Background: Many factors are involved in Alzheimer’s Disease (AD) such as amyloid
plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the
disease the new approach for drug development is to create a single molecule able to act simultaneously
on different targets.
Objective: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and
the scavenging of radicals.
Methods: We synthesised the new molecules by the Passerini multicomponent reaction and evaluated
their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well
as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski’s
rule for drug likeness and in silico ADME prediction was also performed.
Results: Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE]
and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits
for further development.
Conclusion: The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for
the treatment of AD.