Advances in the Development of Reactivators for the Treatment of Organophosphorus Inhibited Cholinesterase

Organophosphorus Compounds (OPCs) are used as pesticides to control pest, as chemical weapons in military conflict and unfortunately in the terrorist attack. These compounds are irreversible inhibitors of acetylcholinesterase, resulting in the accumulation of acetylcholine that leads to severe health complications which may be ended with the death of the victim. Current antidotes used for reactivation of organophosphorus inhibited acetylcholinesterase (OP-AChE) are not able to cross the blood-brain barrier efficiently, therefore being incapable to reactivate OP-AChE of the central nervous system. Due to limitations with current antidotes, there is an urgent need for new effective antidotes that could be included in the treatment regimen of OP poisoning. In this direction, comprehensive work has been done to improve the permeability of existing antidotes using a variety of strategies that include synthesis of oxime bonded to peripheral site binding moiety via an alkyl, aryl, or heteroatom-containing linker, synthesis of sugar oximes, and prodrug of 2-PAM, incorporating fluorine and chlorine in the structure of charged oximes. Other classes of compounds such as the mannich base, N-substituted hydroxyimino acetamide, alkylating agents, have been investigated for reactivation of OP-AChE. This review comprises the development of various classes of reactivators with the aim of either enhancing blood-brain permeability of existing antidotes or discovering a new class of reactivators.