Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes

Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b–4c showing three substitution patterns A–C, s...

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Published inMolecules (Basel, Switzerland) Vol. 28; no. 19; p. 6928
Main Authors Colombo, Eleonora, Olla, Stefania, Minnelli, Cristina, Formato, Alessia, Veroni, Caterina, Corbisiero, Silvia, Pericolo, Mattia, Siguri, Chiara, Mobbili, Giovanna, Agresti, Cristina, Seneci, Pierfausto
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 01.10.2023
MDPI
Subjects
Alcohol
Amyotrophic lateral sclerosis
antioxidant activity
Antioxidants
Azide
Bioavailability
Biological activity
Carbamates
chemical probes
edaravone
mechanism of action
Metabolism
Multiple sclerosis
Nervous system diseases
Permeability
Physiology
prodrugs
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Summary:Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b–4c showing three substitution patterns A–C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4′-carboxylate 2b, 4′-ester 2c and N1-carbamate-4′-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.
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Current address: Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA.
These authors contributed equally to this work.
Current address: Institute of Biochemistry and Cell Biology, IBBC-CNR, Campus Adriano Buzzati Traverso, Via Ercole Ramarini 32, Monterotondo Scalo, 00015 Rome, Italy.
Current address: Institute for Treatment and Research (IRCCS) Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules28196928