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Organophosphorus compounds (organophosphates and organophosphonates) exert their toxicity by phosphylating (i.e. either phosphorylating or phosphonylating) the serine hydroxyl group of the enzyme acetylcholinesterase (AChE) in its active center, thereby inhibiting this enzyme, which inactivates the neurotransmitter acetylcholine (ACh). This results in an accumulation of ACh and an “endogenous ACh poisoning”. Oximes, which can reactivate the inhibited enzyme by dephosphylation, are used in the therapy of organophosphorus compound poisoning. During the reactivation process, oximes become themselves phosphylated. Many of these phosphylated oximes are extremely potent AChE inhibitors, which may reduce their therapeutic efficacy. K-27 is a very promising experimental oxime. In the present study, logP values of phosphylated K-27 are estimated after “in-silico exposure” to a number of organophosphorus esters [ethyl-paraoxon, methylparaoxon, diisopropyl-fluoro-phosphate, VX, soman, tabun, sarin, cyclosarin]. These logP values are compared with those of the native oxime and possible therapeutic relevance is discussed. While our previously published data regarding obidoxime and pralidoxime show that phosphylation increases their lipophilicity, facilitating penetration into the brain where they can inhibit or re-inhibit enzymes, this conclusion does not hold with respect to K-27; phosphylation of K-27 does not generally increase lipophilicity. Possible consequences with regard to blood-brain-barrier passage, toxicity and therapeutic efficacy are discussed.

K-OXIME (K-27): PHOSPHYLATION-INDUCED CHANGES IN LOGP