Design and Microwave-Assisted Synthesis of Aza-Resveratrol Analogs with Potent Cholinesterase Inhibition

Title:Design and Microwave-Assisted Synthesis of Aza-Resveratrol Analogs with Potent Cholinesterase Inhibition

Volume: 19 Issue: 8

Author(s): Brunella Biscussi, Victoria Richmond, Carlos Javier Baier, Pau Arroyo Mañez and Ana Paula Murray*

Affiliation:

• INQUISUR-CONICET, Departamento de Química, Universidad Nacional del Sur, Bahía Blanca,Argentina

Keywords: Aza-resveratrol analogs, cholinesterase inhibitors, Alzheimer's disease, rational design, microwave-assisted synthesis, SH-SY5Y neuroblastoma cells, Molecular modeling.

Abstract:

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.

Cite this article as:

Biscussi Brunella , Richmond Victoria , Baier Javier Carlos, Mañez Arroyo Pau and Murray Paula Ana *, Design and Microwave-Assisted Synthesis of Aza-Resveratrol Analogs with Potent Cholinesterase Inhibition, CNS & Neurological Disorders - Drug Targets 2020; 19 (8) . https://dx.doi.org/10.2174/1871527319666200905121536