Theoretical Parameters to Characterize Antioxidants. Part 2. The cases of melatonin and carvedilol



This theoretical study focuses on two indole derivatives, melatonin (1) and carvedilol (8), with the objective of improving our understanding of the molecular mechanisms underlying their radical-scavenging activity. Quantum-mechanical calculations were carried out using the AM1 semi-empirical method, some results being confirmed by ab initio (3-21G) calculations. The quantum-chemical descriptor Δ Hox (relative adiabatic oxidation potential) and the shape of the SOMO (singly occupied molecular orbital) indicate that the stabilization of its radical cation can partially explain the well-documented antioxidant efficacy of melatonin. This stablization may result from electrostatic interactions and from a hyperconjugative effect existing in a family of conformers of the melatonin radical cation having the side chain almost perpendicular to the plane of the aromatic rings. Furthermore, 6-hydroxymelatonin (7) appears to be a better free-radical scavenger than melatonin (1) in agreement with experimental results. According to the theoretical parameters Δ Hox and Δ Habs (relative bond dissociation enthalpy), carvedilol (8) is not a good antioxidant, in contrast to its ring-hydroxylated metabolites whose powerful antioxidant effects are explained by the formation of an oxyl radical stabilized by delocalization over the carbazole nucleus.