Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to β-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 – l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Aβ42 fibrils using [ 125 I]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 Aβ fibrils.