Lipophilic hydroxytyrosol esters significantly improve the oxidative state of human red blood cells

• Erythrocyte as model for the antioxidant effect of several hydroxytyrosol (HT)-esters.
• A SAR of HT-esters is performed by varying the length of acyl chain.
• The HT-esters tested, with the exception of stearate, show a better activity than HT.
• Hydrophilic–lipophilic balance as driving force for the antioxidant effect in RBC-model.

Hydroxytyrosol (HT), a strongly hydrophilic phenol, shows a broad spectrum of biological properties due to its effectiveness as an antioxidant. A set of HT esters with varying acyl chain lengths and lipophilicity were tested to determine their effect on the oxidative state of human erythrocytes. All the esters tested, with the exception of HT stearate, showed a better activity than HT against haemolysis and lipid peroxidation. Maximum antioxidant efficiency was observed when the acyl chain of the HT derivatives was ten or twelve carbon atoms long. This is probably due to a better intercalation of molecules in the nonpolar internal bilayer of the erythrocyte membrane. A simple description of the system in which HT esters interact with the extracellular and membrane compartment of erythrocytes was then proposed. These encouraging results have prompted further investigations on the modulation of the hydrophobicity of HT, a promising tool for developing new potent antioxidants.