Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives

• DOI: 10.1021/acsptsci.4c00124
• Publication Date: 2024-04-30T13:41:00Z
• Authors: Miguel Pinto; Tiago Barros Silva; Vilma A. Sardão; Rui Simões; Bárbara Albuquerque; Paulo J. Oliveira; Maria João Valente; Fernando Remião; Patrício Soares-d...; Carlos Fernandes; Fernanda Borges
• Keywords: Lipophilicity; Entacapone; Moiety

Nitrocatechols are the standard pharmacophore to develop potent tight-binding inhibitors of catechol O-methyltransferase (COMT), which can be used as coadjuvant drugs manage Parkinson's disease. Tolcapone is most drug this class, but it has raised safety concerns due its potential induce liver damage. Tolcapone-induced hepatotoxicity been attributed nitrocatechol moiety; however, other nitrocatechol-based COMT inhibitors, such entacapone, safe and do not damage liver. There a knowledge gap concerning mechanisms chemical properties govern toxicity inhibitors. Using vast array cell-based assays, we found that tolcapone-induced caused by direct interference with mitochondria does depend on bioactivation P450. Our findings also suggest (a) lipophilicity key property in toxic nitrocatechols; (b) presence carbonyl group directly attached ring seems increase reactivity molecule, (c) cyano moiety double bond stabilizes decreasing cytotoxicity. Altogether, fine balance between nature C1 substituents may explain difference toxicological behavior observed tolcapone entacapone.