Aminoalkoxy-substituted coumarins: Synthesis and evaluation for reactivation of inhibited human acetylcholinesterase

Reactivation of inhibited acetylcholinesterase remains an important therapeutic strategy for the treatment of poisoning by organophosphorus compounds, such as nerve agents or pesticides. Although drugs like obidoxime or pralidoxime have been used with considerable success, there is a need for new substances capable of reactivating acetylcholinesterase with a broader scope and increased efficacy. Possible screening candidates must fulfill two fundamental requirements: They must (i) show an affinity to acetylcholinesterase well balanced between sufficient binding and competitive inhibition and (ii) facilitate the nucleophilic cleavage of the phosphorylated catalytic serine residue. We attached a variety of nonaromatic primary and secondary amines to a coumarin core through selected alkoxy side linkers attached at coumarin positions 6 or 7 to obtain a small set of possible reactivators. Evaluation of their inhibition and reactivation potential in vitro showed some activity with respect to acetylcholinesterase inhibited by cyclosarin.

Automated summary

Reactivation of acetylcholinesterase is important for the treatment of organophosphorus compound poisoning. This study successfully identified a small set of possible reactivators by attaching different nonaromatic amines to a coumarin core and evaluating their potential for inhibiting and reactivating cyclosarin-inhibited acetylcholinesterase in vitro.