engleski

Reactivation efficacy of new chiral N-substituted 2-hydroxyiminoacetamide reactivators of phosphylated 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, respectively. Organophosphorus (OP) nerve agents used as warfare agent in armed conflicts and terrorist attacks act as an irreversible AChE inhibitors making covalent bond between its phosphorus atom and catalytic serine oxygen atom. The current therapy in cases of OP nerve agent poisoning includes the reactivation of AChE by standard quaternary pyridinium oximes. However, due to their permanent positive charge, these compounds do not cross the blood-brain barrier and thus cannot reactivate AChE in the central nervous system. We evaluated the reactivation efficacy of novel centrally acting chiral oxime reactivators I-IV designed using computational methods of molecular modelling and prepared by introducing a phenyl ring in the structure of a previously reported N-substituted 2-hydroxyiminoacetamide scaffold. The azide group in structure of oxime I enabled us to prepare more elaborate structures of oximes II, III, and IV by the well-known copper-catalysed azide-alkyne cycloaddition. Oximes were tested in both racemic and enantiomerically pure form for reactivation of AChE and BChE inhibited with OP nerve agents tabun, sarin, cyclosarin, and VX. Oximes III and IV were efficient reactivators of AChE inhibited with sarin, cyclosarin, and VX. Oxime IV being was the most efficient reactivator in case of AChE inhibited with VX, albeit less efficient than standard oxime 2-PAM. Oximes I-IV were efficient reactivators of BChE inhibited with sarin, cyclosarin, and VX. (S)-enantiomer of oxime III proved to be a promising reactivator of BChE inhibited with cyclosarin with almost three times higher efficiency than the reference oxime 2-PAM. Molecular docking studies confirmed that the oxime group of oxime III is at proper distance from the phosphorus atom conjugated to the catalytic serine residue of BChE which allows nucleophilic substitution of conjugated cyclosarin, but only after rotation around CH–NH bond or distinctive conformational change of the cyclosarin-BChE conjugate.

chiral oxime reactivators ; OP nerve agents ; Acetylcholinesterase ; Butyrylcholinesterase

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