Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents

Acetylcholinesterase
(AChE), a key enzyme in the central and peripheral
nervous systems, is the principal target of organophosphorus nerve
agents. Quaternary oximes can regenerate AChE activity by displacing
the phosphyl group of the nerve agent from the active site, but they
are poorly distributed in the central nervous system. A promising
reactivator based on tetrahydroacridine linked to a nonquaternary
oxime is also an undesired submicromolar reversible inhibitor of AChE.
X-ray structures and molecular docking indicate that structural modification
of the tetrahydroacridine might decrease inhibition without affecting
reactivation. The chlorinated derivative was synthesized and, in line
with the prediction, displayed a 10-fold decrease in inhibition but
no significant decrease in reactivation efficiency. X-ray structures
with the derivative rationalize this outcome. We thus show that rational
design based on structural studies permits the refinement of new-generation
pyridine aldoxime reactivators that may be more effective in the treatment
of nerve agent intoxication.