Title
Discovery of a potent non-oxime reactivator of nerve agent inhibited human acetylcholinesterase
Author
de Koning, M.C.
Horn, G.
van Grol, M.
Publication year
2018
Abstract
Organophosphorous (OP) compounds (such as nerve agents) inhibit the enzyme acetylcholinesterase (AChE) by covalent phosphylation of a key serine residue in the active site of the enzyme resulting in severe symptoms and ultimately death. OP intoxications are currently treated by administration of certain oxime compounds. The presently fielded oximes reactivate OP-inhibited AChE by liberating the phosphylated serine. Recent research towards new reactivators was predominantly devoted to design, synthesis and evaluation of new oxime-based compounds dedicated to overcoming some of the major limitations such as their intrinsic toxicity, their permanent charge which thwarts penetration of brain tissues and their inability to effectively reactivate all types of nerve agent inhibited AChEs. However, in over six decades of research only limited success has been achieved, indicating that there is a need for alternative classes of compounds that could reactivate OP-inhibited AChE. Recently, a number of nonoxime compounds was discovered in which the 4-amino-2-((diethylamino)methyl)phenol (ADOC) motif proved to be able to reactivate OP-inhibited AChE to some extent. In this paper several structural derivatives of ADOC were synthesized and screened for their ability to reactivate human AChE (hAChE) inhibited by the nerve agents VX, sarin, tabun, cyclosarin and paraoxon. We here disclose that one of those compounds showed a remarkable ability to reactivate OP-inhibited hAChE in vitro and that it is the most potent non-oxime reported to date.
Subject
Observation, Weapon & Protection Systems
CBRN - CBRN Protection
Chemistry
Acetylcholinesterase
Nerve agents
Chemical warfare agent
Reactivator
Non-oxime
To reference this document use:
http://resolver.tudelft.nl/uuid:a7bb38dd-a229-4a94-bd27-5ab709d406ee
TNO identifier
818453
Source
European Journal of Medicinal Chemistry, 157, 151-160
Document type
conference paper