Two empirically fitted parameters have been derived for 74 levels of theory. They allow fast and reliable pKa calculations using only the Gibbs energy difference between an acid and its conjugated base in aqueous solution (ΔGs(BA)). The parameters were obtained by least-squares fits of ΔGs(BA) vs experimental pKa values for phenols, carboxylic acids, and amines using training sets of 20 molecules for each chemical family. Test sets of 10 molecules per family-completely independent from the training set-were used to verify the reliability of the fitting parameters method. It was found that, except for MP2, deviations from experiments are lower than 0.5 pKa units. Moreover, mean unsigned errors lower than 0.35 pKa units were found for the 98.6%, 98.6%, and 94.6% of the tested levels of theory for phenols, carboxylic acids and amines, respectively. The parameters estimated here are expected to facilitate computationally based estimations of pKa values of species for which this magnitude is still unknown, with uncertainties similar to the experimental ones. However, the present study deals only with molecules of modest complexity, thus the reliability of the FP method for more complex systems remains to be tested.
A systematic rational search for newly designed melatonin derivatives, was performed using a computer-assisted protocol. A total of 116 derivatives were generated by adding functional groups (i.e., -OH, -NH2, -SH and -COOH) to the melatonin structure. A selection score (SS) was built to sample the search space, simultaneously considering ADME (absorption, distribution, metabolism, excretion) properties, toxicity and manufacturability (i.e., synthetic accessibility). The search characterized the whole set of designed melatonin derivatives and allowed the selection of a reduced subset of 20 melatonin derivatives that are expected to be the most promising, regarding drug-like behavior. For this subset, several reactivity indices were estimated, as well as their pKa values. According to the gathered data, 5 melatonin derivatives have been identified as the most likely candidates to act as chemical antioxidant (directly scavenging free radicals, by electron transfer and/or H transfer). All of them are predicted to be better for that purpose than melatonin itself or trolox (water soluble vitamin E analog). The findings from this work are expected to motivate further investigations on these molecules, using both theoretical and experimental approaches.
Oxidative stress (OS) is a health-threatening process that is involved, at least partially, in the development of several diseases. Although antioxidants can be used as a chemical defense against OS, they might also exhibit pro-oxidant effects, depending on environmental conditions. In this work, such a dual behavior was investigated for phenolic compounds (PhCs) within the framework of the density functional theory and based on kinetic data. Multiple reaction mechanisms were considered in both cases. The presence of redox metals, the pH, and the possibility that PhCs might be transformed into benzoquinones were identified as key aspects in the antioxidant versus pro-oxidant effects of these compounds. The main virtues of PhCs as antioxidants are their radical trapping activity, their regeneration under physiological conditions, and their behavior as OH-inactivating ligands. The main risks of PhCs as pro-oxidants are predicted to be the role of phenolate ions in the reduction of metal ions, which can promote Fenton-like reactions, and the formation of benzoquinones that might cause protein arylation at cysteine sites. Although the benefits seem to overcome the hazards, to properly design chemical strategies against OS using PhCs, it is highly recommended to carefully explore their duality in this context.
Abstract:There is currently no doubt about the serious threat that oxidative stress (OS) poses to human health. Therefore, a crucial strategy to maintain a good health status is to identify molecules capable of offering protection against OS through chemical routes. Based on the known efficiency of the phenolic and melatonin (MLT) families of compounds as antioxidants, it is logical to assume that phenolic MLT-related compounds should be (at least) equally efficient. Unfortunately, they have been less investigated than phenols, MLT and its non-phenolic metabolites in this context. The evidence reviewed here strongly suggests that MLT phenolic derivatives can act as both primary and secondary antioxidants, exerting their protection through diverse chemical routes. They all seem to be better free radical scavengers than MLT and Trolox, while some of them also surpass ascorbic acid and resveratrol. However, there are still many aspects that deserve further investigations for this kind of compounds.
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