Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase

•We design and synthesize novel uncharged bifunctional reactivators hybrids for the reactivation of phosphylated-human acetylcholinesterase.•These molecules exhibit higher reactivation characteristics in comparison to known and currently approved antidotes.•The new compounds exhibit broader reactivity spectrum as well.

A series of new uncharged functional acetylcholinesterase (AChE) reactivators including heterodimers of tetrahydroacridine with 3-hydroxy-2-pyridine aldoximes and amidoximes has been synthesized. These novel molecules display in vitro reactivation potencies towards VX-, tabun- and paraoxon-inhibited human AChE that are superior to those of the mono- and bis-pyridinium aldoximes currently used against nerve agent and pesticide poisoning. Furthermore, these uncharged compounds exhibit a broader reactivity spectrum compared to currently approved remediation drugs.

Graphical abstractBroad spectrum efficacy of uncharged hybrid reactivators: The rational design and synthesis of novel functional tacrine based reactivators heterodimers allowed to reactivate efficiently VX, tabun and paraoxon inhibited human acetylcholine esterase in vitro.Figure optionsDownload full-size imageDownload as PowerPoint slide