated rats was found after administration of HI-6 (40%), compared to 22% for trimedoxime and 6% for obidoxime. Only two of the seven newly synthesized oximes had any effect (K203 at 7%, K156 at 5%). Effective oximes against cyclosarin-inhibited plasma butyrylcholinesterase were HI-6 (42%), trimedoxime (11%), and K156 (4%). The oximes were less effective in brain than in blood, with reactivation values for HI-6 30% against acetylcholinesterase and 10% against butyrylcholinesterase. Values for newly synthesized oximes were less than 10% for K206, K269 and K203.

• Keywords
• acetylcholinesterase, butyrylcholinesterase, cyclosarin, oximes, reactivators,
• MeSH
• Acetylcholinesterase blood   metabolism   MeSH
• Atropine pharmacology   MeSH
• Rats MeSH
• Brain drug effects   enzymology   MeSH
• Organophosphorus Compounds toxicity   MeSH
• Oximes chemistry   pharmacology   MeSH
• Rats, Wistar MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Atropine MeSH
• cyclohexyl methylphosphonofluoridate MeSH Browser
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Cholinesterase Reactivators MeSH

The therapeutical efficacies of eleven oxime-based acetylcholinesterase reactivators were compared in an in vivo (rat model) study of treatment of intoxication caused by tabun. In this group there were some currently available oximes (obidoxime, trimedoxime and HI-6) and the rest were newly synthesized compounds. The best reactivation efficacy for acetylcholinesterase in blood (expressed as percent of reactivation) among the currently available oximes was observed after administration of trimedoxime (16%) and of the newly synthesized K127 (22432) (25%). The reactivation of butyrylcholinesterase in plasma was also studied; the best reactivators were trimedoxime, K117 (22435), and K127 (22432), with overall reactivation efficacies of approximately 30%. Partial protection of brain ChE against tabun inhibition was observed after administration of trimedoxime (acetylcholinesterase 20%; butyrylcholinesterase 30%) and obidoxime (acetylcholinesterase 12%; butyrylcholinesterase 16%).

• Keywords
• Acetylcholinesterase, butyrylcholinesterase, oximes, pretreatment, reactivators,
• Publication type
• Journal Article MeSH