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

C. Albertini, A. Salerno, S. Atzeni, E. Uliassi, F. Massenzio, A. Maruca, R. Rocca, M. Mecava, FSG. Silva, D. Mena, P. Valente, AI. Duarte, D. Chavarria, M. Bissaro, S. Moro, S. Federico, G. Spalluto, O. Soukup, F. Borges, S. Alcaro, B. Monti,...

. 2022 ; 13 (15) : 2252-2260. [pub] 20220722

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc22024917

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 μM) 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 μM) might add a piece to the puzzle of its anti-ALS molecular profile.

Citace poskytuje Crossref.org

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