Design, synthesis and biological activity of novel sulfonatocalix[4]arene-based organophosphorus toxicant scavengers

Chemical scavengers based on macrocyclic compounds have made remarkable progress in combating organophosphate toxicants. However, their structural diversity, structure-activity relationships and in vivo therapeutic effects still need further clarification. Here, 9 sulfonatocalix[4]arene derivatives were designed, synthesized and biologically evaluated using in vitro enzymatic assays. Through systematic structure-activity relationships optimization, compounds 1b, 1f and 1g exhibited particularly remarkable scavenging activities against organophosphate toxicants, with detoxification half-lives of 2.9 min, 4.6 min and 4.1 min, respectively. In vitro studies revealed their cytoprotective effects via reducing intracellular reactive oxygen species, alleviating lipid peroxidation and inhibiting proinflammatory cytokine release. In organophosphate-intoxicated mouse models, these compounds improved survival rates, mitigated seizure severity and reduced multi-organ injury. Notably, compound 1f stood out with the most outstanding performance, emerging as a promising lead compound for the development of novel therapies against organophosphate poisoning.