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 kobswas 0.0087min-1and the reactivation maximum of 90% was achieved within 5h. 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.
Josip Juraj Strossmayer University of Osijek, Faculty of Food Technology, Kuhačeva 20, HR-31000 Osijek, Croatia.
Valentina
V
Bušić
Institute for Medical Research and Occupational Health, Ksaverska c. 2, HR-10001 Zagreb, Croatia. Electronic address: mkatalinic@imi.hr.
Maja
M
Katalinić
Institute for Medical Research and Occupational Health, Ksaverska c. 2, HR-10001 Zagreb, Croatia.
Goran
G
Šinko
Institute for Medical Research and Occupational Health, Ksaverska c. 2, HR-10001 Zagreb, Croatia.
Zrinka
Z
Kovarik
Josip Juraj Strossmayer University of Osijek, Faculty of Food Technology, Kuhačeva 20, HR-31000 Osijek, Croatia.
Dajana
D
Gašo-Sokač
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000931:Antidotes / Q000378:metabolism / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; D011730:Pyridoxal; C028073:pyridoxaloxime; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Acetylcholinesterase; Antidotes; Butyrylcholinesterase; MMB-4; Paraoxon; Tabun; VX