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.
        
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Zhuang Q, Franjesevic AJ, Corrigan TS, Coldren WH, Dicken R, Sillart S, DeYong A, Yoshino N, Smith J, Fabry S, Fitzpatrick K, Blanton TG, Joseph J, Yoder RJ, McElroy CA, Ekici OD, Callam CS, Hadad CM (2018) Demonstration of In Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents Journal of Medicinal Chemistry61: 7034-7042
Zhuang Q, Franjesevic AJ, Corrigan TS, Coldren WH, Dicken R, Sillart S, DeYong A, Yoshino N, Smith J, Fabry S, Fitzpatrick K, Blanton TG, Joseph J, Yoder RJ, McElroy CA, Ekici OD, Callam CS, Hadad CM (2018) Journal of Medicinal Chemistry61: 7034-7042