Inhibition
of β-amyloid peptide (Αβ) aggregation
in Alzheimer’s disease (AD) is among the therapeutic approaches
against AD which still attracts scientific research interest. In the
search for compounds that interact with Aβ and disrupt its typical
aggregation course toward oligomeric or polymeric toxic assemblies,
small organic molecules of natural origin, combining low molecular
weight (necessary blood-brain barrier penetration) and low toxicity
(necessary for pharmacological application), are greatly sought after.
Isatin (1H-indoline-2,3-dione), a natural endogenous
indole, and many of its derivatives exhibit a wide spectrum of neuropharmacological
and chemotherapeutic properties. The synthesis and biological evaluation
of four new isatins as inhibitors of Aβ aggregation is presented
herein. In these derivatives, the N-phenyl thiosemicarbazide
moiety is joined at the 3-oxo position of isatin through Schiff base
formation, and substitutions are present at the indole nitrogen and
position 5 of the isatin core. Biophysical studies employing circular
dichroism, thioflavin T fluorescence assay, and transmission electron
microscopy reveal the potential of the isatin thiosemicarbazones (ITSCs)
to alter the course of Αβ aggregation, with two of the
derivatives exhibiting outstanding inhibition of the aggregation process,
preventing completely the formation of amyloid fibrils. Furthermore,
in in vitro studies in primary neuronal cell cultures,
the ITSCs were found to inhibit the Aβ-induced neurotoxicity
and reactive oxygen species production at concentrations as low as
1 μM. Taken all together, the novel ITSCs can be considered
as privileged structures for further development as potential AD therapeutics.