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.

Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes / E. Colombo, S. Olla, C. Minnelli, A. Formato, C. Veroni, S. Corbisiero, M. Pericolo, C. Siguri, G. Mobbili, C. Agresti, P. Seneci. - In: MOLECULES. - ISSN 1420-3049. - 28:19(2023 Oct 04), pp. 6928.1-6928.13. [10.3390/molecules28196928]

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

P. Seneci
Ultimo
2023

Abstract

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.
absorption-distribution-metabolism-excretion (ADME); amyotrophic lateral sclerosis; antioxidant activity; chemical probes; edaravone; mechanism of action; medicinal chemistry; prodrugs; remyelination;
Settore CHIM/06 - Chimica Organica
4-ott-2023
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1012070
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