Dynamic deconvolution of a pre-equilibrated dynamic combinatorial library of acetylcholinesterase inhibitors.
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 (K(i)=1.09 nM, alphaK(i)=2.80 nM) was selected from the process and the contribution of various structural features to inhibitory potency was evaluated.
Bunyapaiboonsri
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Laboratoire de Chimie Supramoléculaire, CNRS UPRES A 7006, ISIS - Université Louis Pasteur, 4 rue Blaise Pascal, 67000 Strasbourg, France.
Ramström
O
O
Lohmann
S
S
Lehn
J M
JM
Peng
L
L
Goeldner
M
M
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D006835:Hydrazones / Q000737:chemistry; D015394:Molecular Structure; D014101:Torpedo / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D006835:Hydrazones; D000110:Acetylcholinesterase