Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes
2023
Eleonora Colombo | Stefania Olla | Cristina Minnelli | Alessia Formato | Caterina Veroni | Silvia Corbisiero | Mattia Pericolo | Chiara Siguri | Giovanna Mobbili | Cristina Agresti | Pierfausto Seneci
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&ndash:4c showing three substitution patterns A&ndash: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&prime:-carboxylate 2b, 4&prime:-ester 2c and N1-carbamate-4&prime:-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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