Isatin 3-arylhydrazones: from inhibitors of amyloidogenesis to multitarget agents with potential in Alzheimer’s disease.

The research in effective therapeutic strategies for Alzheimer’s disease (AD) and other neurodegenerative disorders is experiencing a “paradigm shift” to a multitarget approach, aimed to confer to a single molecular entity, multiple activities targeting relevant biological processes involved in the disease. In our ongoing research for multitarget agents useful in AD therapy, we disclosed the isatin-3-arylhydrazone moiety as a key scaffold for the synthesis of suitably decorated derivatives, able to interfere in the fibrillogenesis of beta-amyloid protein (1) by disrupting the oligomerization process (2). Cellular tests showed that cytoprotection occurs not only by counteracting the amyloid insult, but also through antioxidant activity related to hydroxy and/or methoxy substituents in suitable positions (3,4). The easy chemical handling of the isatin scaffold allowed preparing its Mannich bases as effective water-soluble prodrugs with favourable drug release kinetics and high cellular tolerability (4). Additionally, the inhibition of acetyl/butyrylcholinesterase (4), the key targets for current AD therapy, gave a further confirmation for the potential of this class of compounds as pleiotropic agents for AD.