Dynamic Deconvolution of a Pre-Equilibrated Dynamic Combinatorial Library of Acetylcholinesterase Inhibitors

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Abstract
A dynamic combinatorial library composed of interconverting acylhydrazones has been generated and screened towards inhibition of acetylcholinesterase from the electric ray Torpedo marmorata. Starting from a small set (13) of initial hydrazide and aldehyde building blocks, a library containing possibly 66 different species was obtained in a single operation. Of all possible acylhydrazones formed, active compounds containing two terminal cationic recognition groups separated by an appropriate distance, permitting two-site binding, could be rapidly identified by using a dynamic deconvolution–screening procedure, based on the sequential removal of starting building blocks. A very potent bis-pyridinium inhibitor (Ki=1.09 nM, αKi=2.80 nM) was selected from the process and the contribution of various structural features to inhibitory potency was evaluated.