Since the use of chemical weapons in Syria in 2013 and 2017, a potential chemical threat using organophosphorus nerve Agents (OPNA) renewed the scientific interest in developing new antidotes against OPNA poisoning. In case of OPNA poisoning, on the battlefield or during a terrorist attack, conventional emergency medical treatment consists in the injection of antidotes composed of pyridinium aldoxime (pralidoxime, HI-6 or obidoxime depending on the country concerned) for reactivation of human acetylcholinesterase (hAChE) and substances countering the effects of excess acetylcholine (ACh) in the central nervous system (diazepam and atropine). Currently, the french army uses a two-compartment auto-injector containing a mixture of pralidoxime methylsulfate, atropine sulfate (blocking muscarinic receptors (mAChRs) responsible for adverse effects: e.g. bronchial hypersecretions, myosis, etc. ), and avizafone (anticonvulsant). However, the current treatment does not address the nicotinic effects responsible for the death of the person intoxicated through respiratory muscles paralysis. Based on a first “hit” developed in the frame or Multidote ANR ASTRID project ANR-17-ASTR-0012, this project aims at developing original multi-target antidotes able to reactivate hAChE, block ACh nicotinic receptors (nAChRs), thus limiting the peripheral nicotinic effects and reactivate the circulating endogenous enzyme Butyrylcholinesterase (hBChE), which will be used as a pseudo-catalytic scavenger to hydrolyze OPNA in the blood. This hit combines 3-hydroxypyridinaldoxime and a quiniclidinium, nAChR orthosteric antagonist, and presents unmatched capabilities to reactivate both esterases. It will be the starting point of this multidisciplinary project combining organic synthesis, medicinal chemistry, electrophysiology, enzymology and in vivo toxicology using the real OPNA.