Discovery of Novel 2‑Aniline-1,4-naphthoquinones as Potential New Drug Treatment for Leber’s Hereditary Optic Neuropathy (LHON)

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.