Identification and characterization of diarylimidazoles as hybrid inhibitors of butyrylcholinesterase and amyloid beta fibril formation

In this contribution, a chemical collection of aromatic compounds was screened for inhibition on butyrylcholinesterase (BChE)'s hydrolase activity using Ellman's reaction. A set of diarylimidazoles was identified as highly selective inhibitors of BChE hydrolase activity and amyloid beta (A beta) fibril formation. New derivatives were synthesized resulting in several additional hits, from which the most active was 6c, 4-(3-ethylthiophenyl)-2-(3-thieny1)-1H-imidazole, an uncompetitive inhibitor of BChE hydrolase activity (IC50 BChE = 0.10 mu M; K-i = 0.073 +/- 0.011 mu M) acting also on Ap fibril formation (IC50 = 5.8 mu M). With the aid of structure-activity relationship (SAR) studies, chemical motifs influencing the BChE inhibitory activity of these imidazoles were proposed. These bifunctional inhibitors represent good tools in basic studies of BChE and/or promising lead molecules for AD therapy. (C) 2011 Elsevier B.V. All rights reserved.