engleski

Potent lipophilic 3-hydroxy-2-pyridinium aldoxime reactivators of phosphorylated cholinesterases

Organophosphate compounds (OPs) poisoning can occur due to exposure to OP pesticides (e.g., parathion) or nerve agents (e.g., sarin, cyclosarin, VX, tabun). OPs irreversibly inhibit acetylcholinesterase (AChE) causing the accumulation of acetylcholine in synapses and cholinergic crisis, which can lead to respiratory arrest and death or result in long- term neurological impairments in survivors. Reactivation of OP-inhibited AChE is one of the possible therapy approaches, but standard oxime reactivators (2- PAM, HI-6, obidoxime) are not potent enough for every OP and achieve low brain concentrations due to a permanent charge (quaternary nitrogen). New class of oximes, 3- hydroxy-2-pyridine aldoximes, without permanent charge have been synthesized and tested in detail. They were proven to be potent reactivators of AChE inhibited by VX, sarin, cyclosarin, tabun, and paraoxon with the affinity of AChE in the micromolar range. Moreover, molecular docking studies predicted optimal orientation of the oximes in the active site of OP-inhibited AChE. Furthermore, these oximes were proven to be lipophilic and by analysing various physicochemical properties that describe their size, charge, lipophilicity, and polarity we predicted their penetration through the blood-brain barrier (BBB). The permeability of these oximes across the membrane was confirmed in vitro using an artificial membrane that mimics the BBB. In addition, most of the oximes were shown to be metabolically stable when incubated with human microsomes and were not cytotoxic for neuroblastoma and astrocytoma cell lines. Finally, the lead oxime crossed the BBB in vivo in mice after intramuscular application proving its potential to be used as a centrally active antidote.

AChE, CNS, molecular docking, nerve agents, oximes, synthesis

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