Imidazole as a Pendant Reactivation Ligand Increases Efficacy Scope for Reactivation and Resurrection of Organophosphorus-Inhibited/Aged Cholinesterases by Quinone Methide Precursors

TL;DR

Scientists developed new compounds that can reactivate and revive a deadly enzyme inhibitor, offering better treatment options than current methods.

Contribution

A novel strategy using Mannich phenol quinone methide precursors with pendant N-heterocyclic rings for broad-scope reactivation and resurrection of OP-inhibited/aged AChE.

Findings

Compound 5 showed efficacy against all tested OP-inhibited/aged forms of AChE.

Compounds 9 and 11 demonstrated >20% recovery for multiple OP-inhibited forms of AChE.

The new QMP therapeutics outperformed oxime controls in reactivation and resurrection.

Abstract

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 μM,
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 μM,
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.

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