|This compound was developed using structure-based optimization, as an antidote for acetylcholinesterase (AChE) inhibition by organophosphorus nerve agents . The mechanism of enzyme reactivation depends on antidote-induced displacement of the phosphyl group from AChE's active-site serine. The main goal of the optimization campaign was to design an AChE reactivator with improved efficacy and brain penetrance compared to existing antidotes. In in vitro AChE reactivation assays, reactivator 2 outperformed the reference reactivators 2-PAM, HI-6, and obidoxime for AChE inhibited by various organophosphate nerve agents (VX, a sarin surrogate, tabun and ethyl papaoxon). Kinetic measurements and structural studies have confirmed the potential efficacy of reactivator 2 but it has not yet been evaluated in vivo.