title: Dynamic deconvolution of a pre-equilibrated dynamic combinatorial library of acetylcholinesterase inhibitors.
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 (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.
authors.affiliation: Laboratoire de Chimie Supramoléculaire, CNRS UPRES A 7006, ISIS - Université Louis Pasteur, 4 rue Blaise Pascal, 67000 Strasbourg, France.
authors.forename: T
authors.initials: T
authors.lastname: Bunyapaiboonsri
authors.forename: O
authors.initials: O
authors.lastname: Ramström
authors.forename: S
authors.initials: S
authors.lastname: Lohmann
authors.forename: J M
authors.initials: JM
authors.lastname: Lehn
authors.forename: L
authors.initials: L
authors.lastname: Peng
authors.forename: M
authors.initials: M
authors.lastname: Goeldner
mesh_terms: 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
chemical_list: D002800:Cholinesterase Inhibitors; D006835:Hydrazones; D000110:Acetylcholinesterase