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

Bioorg Med Chem Lett. 2008 Mar 1;18(5):1628-31. doi: 10.1016/j.bmcl.2008.01.066. Epub 2008 Jan 19.

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 Abeta42 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 Abeta fibrils.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Aniline Compounds
  • Benzothiazoles / chemistry
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology*
  • Indoprofen / chemistry
  • Isoindoles / chemistry*
  • Isoindoles / pharmacology*
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship
  • Thiazoles

Substances

  • 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
  • Amyloid beta-Peptides
  • Aniline Compounds
  • Benzothiazoles
  • Heterocyclic Compounds
  • Isoindol-1-one
  • Isoindoles
  • Thiazoles
  • Indoprofen