Lovins_2026_ACS.Chem.Neurosci__

Organophosphorus (OP) inhibition of acetylcholinesterase (AChE) continues to pose a deadly risk to human health. Despite decades of research on oximes, improved therapeutics are still needed as most oximes fail to cross the blood-brain barrier, none exhibit efficacy against the OP-aged form of AChE, and reactivation by oximes results in a toxic byproduct. However, despite efforts to replace oxime therapeutics, many of the new candidates fall short in broad-scope activity or sufficient efficacy relative to the oxime therapeutics. Previously, researchers have used imidazole or Mannich phenol moieties as a basic therapeutic handle for reactivation of OP-inhibited forms of AChE. Herein, we report a novel strategy of utilizing Mannich phenol quinone methide precursors (QMPs), which are capable of reactivation and resurrection of OP-inhibited and OP-aged AChE, linked to a pendant N-heterocyclic ring reactivator moiety we hypothesize to act in both the mechanism for reactivation of OP-inhibited AChE and resurrection of OP-aged AChE. We tested our hypothesis via the synthesis and in vitro evaluation of 24 novel QMP therapeutics across 20 frameworks containing various N-heterocyclic ring linkages. These QMP therapeutics were tested against eight OP-inhibited forms of AChE, seven OP-inhibited forms of BChE, and four OP-aged forms of AChE to determine broad-scope efficacy. We identify 5 as an impressive lead therapeutic with efficacy against all tested OP-inhibited/aged forms of AChE alongside 3, 9 and 11 as lead reactivators due to their impressive efficacy against all OP-inhibited forms of AChE. For reactivation against the tested OP compounds (250 microM, 1 h), 5 and 9 demonstrate >20% recovery of six of the eight OP-inhibited forms of AChE while 11 demonstrates >20% recovery of seven of the eight OP-inhibited forms of AChE. For resurrection against the tested OP compounds (250 microM, 24 h), 5 demonstrates >20% recovery of two of the four OP-aged forms of AChE. Indeed, 5, 9, and 11 demonstrate superior efficacy to the oxime controls.