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

Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a–k and isoindol-1-ones 2a–l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Aβ42 fibrils using [125I]TZDM. All the isoindolone derivatives showed very good binding affinities with Ki 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 (Ki = 0.42–0.44 and 0.46–0.49 nM) than those of Indoprofen (Ki = 0.52 nM) and PIB (Ki = 0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Aβ fibrils.