Discovery of a potent non-oxime reactivator of nerve agent inhibited human acetylcholinesterase

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

“…[160] pletely recovered the activity of the enzyme up to the level of the positive controla nd the other two reached 60-70%.T hese results are in good agreement with an umber of studies which found that Mannich bases are reactivators of OP-inhibited AChE. [91,113,114,116] While the kinetic assays confirmed recovery of the native enzyme,b ottom-up proteomics were conducted to try and isolate the enzyme in the native, inhibited (re-alkylated), and aged states. As olution of the lead compound 103 wasi ncubated with aged eeAChE for 11 days beforeb eing digested with trypsin.…”

“…The interest in reactivators with aM annich phenol base continued as de Koning et al expanded on the work conducted by Cerasoli and co-workersi ns ynthesizing additional derivatives of ADOC and then did testing with human erythrocyte AChE. [114,116] At otal of 14 derivatives of ADOC were synthesized, with focus on variations in the amine leaving group. IC 50 values were determined for all compounds ands howed that simple modifications can have great effects.…”

“…Morereactive Mannich base for the reac-tivationofA ChE. [116] are critical, and different resultscan be obtained based on conditions including:A ChE sources,i np articular human compared to non-human, and the chosen experimental conditions including time of reactivation, buffer choice, pH, temperature, concentration, dilution, and calculation method. [35,99,107,119] These experimental parameters are only those associated with in vitro experiments and the issues become even more widespread when movingt oi nv ivo models.…”

“…Twop romising families of compounds have been most notable,i ncludingt hose with ap endant base attached to an aryl anchora nd then Mannich bases. [91,113,114,116,160] While all of these compounds were discovered independently,the structuralfeatures continuetobesimilar.W hat is conserved between both types of compounds is the basic nitrogen attached to an aromaticc ore;f or the Mannich bases, ortho substitution relative to ap henol is the most effective. Continued efforts are needed to better understand the mechanism of action for these particular types of molecules to aid in future drug design,w hether those efforts are computational and crystallographic studies or structure-activity relationships.…”

The Role of the Phosphorus Atom in Drug Design

“…In fact, much effort has been made at finding ways to restoret he activity of AChE. [150,153,154] The proposed mechanism of enzyme inhibition and enzyme reactivation is summarized in Scheme 9.…”