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.

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. All the isoindolone derivatives showed very good binding affinities with Ki values in the subnanomolar range (0.42–0.94 nM) against aggregated Aβ42 fibrils. Among them, several compounds exhibited excellent binding affinities (Ki = 0.42–0.49 nM) than those of Indoprofen (Ki = 0.52 nM) and PIB (Ki = 0.70 nM).Figure optionsDownload as PowerPoint slide