Pyridoxal oxime derivative potency to reactivate cholinesterases inhibited by organophosphorus compounds. (16th November 2016)

• Record Type: Journal Article
• Authors: Bušić, Valentina; Katalinić, Maja; Šinko, Goran; Kovarik, Zrinka; Gašo-Sokač, Dajana
• Is Part Of: Toxicology letters. Volume 262(2016)
• Page Start: 114
• Page End: 122
• Publication Date: 2016-11-16
• Subjects: Acetylcholinesterase -- Butyrylcholinesterase -- Antidotes -- MMB-4 -- VX -- Tabun -- Paraoxon; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2016.09.015
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Pyridoxal oximes as reactivators of inhibited hAChE and hBChE show a similar binding pattern within the enzymes creating interactions close to the targeted active site serine. Highlights: Nine pyridoxal oximes were tested as reactivators of inhibited ChEs. Tested oximes were more efficient in the reactivation of inhibited BChE than AChE. Substituents at the vicinity of the oxime moiety presented a steric hindrance for reactivation. A positive correlation between affinity for an oxime and its reactivation efficacy was not observed. Abstract: Organophosphorus (OP) nerve agents (sarin, tabun VX and soman) inhibit the enzyme acetylcholinesterase (AChE, EC 3.1.1.7) by binding to its active site while preventing neurotransmission in the cholinergic synapses. The protection and treatment of this kind of poisoning are still a challenge as we are yet to discover an antidote that would be effective in all cases of poisoning. To aid the search for more efficient antidotes, we evaluated the ability of nine pyridoxal oxime derivatives, prepared by a novel synthetic pathway, to reactivate recombinant human AChE and the related purified human plasma butyrylcholinesterase (BChE, EC 3.1.1.8) inhibited by VX, tabun and paraoxon. Oximes are derivatives of vitamin B6 bearing a phenacyl moiety attached to the quaternary nitrogen atom and having various substituents on the phenyl ring. As the results have shown, the tested oximes were in general more efficient in the reactivation of OP-inhibited BChE than AChE. The highest observed rate was in the case of VX-inhibited BChE reactivation, where k obs was 0.0087 min −1 and the reactivation maximum of 90% was achieved within 5 h. The cholinesterases displayed a binding affinity for these derivatives in a μmolar range no matter the substituent on their rings which was in accordance with the molecular modelling results showing a similar binding pattern for all oximes within the active site of both AChE and BChE. Such a positioning reveals also that hydroxy and a metoxy substituents at the vicinity of the oxime moiety present a possible steric hindrance explaining the reactivation results.