Title: The discovery of novel 2- aniline-1,4 naphthoquinones as potential new drug treatment for Leber’s hereditary optic neuropathy ( LHON)

: 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 United Kingdom. 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. 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 a comparable ATP rescue activity of idebenone. Among these, three compounds showed activity in the nM range and one, 2-((4- fluoro-3-(trifluoromethyl)phenyl)amino)-3-(methylthio)naphthalene-1,3-dione

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