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Pyridoxal oxime derivative potency to reactivate cholinesterases inhibited by organophosphorus compounds (CROSBI ID 231946)

Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija

Bušić, Valentina ; Katalinić, Maja ; Šinko, Goran ; Kovarik, Zrinka ; Gašo-Sokač, Dajana Pyridoxal oxime derivative potency to reactivate cholinesterases inhibited by organophosphorus compounds // Toxicology letters, 262 (2016), 114-122. doi: 10.1016/j.toxlet.2016.09.015

Podaci o odgovornosti

Bušić, Valentina ; Katalinić, Maja ; Šinko, Goran ; Kovarik, Zrinka ; Gašo-Sokač, Dajana

engleski

Pyridoxal oxime derivative potency to reactivate cholinesterases inhibited by organophosphorus compounds

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 kobs was 0.0087 min1 and the reactivation maximum of 90% was achieved within 5 h. The cholinesterases displayed a binding affinity for these derivatives in a mmolar 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.

Acetylcholinesterase ; Butyrylcholinesterase ; Antidotes ; MMB-4 ; VX ; Tabun ; Paraoxon

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Podaci o izdanju

262

2016.

114-122

objavljeno

0378-4274

1879-3169

10.1016/j.toxlet.2016.09.015

Povezanost rada

Biotehnologija, Farmacija, Kemija

Poveznice
Indeksiranost