Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

• Keywords
• Isatin, antidotes, cholinesterase reactivators, nerve agents, organophosphorus poisoning, pyridine oximes,
• MeSH
• Acetylcholinesterase drug effects   MeSH
• Isatin pharmacology   MeSH
• Computer Simulation MeSH
• Pyridines pharmacology   MeSH
• Cholinesterase Reactivators pharmacology   MeSH
• In Vitro Techniques MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Isatin MeSH
• pyridine MeSH Browser
• Pyridines MeSH
• Cholinesterase Reactivators 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

This article describes acetylcholinesterase (AChE), an enzyme involved in parasympathetic neurotransmission, its activity, and how its inhibition can be pharmacologically useful for treating dementia, caused by Alzheimer's disease, or as a warfare method due to the action of nerve agents. The chemical concepts related to the irreversible inhibition of AChE, its reactivation, and aging are discussed, along with a relationship to the current international legislation on chemical weapons.

• Keywords
• Alzheimer’s disease, Chemical Weapons Convention, acetylcholinesterase, nerve agents,
• MeSH
• Acetylcholinesterase * metabolism   MeSH
• Alzheimer Disease * drug therapy   enzymology   MeSH
• Chemical Warfare legislation & jurisprudence   MeSH
• Cholinesterase Inhibitors therapeutic use   MeSH
• GPI-Linked Proteins antagonists & inhibitors   metabolism   MeSH
• Humans MeSH
• Nerve Agents * MeSH
• Aging metabolism   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
• Cholinesterase Inhibitors MeSH
• GPI-Linked Proteins MeSH
• Nerve Agents * MeSH

Organophosphorus compounds (OP) are chemicals widely used as pesticides in different applications such as agriculture and public health (vector control), and some of the highly toxic forms have been used as chemical weapons. After application of OPs in an environment, they persist for a period, suffering a degradation process where the biotic factors are considered the most relevant forms. However, to date, the biodegradation of OP compounds is not well understood. There are a plenty of structure-based biodegradation estimation methods, but none of them consider enzymatic interaction in predicting and better comprehending the differences in the fate of OPs in the environment. It is well known that enzymatic processes are the most relevant processes in biodegradation, and that hydrolysis is the main pathway in the natural elimination of OPs in soil samples. Due to this, we carried out theoretical studies in order to investigate the interactions of these OPs with a chosen enzyme-the phosphotriesterase. This one is characteristic of some soils' microorganisms, and has been identified as a key player in many biodegradation processes, thanks to its capability for fast hydrolyzing of different OPs. In parallel, we conducted an experiment using native soil in two conditions, sterilized and not sterilized, spiked with specific amounts of two OPs with similar structure-paraoxon-ethyl (PXN) and O-(4-nitrophenyl) O-ethyl methylphosphonate (NEMP). The amount of OP present in the samples and the appearance of characteristic hydrolysis products were periodically monitored for 40 days using analytical techniques. Moreover, the number of microorganisms present was obtained with plate cell count. Our theoretical results were similar to what was achieved in experimental analysis. Parameters calculated by enzymatic hydrolysis were better for PXN than for NEMP. In soil, PXN suffered a faster hydrolysis than NEMP, and the cell count for PXN was higher than for NEMP, highlighting the higher microbiological toxicity of the latter. All these results pointed out that theoretical study can offer a better comprehension of the possible mechanisms involved in real biodegradation processes, showing potential in exploring how biodegradation of OPs relates with enzymatic interactions.

• Keywords
• bioremediation, molecular modeling, organophosphorus compounds, phosphotriesterase,
• MeSH
• Biodegradation, Environmental * MeSH
• Chemical Warfare MeSH
• Hydrolysis MeSH
• Insecticides chemistry   metabolism   MeSH
• Humans MeSH
• Organophosphorus Compounds chemistry   metabolism   MeSH
• Paraoxon analogs & derivatives   chemistry   MeSH
• Pesticides chemistry   toxicity   MeSH
• Soil chemistry   MeSH
• Pyrrolidines chemistry   MeSH
• Public Health MeSH
• Agriculture MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ethylparaoxon MeSH Browser
• Insecticides MeSH
• N-ethylmercapto-3-4-dihydroxy-2-hydroxymethylpyrrolidine MeSH Browser
• Organophosphorus Compounds MeSH
• Paraoxon MeSH
• Pesticides MeSH
• Soil MeSH
• Pyrrolidines MeSH