The Antioxidant Additive Approach for Alzheimer’s Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators

Novel
multifunctional tacrines for Alzheimer’s disease were obtained
by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde,
and tacrine derivatives, according to the antioxidant additive approach
in order to modulate the oxidative stress as therapeutic strategy.
Compound 5c has been identified as a promising permeable
agent showing excellent antioxidant properties, strong cholinesterase
inhibitory activity, less hepatotoxicity than tacrine, and the best
neuroprotective capacity, being able to significantly activate the
Nrf2 transcriptional pathway.