Abstract
In the last decade, our group has been very active at developing and assaying complex
libraries of scaffolds with a focus on their potential to identify bioactive drug
candidates for neurodegenerative diseases, particularly Alzheimer’s disease (AD).
Attention has been focused on isatin-based oxindole scaffolds, for which promising
results concerning butyrylcholinesterase (BuChE) inhibitory activity have previously
been obtained. Considering some published reports and detailed analysis of the pharmacophores
of commercially available drugs for AD (powerful cholinesterase (ChE) inhibitors),
we performed a strategic structural modification of the isatin core and generated
a new family of isatin-based oxindole hybrids (27 new compounds) possessing crucial
key functional units in their framework. The syntheses were accomplished using multiple
approaches, including simple N-alkylation reactions, copper-catalyzed amination reactions, and click chemistry.
The resulting library was evaluated on ChE and MAO enzymes, both of which are involved
in the pathophysiology of neurodegeneration. IC50 values of 1.6 and 2.6 μM (BuChE assays), were achieved for the best inhibitors.
Key words
isatin-oxindole - hybrids - Alzheimer’s disease (AD) - inhibition - cholinesterase
(ChE) - monoamine oxidase (MAO)
