Design, synthesis and biological evaluation of indane-2-arylhydrazinylmethylene-1,3-diones and indol-2-aryldiazenylmethylene-3-ones as beta-amyloid aggregation inhibitors.

Biological screening of (hetero)aromatic compounds allowed the identification of some novel inhibitors of Abeta(1-40) aggregation, bearing indane and indole rings as common scaffolds. Molecular decoration of lead compounds led to inhibitors exhibiting a potency, measured by the Thioflavin T fluorimetric assay, ranging from high to low micromolar IC(50). The 2-(p-isopropylphenyldiazenylmethylene)indolone derivative 6c resulted as the most potent aggregation inhibitor exhibiting an IC(50) of 1.4 muM, with complete lack of fibril formation as confirmed by transmission electron microscopy. Structure-activity relationships suggested that binding to the Abeta peptide may be largely guided by pi-stacking and hydrogen bond interactions. Copyright (c) 2009 Elsevier Masson SAS. All rights reserved.