The acute toxicity of OPNA (organophosphorus nerve agent) results from irreversible inhibition of AChE, a key enzyme in neurotransmission, via the formation of a covalent P-O bond at the catalytic serine. Inhibition of AChE leads to the accumulation of acetylcholine neurotransmitter (ACh) in the synaptic cleft causing among other symptoms, seizures and respiratory arrest leading to death. Only strong nucleophiles (typically oximes) are able to reactivate the phosphylated-enzyme. The current urgency treatment of OPNA poisoning is based on the administration of a cocktail of three components: an antimuscarinic agent (e.g. atropine), an anticonvulsant drug (e.g. diazepam), and mono or bispyridinium AChE reactivator (e.g. pralidoxime, obidoxime, trimedoxime), which have no broad spectrum reactivation against the different OP and poorly cross the Blood Brain Barrier (BBB) to reactivate phosphylated central AChE. After 50 years of research, there is no broad spectrum reactivator and the development of medical countermeasure against both acute and chronic intoxications by organophosphorus (OP) nerve agents continues to be a challenge. The aim of this project is to find new and more efficient reactivators are composed of an AChE peripheral site binder (e.g. tetrahydroisoquinoline, donepezil-inspired, coumarine, indole, morpholine, ...) linked to an oxime through a linker. They display in vitro reactivation potencies towards VX-, tabun- and paraoxon- inhibited human AChE that are superior to those of the mono- and bis-pyridinium aldoximes (e.g. 2-PAM, HI-6, obidoxime, HLo-7, TMB-4) used in the armed forces, with the potential to cross the BBB.