Synthesis\nand Evaluation of Halogenated Pralidoximes\nin Reactivation of Organophosphate-Inhibited Cholinesterases

Organophosphorus compounds are highly toxic irreversible\ninhibitors\nof cholinesterases, causing the disruption of cholinergic functions.\nTreatment of poisoning includes causal antidotes (oximes) used as\nreactivators of inhibited cholinesterases, such as pralidoxime. In\nthis work, new halogenated oxime reactivators derived from pralidoxime\nwere developed. The oximes were designed with a halogen substituent\nthat lowers the p<i>K</i><sub>a</sub> and enhances oximate\nformation. Their synthesis, stability, physicochemical properties,\ninhibition of native cholinesterases, and <i>in vitro</i> reactivation of organophosphate-inhibited cholinesterases were investigated.\nA series of C4 and C6 halogenated oximes showed instability and their\ndegradation products were identified, while C3 and C5 oximes exhibited\nsufficient stability for the evaluation. C3 oximes displayed overall\nlow inhibition of cholinesterases and high reactivation ability of\norganophosphate-inhibited cholinesterases compared to pralidoxime,\nindicating the significant impact of halogen substitution on reactivation\nability.