Discovery of novel benzofuran-based compounds with neuroprotective and immunomodulatory properties for Alzheimer's disease treatment.

Abstract

To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aβ1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.

• Authors: Serena Montanari, Ali Mokhtar Mahmoud, Letizia Pruccoli, Alessandro Rabbito, Marina Naldi, Sabrina Petralla, Ignacio Moraleda, Manuela Bartolini, Barbara Monti, Isabel Iriepa, Federica Belluti, Silvia Gobbi, Vincenzo Di Marzo, Alessandra Bisi, Andrea Tarozzi, Alessia Ligresti, Angela Rampa
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 178 Pg. 243-258 (Sep 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31185414 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Benzofurans
• Cholinesterase Inhibitors
• Immunologic Factors
• Neuroprotective Agents
• Peptide Fragments
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• Small Molecule Libraries
• amyloid beta-protein (1-42)
• Acetylcholinesterase
• Butyrylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (antagonists & inhibitors)
• Animals
• Benzofurans (chemical synthesis, chemistry, metabolism, pharmacology)
• Butyrylcholinesterase (chemistry, metabolism)
• CHO Cells
• Catalytic Domain
• Cell Line, Tumor
• Cholinesterase Inhibitors (chemical synthesis, chemistry, metabolism, pharmacology)
• Cricetulus
• Drug Design
• Humans
• Immunologic Factors (chemical synthesis, chemistry, metabolism, pharmacology)
• Mice
• Microglia (drug effects)
• Molecular Docking Simulation
• Neuroprotective Agents (chemical synthesis, chemistry, metabolism, pharmacology)
• Peptide Fragments (antagonists & inhibitors)
• Protein Binding
• Receptor, Cannabinoid, CB1 (metabolism)
• Receptor, Cannabinoid, CB2 (metabolism)
• Small Molecule Libraries (chemical synthesis, chemistry, metabolism, pharmacology)