Organophosphate pesticides and chemical warfare are responsible for poisoning that pose to health security issues. The research of therapeutic solutions to overcome the lack of effective means to counter these poisonings is essential. Acetylcholinesterase (AChE), the enzyme involved in the regulation of nerve impulses, is the main target. ln this thesis, we have, first, set up a strategy for designing molecules that can reactivate aged cholinesterases. To this purpose, severa! dozen molecules have been designed and synthesized. Evaluation in silico by molecular docking and in vitro by rneasuring affinity for the enzyme and crystallographic study did not observe the desired realkylation. But this work opened new perspectives.Secondly, our crystallographic work on the inhibition of human butyrylcholinesterase by V-agents and sarin shows that cholinesterase has altered enantioselectivity for these chiral inhibitors of human AChE. This implies that larger amounts of enzyme are required for the desired protection and thus, a significant additional cost. Human AChE seems finally a more suitable neurotoxic bioscavenger.
