Most cited article - PubMed ID 30862059
Novichoks: The Dangerous Fourth Generation of Chemical Weapons
Organophosphorus compounds, including pesticides and nerve agents, irreversibly inhibit acetylcholinesterase, leading to an accumulation of acetylcholine that can cause a cholinergic crisis. Standard treatment of organophosphate poisoning relies on oxime-based reactivators, such as pralidoxime, obidoxime, or asoxime. However, these compounds have several limitations, including poor penetration through the blood-brain barrier and limited efficacy across a broad spectrum of organophosphorus compounds. For this reason, non-oxime reactivators were introduced as potential alternatives. The most promising non-oxime reactivators contain Mannich phenol moiety, imidazole group or combination of both. Some of the non-oxime derivatives demonstrated better efficacy than standard oximes during in vitro evaluation. Nevertheless, these structures have significant drawbacks such as high intrinsic acetylcholinesterase inhibition or high toxicity profile which make them unsuitable for further in vivo tests. In this review, the current progress in the development of non-oxime reactivators is summarized and their bioactivity as well as their limitations are critically discussed.
- Keywords
- Acetylcholinesterase, Butyrylcholinesterase, Nerve agent, Non-oxime, Reactivator,
- Publication type
- Journal Article MeSH
The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.
- Keywords
- A-230, Acetylcholinesterase, Antidotes, Chemical Weapons Convention, Nerve agent surrogates,
- MeSH
- Acetylcholinesterase * metabolism MeSH
- Antidotes pharmacology MeSH
- Chemical Warfare Agents * toxicity MeSH
- Cholinesterase Inhibitors * toxicity MeSH
- Nerve Agents * toxicity MeSH
- Organothiophosphorus Compounds toxicity MeSH
- Oximes * pharmacology MeSH
- Pralidoxime Compounds pharmacology MeSH
- Pyridinium Compounds * pharmacology MeSH
- Cholinesterase Reactivators * pharmacology MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase * MeSH
- Antidotes MeSH
- Chemical Warfare Agents * MeSH
- Cholinesterase Inhibitors * MeSH
- Nerve Agents * MeSH
- Organothiophosphorus Compounds MeSH
- Oximes * MeSH
- pralidoxime MeSH Browser
- Pralidoxime Compounds MeSH
- Pyridinium Compounds * MeSH
- Cholinesterase Reactivators * MeSH
A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.
- Keywords
- Acute toxicity, Hydrolysis, Nerve agent A-234, Reactivation, Therapy,
- MeSH
- Acetylcholinesterase MeSH
- Antidotes pharmacology MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors toxicity MeSH
- Phosphorus MeSH
- Rats MeSH
- Oxygen MeSH
- Humans MeSH
- Oximes pharmacology MeSH
- Pralidoxime Compounds * MeSH
- Pyridinium Compounds pharmacology MeSH
- Cholinesterase Reactivators * pharmacology MeSH
- Taurine analogs & derivatives MeSH
- Trimedoxime pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 2-(N-cyclohexylamino)ethanesulfonic acid MeSH Browser
- Acetylcholinesterase MeSH
- Antidotes MeSH
- asoxime chloride MeSH Browser
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Phosphorus MeSH
- Oxygen MeSH
- N,N'-monomethylenebis(pyridiniumaldoxime) MeSH Browser
- Oximes MeSH
- pralidoxime MeSH Browser
- Pralidoxime Compounds * MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators * MeSH
- Taurine MeSH
- Trimedoxime MeSH
"Novichok" refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR. This review is based on original chemical entities from Mirzayanov's memoirs published in 2008. Due to classified research, a considerable debate arose about their structures, and hence, various structural moieties were speculated. For this reason, the scientific literature is highly incomplete and, in some cases, contradictory. This review critically assesses the information published to date on this class of compounds. The scope of this work is to summarize all the available and relevant information, including the physicochemical properties, chemical synthesis, mechanism of action, toxicity, pharmacokinetics, and medical countermeasures used to date. The environmental stability of A-series agents, the lack of environmentally safe decontamination, their high toxicity, and the scarcity of information on post-contamination treatment pose a challenge for managing possible incidents.
- Keywords
- A-series agents, Analysis, Environmental stability, Physicochemical properties, Therapy, Toxicity,
- MeSH
- Drug Contamination * MeSH
- Nerve Agents * toxicity MeSH
- Organophosphorus Compounds MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Nerve Agents * MeSH
- Organophosphorus Compounds MeSH
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
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