Short-chain
quinones (SCQs) have been identified as potential
drug candidates against
mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active
quinone core. We recently synthesized a SCQ library of > 148
naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used
benzoquinone idebenone. One of the major drawbacks of
idebenone is its high metabolic conversion in the liver, which significantly restricts is therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified
naphthoquinone derivatives 1-16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than
idebenone over 6 h (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced
idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of
naphthoquinone-based SCQs and provide essential insights for future
drug design,
prodrug therapy, and polytherapy, respectively.