Mono- and bis-pyridinium aldoximes are the only causal antidotes that are designated for the treatment of organophosphate (OP) poisoning. Intoxication by OPs is caused either by pesticides or by the nerve agents, the latter belong to group of chemical warfare agents. These compounds irreversibly inhibit enzyme acetylcholinesterase (AChE) that is no more able to fulfill its physiological function. Mono- and bis-pyridinium aldoximes are able to restore catalytic function of AChE. The reactivating ability of aldoximes is limited by several drawbacks like low blood-brain barrier permeation, low reactivation potency against specific nerve agents etc. In order to obtain efficient treatment of OP, the introduction of novel AChE reactivators raised as an important issue. For over 60 years of intensive research, none of the reactivators reached sufficient activity. Herein, we present novel mono quaternary reactivators that possess excellent in vitro activity to restore AChE activity after intoxication with different nerve agents as well as pesticides. The molecular docking simulations, total synthesis and biological evaluation will be discussed.