Background: Currently approved Alzheimer’s disease medications mainly comprise acetylcholinesterase
inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules
inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme
could lead to the discovery of effective multitarget drugs.
Objective: To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl-
and butyrylcholinesterase inhibitors.
Methods: The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially
available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus
(Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact
both with the peripheric anionic site and the catalytic site of the enzyme.
Results: All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate
to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC50 = 0.43
μM) and 12a (IC50 = 0.31 μM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a
and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma
cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor
12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what
makes it able to modulate the self-induced β-amyloid aggregation. Furthermore, the molecular modeling
analysis helps to assess the impact of the linker length in the inhibitory activity of this family of
new cholinesterase inhibitors.
Conclusion: These compounds have the potential to serve as a dual binding site inhibitor and might
provide a useful template for the development of new anti-Alzheimer’s disease agents.