Lipophilic conjugates of idebenone with short and medium alkylamino acids: synthesis and antioxidant activity

Lipophilic conjugates of idebenone (IDE) were synthesized; they would be expected to possess a high degree of "membrane-like character", thus facilitating the crossing of cell membranes. A carbodiimide-assisted (EDAC HCl) coupling reaction was used to link 2-alkylamino acids with increasing chain length (4 to 7 carbon atoms) to the primary hydroxyl group of IDE. A preliminary stability test was carried out to delineate the hydrolytic degradation of these conjugates into IDE, showing no sign of further degradation of the latter drug. The in vitro free-radical scavenging activity of IDE-conjugates was investigated, in particular the scavenger effect on superoxide anion test, their ability, to bleach the stable DPPH radical, and the inhibition of lipid peroxidation in human plasma, as well as their capacity of inhibiting the xanthine oxidase activity. In all assays but the last one, compounds endowed with a short aminoacyl chain (C4 and C5) showed a strong dose-dependent antioxidant activity, close to or higher than IDE. This preliminary study indicated that the derivatization of IDE molecule did not suppress the biological antioxidant activity of the drug, and that the shorter-chain alkylamino acid esters showed higher activity as radical scavengers.