Demonstration of In Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents

Journal of Medicinal Chemistry
2018.0

Abstract

After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE.

Knowledge Graph

Similar Paper

Demonstration of In Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents
Journal of Medicinal Chemistry 2018.0
Synthesis and anti-acetylcholinesterase properties of novel β- and γ-substituted alkoxy organophosphonates
Bioorganic & Medicinal Chemistry Letters 2013.0
Pyridinium Oximes withOrtho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents
Journal of Medicinal Chemistry 2018.0
Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase
European Journal of Medicinal Chemistry 2014.0
Dual acting oximes designed for therapeutic decontamination of reactive organophosphates via catalytic inactivation and acetylcholinesterase reactivation
RSC Medicinal Chemistry 2021.0
NMR determination of Electrophorus electricus acetylcholinesterase inhibition and reactivation by neutral oximes
Bioorganic & Medicinal Chemistry 2013.0
Stereospecific cholinesterase inhibition by O , S -diethylphenylphosphonothioate
Bioorganic & Medicinal Chemistry 2017.0
Sulfur derivatives of 2-oxopropanal oxime as reactivators of organophosphate-inhibited acetylcholinesterase in vitro: synthesis and structure-reactivity relationships
Journal of Medicinal Chemistry 1988.0
Application of the Ugi Multicomponent Reaction in the Synthesis of Reactivators of Nerve Agent Inhibited Acetylcholinesterase
Journal of Medicinal Chemistry 2017.0
Fluorinated pyridinium oximes as potential reactivators for acetylcholinesterases inhibited by paraoxon organophosphorus agent
Bioorganic & Medicinal Chemistry 2009.0