“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.

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.

Chlormequat is a quaternary ammonium salt used as a plant growth-regulating agent. It is structurally similar to choline, acting at muscarinic and nicotinic receptors. Herein, we present the case of suicidal poisoning with an unknown dose of chlormequat by a 45-year-old woman. Initially, carbofuran was suspected of ingestion. Following ingestion, circulatory arrest occurred. After hospital admission, gastric lavage was performed, and activated charcoal was administered. Initial toxicological analysis identified mild alcohol intoxication, while high-resolution mass spectrometry later discovered a high concentration of chlormequat in the blood and urine. Continuous hemodialysis was indicated to accelerate chlormequat elimination. Antioxidant and Cytosorb therapy were applied to reduce oxidative stress and inflammation. Laboratory results further showed that chlormequat is a mild acetylcholinesterase inhibitor, revealing an additional mechanism of toxicity. However, despite all initial efforts, deep coma persisted with clinical signs of areflexia above C1 and malignant brain edema described on the CT scan. The patient died on day 3 of the ICU stay in palliative care. The authors present complete laboratory and toxicological results, including toxicokinetic data, oxidative stress parameters, acetylcholinesterase, and butyrylcholinesterase activity. In conclusion, modern analytical methods are necessary to provide more effective targeted treatment and could help uncover previously unknown mechanisms of toxicity.

The primary toxicological mechanism of organophosphorus compounds (OPCs) is the irreversible inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine and subsequent cholinergic crisis, which can result in fatal respiratory failure. Conventional oxime reactivators, such as pralidoxime and obidoxime, are limited by their inability to permeate the blood-brain barrier (BBB) and inconsistent efficacy across different OPC types. To address these limitations, we designed a novel nonquaternary oxime reactivator codenamed K1396, with enhanced lipophilicity for improved BBB penetration and dual-binding capability at both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. This study compares the in vitro reactivation potency, cytotoxicity, and BBB penetration potential of K1396 with standard oximes. K1396 demonstrated comparable or superior reactivation potency, particularly against VX-inhibited AChE, and showed lower cytotoxicity in specific cell lines. Furthermore, K1396 exhibited favorable permeability across the lipid layer, suggesting potential CNS availability. The findings support the therapeutic potential of K1396 as an effective and broad-spectrum reactivator for OPC poisoning.