V-agents are exceedingly toxic organophosphate nerve agents. The most widely known V-agents are the phosphonylated thiocholines VX and VR. Nonetheless, other V-subclasses have been synthesized. Here, a holistic overview of V-agents is provided, where these compounds have been categorized based on their structures to facilitate their study. A total of seven subclasses of V-agents have been identified, including phospho(n/r)ylated selenocholines and non-sulfur-containing agents, such as VP and EA-1576 (EA: Edgewood Arsenal). Certain V-agents have been designed through the conversion of phosphorylated pesticides to their respective phosphonylated analogs, such as EA-1576 derived from mevinphos. Further, this review provides a description of their production, physical properties, toxicity, and stability during storage. Importantly, V-agents constitute a percutaneous hazard, while their high stability ensures the contamination of the exposed area for weeks. The danger of V-agents was highlighted in the 1968 VX accident in Utah. Until now, VX has been used in limited cases of terrorist attacks and assassinations, but there is an increased concern about potential terrorist production and use. For this reason, studying the chemistry of VX and other less-studied V-agents is important to understand their properties and develop potential countermeasures.

Compounds bearing the phosphorus–carbon (P–C) bond have important pharmacological, biochemical, and toxicological properties. Historically, the most notable reaction for the formation of the P–C bond is the Michaelis–Arbuzov reaction, first described in 1898. The classical Michaelis–Arbuzov reaction entails a reaction between an alkyl halide and a trialkyl phosphite to yield a dialkylalkylphosphonate. Nonetheless, deviations from the classical mechanisms and new modifications have appeared that allowed the expansion of the library of reactants and consequently the chemical space of the yielded products. These involve the use of Lewis acid catalysts, green methods, ultrasound, microwave, photochemically-assisted reactions, aryne-based reactions, etc. Here, a detailed presentation of the Michaelis–Arbuzov reaction and its developments and applications in the synthesis of biomedically important agents is provided. Certain examples of such applications include the development of alkylphosphonofluoridates as serine hydrolase inhibitors and activity-based probes, and the P–C containing antiviral and anticancer agents.

Dimethyl fumarate (DMF) is an electrophilic compound used clinically for multiple sclerosis and psoriasis. We elaborate here that the pharmacological effects of DMF extend beyond the well-known activation of the NRF2 antioxidative pathway. Indeed, DMF directly modifies reactive cysteine residues on multiple proteins in immune and neural cells, leading to diverse anti-inflammatory, immunomodulatory, and neuroprotective actions. Recent studies revealed that DMF may affect proteins involved in inflammasome activation, glycolysis, and cell signaling pathways, including JAK-STAT and NF-kB. These effects may expand the potential clinical applications of DMF in diverse pathologies, including neurodegenerative, cardiovascular, and pulmonary diseases. We summarize current findings on chemical reactivity, target proteins, and emerging clinical applications of DMF, highlighting new opportunities for DMF repurposing.

V-agents are exceedingly toxic nerve agents. Recently, it was highlighted that V-agents constitute a diverse subclass of compounds with most of them not extensively studied. Although chemical weapons have been banned under the Chemical Weapons Convention (CWC), there is an increased concern for chemical terrorism. Thus, it is important to understand their properties and toxicities, especially since some of these agents are not included in the CWC list. Nonetheless, to achieve this goal, the testing of a huge number of compounds is needed. Alternatively, in silico toxicology offers a great advantage for the rapid assessment of toxic compounds. Here, various in silico tools (TEST, VEGA, pkCSM ProTox-II) were used to estimate the acute oral toxicity (LD50) of different V-agents and compare them with experimental values. These programs underestimated the toxicity of V-agents, and certain V-agents were estimated to be relatively non-toxic. TEST was also used to estimate the physical properties and found to provide good approximations for densities, surface tensions and vapor pressures but not for viscosities. Thus, attention should be paid when interpreting and estimating the toxicities of V-agents in silico, and it is necessary to conduct future detailed experiments to understand their properties and develop effective countermeasures.