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.
Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis / Albertini, C; Salerno, A; Atzenti, S; Uliassi, E; Massenzio, F; Maruca, A; Rocca, R; Mecava, M; Silva, FSG; Mena, D; Valente, P; Duarte, AI; Chavarria, D; Bissaro, M; Moro, S; Federico, S; Spalluto, G; Soukup, O; Borges, F; Alcaro, S; Monti, B; Oliveira, PJ; Menendez, JC; Bolognesi, ML. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - ELETTRONICO. - 13:15(2022), pp. 2252-2260. [10.1021/acschemneuro.2c00261]
Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis
Albertini, C;Salerno, A;Uliassi, E;Massenzio, F;Monti, B;Bolognesi, ML
2022
Abstract
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.File | Dimensione | Formato | |
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