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

Abstract

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 conlirmed by nh initio (3-21'3) calculations. The quantum-chemical descriptor AH,, (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 stabilization may result froin 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 experimentel results. According to the theoretical parameters AH", and AHab, (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.

Melatonin as a natural ally against oxidative stress: a physicochemical examination

“…The first two theoretical studies on the free radical–scavenging activity of melatonin appeared in 1998 [264, 265]. Migliavacca et al.…”

“…Migliavacca et al. [264] investigated the viability of the SET mechanism. For that purpose, they located and characterized six conformers of the radical cation of melatonin.…”

Protein Protection by Antioxidants: Development of a Convenient Assay and Structure-Activity Relationships of Natural Polyphenols

“…As already demonstrated in the case of vitamin E analogues [36], melatonin, and carvedilol [43], semi-empirical calculations yield useful parameters to characterize antioxidants, namely their adiabatic ionization potential and OÀH bond dissociation energy. These parameters were calculated for the natural polyphenols according to the following strategy:…”

A density functional theory study of structure‐activity relationships in caffeic and dihydrocaffeic acids and related monophenols

“…The capacity to predict antioxidant activity is important, because it improves the selection of effective new compounds with low toxicity and saves experimental work. The interest in the relative evaluation of antioxidants (AH) through theoretical calculations is increasing, and several molecular descriptors have been used so far in an attempt to find suitable theoretical parameters characterizing the activity of the antioxidants (1)(2)(3)(4)(5)(6). The main mechanism of action by phenolic antioxidants (AH) is considered to be the scavenging of free radicals by donation of their phenolic hydrogen atom (7).…”