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“Novichoks” is the name given to the controversial chemical weapons supposedly developed in the former Soviet Union between the 1970s and the 1990s. Designed to be undetectable and untreatable, these chemicals became the most toxic of the nerve agents, being very attractive for both terrorist and chemical warfare purposes. However, very little information is available in the literature, and the Russian government did not acknowledge their development. The intent of this review is to provide the IJMS readers with a general overview on what is known about novichoks today. We briefly tell the story of the secret development of these agents, and discuss their synthesis, toxicity, physical-chemical properties, and possible ways of treatment and neutralization. In addition, we also wish to call the attention of the scientific community to the great risks still represented by nerve agents worldwide, and the need to keep constant investments in the development of antidotes and ways to protect against such deadly compounds.

Nerve agents (NAs) are a highly toxic group of chemical warfare agents. NAs are organophosphorus esters with varying physical and chemical properties depending on the individual agent. The most recently developed class of NA is ‘ Novichok ’, the existence of which was first revealed in the early 1990s, just before Russia signed the Chemical Weapons Convention. In 1984, Iraq became the first nation to deploy NA on the battlefield when they used tabun against Iranian military forces in Majnoon Island near Basra. The first terrorist use of an NA is believed to be the attack in Matsumoto, Japan, on 27 June 1994 by the Aum Shinrikyo doomsday cult. Symptoms and ultimate toxicity from NA poisoning are related to the agent involved, the form and degree of exposure, and rapidity of medical treatment. The classic toxidrome of significant exposure to NA comprises bronchorrhoea, bronchospasm, bradycardia and convulsions, with an onset period of as early as a few seconds depending on the mode and extent of exposure. If medical management is not instituted rapidly, death may occur in minutes by asphyxiation and cardiac arrest. In the UK, emergency preparedness for NA poisoning includes an initial operational response programme across all blue light emergency services and key first responders. This paper describes the development, pathophysiology, clinical effects and current guidance for management of suspected NA poisoning. It also summarises the known events in which NA poisoning has been confirmed.

Novichok is the name given to the group of nerve agents created stealthily in the later phases of the Cold War by the Soviet Union. Constitute the fourth generation of chemical warfare agents; like other nerve agents, they are organophosphorus compounds designed to be incurable and undetectable. The mechanism of action is based on the non-competitive and irreversible inhibition of acetylcholinesterase. Due to their enormous toxicity, Novichoks have become attractive targets for terrorists. However, little information is known about the identity of nerve agents. Furthermore, these compounds have never been submitted to the Chemical Weapons Convention. Our article aspires to provide a general overview of Novichoks knowledge. As part of this, we reviewed the available literature data to answer the question, what are Novichoks? In addition to the physical and chemical properties of A-agents, synthesis, mechanism of action, and toxicity of nerve agents were also reviewed. We hope that this review will highlight the tremendous threat posed by nerve agents and will inspire further studies on the interdisciplinary aspects of these compounds. Highlights Novichoks, an extremely life-threatening nerve agents. General overview of the information on Novichoks: physical and chemical properties, mechanism of action and toxicity data. Novichoks should be treated as a separate group of chemical warfare compounds due to their hazardous properties.

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.

Nerve agents, one of the most toxic chemical warfare agents, seriously threaten human life and public security. The high toxicity of nerve agents makes the development of fluorescence sensors with suitable limit of detection challenging. Here, we propose a sensor design based on a conjugated microporous polymer film for the detection of diethyl chlorophosphate, a substitute of Sarin, with low detection limit of 2.5 ppt. This is due to the synergy of the susceptible on-off effect of hybridization and de-hybridization of hybrid local and charge transfer (HLCT) materials and the microporous structure of CMP films facilitating the inward diffusion of DCP vapors, and the extended π-conjugated structure. This strategy provides a new idea for the future development of gas sensors. In addition, a portable sensor is successfully integrated based on TCzP-CMP films that enables wireless, remote, ultrasensitive, and real-time detection of DCP vapors. The high toxicity of nerve agents makes the development of fluorescence sensors with suitable limit of detection challenging. Here, the authors propose a sensor design based on a conjugated microporous polymer film for the detection of diethyl chlorophosphate, a substitute of Sarin, with low detection limit of 2.5 ppt.

“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.

V-type nerve agents are exceedingly toxic chemical warfare agents that irreversibly inhibit acetylcholinesterase (AChE), leading to acetylcholine accumulation in synapses and the disruption of neurotransmission. VG or O.O-diethyl S-(diethylamino)ethyl phosphorothiolate was the first compound of this class that was synthesized. The selenocholines (-Se-), cholines (-O-), and methylene-cholines (-CH2-) analogs of V-agents have been synthesized and their anti-AChE activities reported. Nevertheless, the aminocholine derivatives have not been pursued. Here, we have designed and synthesized a series of phosphorylated aminocholines analogs of VG that were characterized by NMR spectroscopy (H1, C13, P31, and TOCSY). Their pharmacological properties were analyzed in silico, while their toxicological properties were in vitro investigated using the SH-SY5Y cellular model. Despite the drug likeness of the new compounds, these fail to inhibit AChE in vitro and in cellulo. This may be partially explained by the fact that aminocholine is not a good leaving group compared to thiocholine. Remarkably, one of the compounds (P4) was found to even increase the activity of AChE. These compounds may serve as new nerve agent mimics that are safer alternatives for testing countermeasures. Importantly, P4 may act as a lead compound for developing a new class of alternative nerve agent pretreatments that are safer from pyridostigmine.

The C5-C6 nerve roots are usually spared from avulsion after brachial plexus injury (BPI) and can thus be used as donors for nerve repair. A BPI rat model with C5-C6 nerve root stumps has been established in our previous work. The aim of this study was to test whether riluzole loaded into a thermosensitive hydrogel could applied locally in the nerve root stumps of this BPI rat model, thus increasing the reparative effect of the nerve root stumps. Nile red (a hydrophobic dye) was used as a substitute for riluzole since riluzole itself does not emit light. Nile red, loaded into a thermosensitive hydrogel, was added to the nerve root stumps of the BPI rat model. Additionally, eighteen rats, with operation on right brachial plexus, were evenly divided into three groups: control (Con), thermosensitive hydrogel (Gel) and thermosensitive hydrogel loaded with riluzole (Gel + Ri) groups. Direct nerve repair was performed after local riluzole release for two weeks. Functional and electrophysiological evaluations and histological assessments were used to evaluate the reparative effect 8 weeks after nerve repair. Nile red was slowly released from the thermosensitive hydrogel and retrograde transport through the nerve root stumps to the motoneurons, according to immunofluorescence. Discernible functional recovery began earlier in the Gel + Ri group. The compound muscle action potential, ChAT-expressing motoneurons, positivity for neurofilaments and S100, diameter of regenerating axons, myelin sheath thickness and density of myelinated fibers were markedly increased in the Gel + Ri group compared with the Con and Gel groups. Our results indicate that the local administration of riluzole could undergo retrograde transportation through C5-C6 nerve root stumps, thereby promoting neuroprotection and increasing nerve regeneration.

A novel two-site chemodosimeter (SWJT-4) based on fluorescein skeleton to detect diethyl chlorophosphate (DCP) was designed and synthesized. It is a turn-on fluorescent probe for DCP with good selectivity and obvious color change in aqueous solution. Interestingly, the two oxime groups of SWJT-4 as dual response sites initiated different reactions with DCP to form a cyano group and an isoxazole ring, respectively. The corresponding mechanism was confirmed by 1H NMR, MS and DFT calculation. Moreover, SWJT-4 could be used as a fluorescent test paper to detect DCP vapor.

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC50: 66.97–99.62 µM), compared to cisplatin (IC50: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer.