Computational Chemistry and Toxicology of Phosphonate Esters of Alkyl Acetoacetates, an Unexplored Class of V-Agents

V-agents are exceedingly toxic oily substances, among which phosphonothiolates VX and VR have been extensively studied. Nevertheless, V-agents encompass a large family of nerve agents with diverse structures, including the phosphonate esters of alkyl acetoacetates or 2-alkoxycarbonyl-1-methylvinyl cycloalkyl methylphosphonates. These agents exist in two geometric isomers, and their properties remain largely unknown. Due to continuous concerns about chemical terrorism and safety, it is necessary to study their properties in order to develop effective countermeasures. Here, we applied computational tools to predict their ADME profile, chemical properties, and structure-related toxicity. These agents exhibited optimal drug-like properties, and it was predicted that they can penetrate the skin, acting as percutaneous hazards, and further penetrate the gastrointestinal tract and the blood–brain barrier. Certain CYP450 enzymes could differentially recognize the E- and Z-isomers, and this may explain the observation that E-isomers are significantly more toxic than their Z-counterparts. Analyses of the E- and Z-isomer stabilities also offered evidence for the reported lability of the Z-isomers. In conclusion, this study provides the first detailed in silico description of these V-agents, requiring future targeted experimental validation.