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 Aβ1–40 aggregation using a thioflavin T fluorescence method. An exploration of the effects on Aβ1–40 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 IC50 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 (IC50 = 0.4 μM) and 42 (IC50 = 1.1 μM). The in vitro effects of the highly active, water soluble, compound 42 on the temporal evolution of Aβ1–40 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.