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

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.
Serena Montanari 1,  Ali Mokhtar Mahmoud 2,  Letizia Pruccoli 3,  Alessandro Rabbito 2,  Marina Naldi 1,  Sabrina Petralla 1,  Ignacio Moraleda 4,  Manuela Bartolini 1,  Barbara Monti 1,  Isabel Iriepa 5,  Federica Belluti 1,  Silvia Gobbi 1,  Vincenzo Di Marzo 2,  Alessandra Bisi 1,  Andrea Tarozzi 3,  Alessia Ligresti 2,  Angela Rampa 6
Affiliations

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 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.

Keywords

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

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