Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Albertini, C (Author) Other; Salerno, A (Author) Other; Atzenti, S (Author) Other; Uliassi, E (Author) Other; Massenzio, F (Author) Other; Maruca, A (Author) Other; Rocca, R (Author) Other; Mecava, M (Author) Other; Silva, FSG (Author) Other; Mena, D (Author) Other; Valente, P (Author) Other; Duarte, AI (Author) Other; Chavarria, D (Author) Other; Bissaro, M (Author) Other; Moro, S (Author) Other; Federico, S (Author) Other; Spalluto, G (Author) Other; Soukup, O (Author) Other; Fernanda Borges (Author) FCUP; Alcaro, S (Author) Other; Monti, B (Author) Other; Oliveira, PJ (Author) Other; Menendez, JC (Author) Other; Bolognesi, ML (Author) Other

Journal

Title: Acs Chemical Neuroscience

Serial No. 12 Vol. 13

Pages: 2252-2260

ISSN: 1948-7193

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-00W-Y2B

DOI: 10.1021/acschemneuro.2c00261

Abstract (EN): Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 mu M) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 mu M) might add a piece to the puzzle of its anti-ALS molecular profile.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9