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

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

doi:10.1016/j.ejmech.2019.05.080

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

Eur J Med Chem. 2019 Sep 15:178:243-258. doi: 10.1016/j.ejmech.2019.05.080. Epub 2019 May 31.

Authors

Serena Montanari¹, Ali Mokhtar Mahmoud², Letizia Pruccoli³, Alessandro Rabbito², Marina Naldi¹, Sabrina Petralla¹, Ignacio Moraleda⁴, Manuela Bartolini¹, Barbara Monti¹, Isabel Iriepa⁵, Federica Belluti¹, Silvia Gobbi¹, Vincenzo Di Marzo², Alessandra Bisi¹, Andrea Tarozzi³, Alessia Ligresti², Angela Rampa⁶

Affiliations

¹ Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
² Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, 80078, Pozzuoli, NA, Italy.
³ Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
⁴ Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28805, Alcalá de Henares, Madrid, Spain.
⁵ Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28805, Alcalá de Henares, Madrid, Spain; Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá, 28805, Alcalá de Henares, Madrid, Spain.
⁶ Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: angela.rampa@unibo.it.

PMID: 31185414
DOI: 10.1016/j.ejmech.2019.05.080

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 Aβ_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.

Keywords: Anti-inflammatory M2 phenotype; Aβ peptide; Benzofuran scaffold; CB receptors; MTDL; Neuroprotection.

MeSH terms

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

Substances

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