An Optimized Pyrimidinol Multifunctional Radical Quencher

A series of aza analogues (4–9) of the experimental neuroprotective drug idebenone (1) have been prepared and evaluated for their ability to attenuate oxidative stress induced by glutathione depletion and to compensate for the decrease in oxidative phosphorylation efficiency in cultured Friedreich’s ataxia (FRDA) fibroblasts and lymphocytes and also coenzyme Q₁₀-deficient lymphocytes. Modification of the redox core of the previously reported 3 improved its antioxidant and cytoprotective properties. Compounds 4–9, having the same redox core, exhibited a range of antioxidant activities, reflecting side chain differences. Compounds having side chains extending 14–16 atoms from the pyrimidinol ring (6, 7, and 9) were potent antioxidants. They were superior to idebenone and more active than 3, 4, 5, and 8. Optimized analogue 7 and its acetate (7a) are of interest in defining potential therapeutic agents capable of blocking oxidative stress, maintaining mitochondrial membrane integrity, and augmenting ATP levels. Compounds with such properties may find utility in treating mitochondrial and neurodegenerative diseases such as FRDA and Alzheimer’s disease.