engleski

Enantioseparation of N substituted 2-hydroxyiminoacetamides and interactions with cholinesterases

Acetylcholinesterase (AChE ; EC 3.1.1.7) and butyrylcholinesterase (BChE ; EC 3.1.1.8) play an important role in the neurotransmission and biotransformation of xenobiotics. Reversible AChE inhibitors are being used in the medical treatment of . Also, organophosphorus (OP) nerve agents acting as an irreversible AChE inhibitors are a persistent threat to the general population because of their use as warfare agents in armed conflicts and terrorist attacks. The current therapy in cases of OP nerve agent poisoning includes the reactivation of AChE by quaternary pyridinium oximes. Cholinesterases (ChEs) are also known for displaying stereoselectivity toward reversible inhibitors and OP nerve agents. Therefore, we have designed and synthesized four chiral N-substituted 2-hydroxyiminoacetamides in racemic form with an aim to develop new reactivators of OP nerve agent-inhibited ChE. N-substituted 2-hydroxyiminoacetamides were prepared from previously reported 1-phenyl-allylamine. The presumed peripheral site-binding moiety ranged from an azide group to functionalized heterocycles connected with central N-(1-phenylpropyl)-2-hydroxyiminoacetamide scaffold via a 1, 2, 3-triazole ring. All racemic N-substituted 2-hydroxyiminoacetamides reversibly inhibited cholinesterases with clear preference for binding to BChE and reversible inhibition constants ranging from 45 245 micromol/L for AChE and from 0.3 to 115 micromol/L for BChE. To study the stereoselectivity of cholinesterases, we separated the enantiomers of N-substituted 2-hydroxyiminoacetamides using chiral HPLC with very good to excellent enantiomeric excess (88 % to 99 %). The absolute configuration of the enantiomers was determined by comparing their retention times with N-substituted 2-hydroxyiminoacetamides prepared from (S)-1-phenyl-allylamine. The enzymatic resolution of the racemic 1-phenyl-allylamine was performed using lipase B from C. antarctica (CaLB). This work was supported in part by the Croatian Science Foundation (project 4307).

reversible inhibition; acetylcholinesterase; reactivation; nerve agents

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