A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning

Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesteraselocated in the central nervous system and neuro-muscularjunctions. One major drawback of these charged acetylcholinester-ase reactivators is their poor ability to cross the blood-brainbarrier. In this study, we propose to evaluate glucoconjugatedoximes devoid of permanent charge as potential central nervoussystem reactivators. We determined theirin vitroreactivationefficacy on inhibited human acetylcholinesterase, the crystalstructure of two compounds in complex with the enzyme, their protective index on intoxicated mice, and their pharmacokinetics.We then evaluated their endothelial permeability coefficients with a humanin vitromodel. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the glucose transporter located at the blood-brain barrier