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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Synthesis, Biological Evaluation, and Docking Studies of Open-Chain Carbohydrate Amides as Acetylcholinesterase Inhibitors

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*

Volume 19, Issue 6, 2023

Published on: 06 January, 2023

Page: [570 - 577] Pages: 8

DOI: 10.2174/1573406419666221202154219

Price: $65

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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.

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