Synthesis and biophysical evaluation of arylhydrazono-1H-2-indolinones as β-amyloid aggregation inhibitors

Abstract

A series of isatin-3-arylhydrazones were synthesized and evaluated in vitro as inhibitors of Aβ(1-40) aggregation using a thioflavin T fluorescence method. An exploration of the effects on Aβ(1-40) aggregation of a number of diverse substituents at phenylhydrazone group and 5,6- positions of the indolinone nucleus led us to single out some new anti-aggregating compounds with IC(50) values in the low micromolar range. The most active compounds carry methoxy- or hydroxy- substituents in the indolinone 5,6-positions and lipophilic groups such as iPr and Cl at 4'- and 3'-position, respectively, of the phenylhydrazone moiety. Two derivatives are noteworthy, namely 18 (IC(50) = 0.4 μM) and 42 (IC(50) = 1.1 μM). The in vitro effects of the highly active, water soluble, compound 42 on the temporal evolution of Aβ(1-40) fibrils formation were further investigated by circular dichroism spectroscopy, transmission electron microscopy and dynamic light scattering studies, which clearly showed that this compound delayed and lowered the amyloid fibril formation.