Discovery of Novel 2-Aniline-1,4-naphthoquinones as potential new drug treatment for Leber’s hereditary optic neuropathy (LHON)

Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Beirne, Kathy, Aeschlimann, Pascale, Heard, Charles ORCID: https://orcid.org/0000-0001-9703-9777, Rozanowska, Malgorzata ORCID: https://orcid.org/0000-0003-2913-8954, Votruba, Marcela ORCID: https://orcid.org/0000-0002-7680-9135 and Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 2020. Discovery of Novel 2-Aniline-1,4-naphthoquinones as potential new drug treatment for Leber’s hereditary optic neuropathy (LHON). Journal of Medicinal Chemistry 63 (22) , 13638 -13655. 10.1021/acs.jmedchem.0c00942

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Abstract

Leber’s hereditary optic neuropathy (LHON) is a rare genetic mitochondrial disease and the primary cause of chronic visual impairment for at least 1 in 10 000 individuals in the U.K. Treatment options remain limited, with only a few drug candidates and therapeutic approaches, either approved or in development. Recently, idebenone has been investigated as drug therapy in the treatment of LHON, although evidence for the efficacy of idebenone is limited in the literature. NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex III were identified as the major enzymes involved in idebenone activity. Based on this mode of action, computer-aided techniques and structure–activity relationship (SAR) optimization studies led to the discovery of a series naphthoquinone-related small molecules, with comparable adenosine 5′-triphosphate (ATP) rescue activity to idebenone. Among these, three compounds showed activity in the nanomolar range and one, 2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-3-(methylthio)naphthalene-1,3-dione (1), demonstrated significantly higher potency ex vivo, and significantly lower cytotoxicity, than idebenone.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Optometry and Vision Sciences
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	20 November 2020
Date of Acceptance:	28 October 2020
Last Modified:	09 Jan 2025 22:30
URI:	https://orca.cardiff.ac.uk/id/eprint/136367

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