Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to beta-amyloid fibrils

Abstract

Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-1 were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated A beta 42 fibrils using [I-125]TZDM. All the isoindolone derivatives showed very good binding affinities with K-i values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (K-i = 0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (K-i = 0.52 nM) and PIB (K-i = 0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor A beta fibrils. (c) 2008 Elsevier Ltd. All rights reserved.