Structure-Dependent Antioxidant Activity of Ibogalogs: Impact of Methoxy Group Position on the Protective Activity in...

Indole-tetrahydroazepine derivatives of iboga alkaloids (ibogalogs) exhibit antidepressant, anxiolytic, promnesic, and antineuropathic effects, mainly via serotonergic targets. However, their physicochemical properties relevant to redox biology, including antioxidant activity and membrane stability, have remained poorly characterized. We investigated the antioxidant properties of three ibogalogs: ibogaminalog (DM506), ibogainalog (IBG), and tabernanthalog (TBG), using model lipid membranes (liposomes), human erythrocytes, and rat hippocampal and cortical synaptosomes exposed to AAPH-induced oxidative stress. Physicochemical descriptors, bond dissociation enthalpies, and ionization potentials were also calculated to assess membrane interactions and the antioxidant potential. All ibogalogs protected erythrocytes by reducing hemolysis, potassium efflux, and malondialdehyde levels, with the strongest effects observed for TBG; none induced hemolysis or K⁺ efflux at 0.01-10 μM. Ibogalogs also decreased lipid peroxidation in rat hippocampal and cortical synaptosomes. In liposomal systems, TBG showed the highest efficacy against lipid-peroxyl-radical-induced peroxidation, whereas DM506 and IBG mainly slowed autoxidation. Theoretical analysis indicated that the methoxy group substitution critically influences bond dissociation enthalpies, radical delocalization, and antioxidant potency. This first physicochemical characterization of antioxidant properties of ibogalogs enhances the understanding of their membrane-protective actions, complementing their neuromodulatory profiles.