Title:Synthesis, Biological Evaluation, and Docking Studies of Open-Chain
Carbohydrate Amides as Acetylcholinesterase Inhibitors
Volume: 19
Issue: 6
Author(s): Rita Gonçalves-Pereira, Jose A. Figueiredo, Susana D. Lucas, Maria I. García-Moreno, Carmen O. Mellet, Amelia P. Rauter and Maria I. Ismael*
Affiliation:
- Department Química, Unidade I&D FibEnTech, Universidade da Beira Interior, Av. Marquês d’Ávila e Bolama, 6201-
001 Covilhã, Portugal
- Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências,
Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
Keywords:
Sugar amides, synthesis, acetylcholinesterase inhibitors, docking studies, Alzheimer’s disease, open chain carbohydrate.
Abstract:
Introduction: Alzheimer’s disease is a multifactorial syndrome, which is not yet fully
understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors
are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new
synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors.
Methods: Commercially available diacetone glucose was converted into perbenzyl D-glucono-1,4-
lactone, which reacted with aromatic or aliphatic amines to afford the corresponding new amides in a
high isolated yield. Docking studies of the most promising hydroxybutylamide and benzylamide
were performed to assign binding interactions with acetylcholinesterase and determine the key features
for bioactivity.
Results: The inhibitors are accommodated in enzyme gorge, blocking the access to Ser203 mainly
due to π-π stacking interactions of sugar benzyl groups with the aromatic gorge residues, Tyr337 and
Tyr341 for both inhibitors and Trp439 only for the hydroxybutylamide.
Conclusion: Bonding is also significant through sugar interaction with the residues Tyr124 and
Ser125-OH in both inhibitors. Flexibility of these open-chain structures seems to be quite relevant
for the observed binding to acetylcholinesterase.
