naphthoquinones and Optic-Atrophy--Hereditary--Leber

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 (

Topics: Animals; Cell Survival; Dose-Response Relationship, Drug; Female; Hep G2 Cells; Humans; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Optic Atrophy, Hereditary, Leber; Pharmaceutical Preparations; Treatment Outcome