1. Discovery of novel benzofuran-based compounds with neuroprotective and immunomodulatory properties for Alzheimer's disease treatment
- Author
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Silvia Gobbi, Alessandra Bisi, Letizia Pruccoli, Manuela Bartolini, Ignacio Moraleda, Serena Montanari, Marina Naldi, Sabrina Petralla, Barbara Monti, Alessia Ligresti, Isabel Iriepa, Alessandro Rabbito, Vincenzo Di Marzo, Ali M. Mahmoud, Federica Belluti, Andrea Tarozzi, Angela Rampa, Montanari S., Mahmoud A.M., Pruccoli L., Rabbito A., Naldi M., Petralla S., Moraleda I., Bartolini M., Monti B., Iriepa I., Belluti F., Gobbi S., Di Marzo V., Bisi A., Tarozzi A., Ligresti A., and Rampa A.
- Subjects
Amyloid beta-Peptide ,Cannabinoid receptor ,Pharmacology ,01 natural sciences ,Receptor, Cannabinoid, CB2 ,Mice ,Immunologic Factor ,Peptide Fragment ,Receptor, Cannabinoid, CB1 ,Catalytic Domain ,Drug Discovery ,Cannabinoid receptor type 2 ,Cholinesterase Inhibitor ,Anti-inflammatory M2 phenotype ,Butyrylcholinesterase ,0303 health sciences ,Chemistry ,CB receptor ,General Medicine ,Ligand (biochemistry) ,Endocannabinoid system ,Neuroprotection ,Molecular Docking Simulation ,Neuroprotective Agents ,CB receptors ,Acetylcholinesterase ,lipids (amino acids, peptides, and proteins) ,Microglia ,Cricetulu ,Alzheimer's disease ,Benzofuran scaffold ,Human ,Protein Binding ,Neuroprotective Agent ,CHO Cells ,MTDL ,Small Molecule Libraries ,03 medical and health sciences ,Cricetulus ,Alzheimer Disease ,Cell Line, Tumor ,Aβ peptide ,medicine ,Animals ,Humans ,Immunologic Factors ,Inverse agonist ,Benzofurans ,030304 developmental biology ,Amyloid beta-Peptides ,Animal ,A beta peptide ,010405 organic chemistry ,Organic Chemistry ,medicine.disease ,Peptide Fragments ,0104 chemical sciences ,CHO Cell ,Drug Design ,Cholinesterase Inhibitors ,Benzofuran - 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 A beta(1-42) 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. (C) 2019 Elsevier Masson SAS. All rights reserved.
- Published
- 2019