Synthesis and Biophysical Evaluation of ARYLHYDRAZONO-1H-2-INDOLINONES as B-AMYLOID Aggregation Inhibitors

A series of isatin-3-arylhydrazones were synthesized and evaluated in vitro as inhibitors of Ab1-40 aggregation using a thioflavin T fluorescence method. An exploration of the effects on Ab1-40 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 40- and 30-position, respectively, of the phenylhydrazone moiety. Two derivatives are noteworthy, namely 18 (IC50 = 0.4 mM) and 42 (IC50 = 1.1 mM). The in vitro effects of the highly active, water soluble, compound 42 on the temporal evolution of Ab1-40 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