Mitochondriotropic antioxidants (MC₃, MC_6.2, MC₄ and MC_7.2) based on dietary antioxidants and analogs (caffeic, hydrocaffeic, trihydroxyphenylpropanoic and trihydroxycinnamic acids) were developed. In this study, we evaluate and compare the cytotoxicity profile of novel mitochondria-targeted molecules (generally known as MitoCINs) on human HepG2 and differentiated SH-SY5Y cells with the quinone-based mitochondria-targeted antioxidants MitoQ and SkQ₁ and with two non-targeted antioxidants, resveratrol and coenzyme Q₁₀ (CoQ₁₀). We further evaluate their effects on mitochondrial membrane potential, cellular oxygen consumption and extracellular acidification rates. Overall, MitoCINs derivatives reduced cell viability at concentrations about six times higher than those observed with MitoQ and SkQ1. A toxicity ranking for both cell lines was produced: MC₄ < MC_7.2 < MC₃ < MC_6.2. These results suggest that C-6 carbon linker and the presence of a pyrogallol group result in lower cytotoxicity. MC₃ and MC_6.2 affected the mitochondrial function more significantly relative to MitoQ, SkQ1, resveratrol and CoQ₁₀, while MC₄ and MC_7.2 displayed around 100-1000 times less cytotoxicity than SkQ1 and MitoQ. Based on the mitochondrial and cytotoxicity cellular data, MC₄ and MC_7.2 are proposed as leads that can be optimized to develop safe drug candidates with therapeutic application in mitochondrial oxidative stress-related diseases.

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