CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants.

A computational protocol aimed to design new antioxidants with versatile behavior is presented. It is called Computer-Assisted Design of Multifunctional Antioxidants and is based on chemical properties (CADMA-Chem). The desired multi-functionality consists of in different methods of antioxidant protection combined with neuroprotection, although the protocol can also be used to pursue other health benefits. The dM38 melatonin derivative is used as a study case to illustrate the protocol in detail. This was found to be a highly promising candidate for the treatment of neurodegeneration, in particular Parkinson's and Alzheimer's diseases. This also has the desired properties of an oral-drug, which is significantly better than Trolox for scavenging free radicals, and has chelates redox metals, prevents the ●OH production, via Fenton-like reactions, repairs oxidative damage in biomolecules (lipids, proteins, and DNA), and acts as a polygenic neuroprotector by inhibiting catechol-O-methyl transferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase B (MAOB). To the best of our best knowledge, CADMA-Chem is currently the only protocol that simultaneously involves the analyses of drug-like behavior, toxicity, manufacturability, versatile antioxidant protection, and receptor-ligand binding affinities. It is expected to provide a starting point that helps to accelerate the discovery of oral drugs with the potential to prevent, or slow down, multifactorial human health disorders.

Chalcone Derivatives with a High Potential as Multifunctional Antioxidant Neuroprotectors.

A systematic, rational search for chalcone derivatives with multifunctional behavior has been carried out, with the support of a computer-assisted protocol (CADMA-Chem). A total of 568 derivatives were constructed by incorporating functional groups into the chalcone structure. Selection scores were calculated from ADME properties, toxicity, and manufacturability descriptors. They were used to select a subset of molecules (23) with the best drug-like behavior. Reactivity indices were calculated for this subset. They were chosen to account for electron and hydrogen atom donating capabilities, which are key processes for antioxidant activity. The indexes showed that four chalcone derivatives (dCHA-279, dCHA-568, dCHA-553, and dCHA-283) are better electron and H donors than the parent molecule and some reference antioxidants (Trolox, ascorbic acid, and α-tocopherol). In addition, based on molecular docking, they are predicted to act as catechol-O-methyltransferase (COMT), acetylcholinesterase (AChE), and monoamine oxidase B (MAO-B) inhibitors. Therefore, these four molecules are proposed as promising candidates to act as multifunctional antioxidants with neuroprotective effects.

Antioxidants into Nopal (Opuntia ficus-indica), Important Inhibitors of Free Radicals' Formation.

Nopal (Opuntia ficus indica) belonging to the Cactacea family has many nutritional benefits attributed to a wide variety of phenolic and flavonoid compounds. Coumaric acid (COA), ferulic acid (FLA), protocatechuic acid (PRA), and gallic acid (GAA) are the phenolic acids (PhAs) present in nopal. In this study, the role of these PhAs in copper-induced oxidative stress was investigated using the density functional theory (DFT). The PhAs form 5 thermodynamically favorable complexes with Cu(II), their conditional Gibbs free energies of reaction (ΔG', at pH = 7.4, in kcal/mol) are from -23 kcal/mol to -18 kcal/mol. All of them are bi-dentate complexes. The complexes of PRA and GAA are capable of inhibiting the Cu(II) reduction by both O2•- and Asc-, their reactions with the chelated metal are endergonic having rate constants about ~10-5-102 M-1 s-1, PhAs can prevent the formation of hydroxyl free radicals by chelating the copper ions. Once the hydroxyl radicals are formed by Fenton reactions, the complexes of PhAs with Cu(II) can immediately react with them, thus inhibiting the damage that they can cause to molecules of biological interest. The reactions between PhAs-Cu(II) complexes and hydroxyl free radical were estimated to be diffusion-limited (~108 M-1s-1). Thus, these chelates can reduce the harmful effects caused by the most reactive free radical existent immediately after it is formed by Fenton reactions.

Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA.

Oxidative stress mediates chemical damage to DNA yielding a wide variety of products. In this work, the potential capability of melatonin and several of its metabolites to repair directly (chemically) oxidative lesions in DNA was explored. It was found that all the investigated molecules are capable of repairing guanine-centered radical cations by electron transfer at very high rates, that is, diffusion-limited. They are also capable of repairing C-centered radicals in the sugar moiety of 2'-deoxyguanosine (2dG) by hydrogen atom transfer. Although this was identified as a rather slow process, with rate constants ranging from 1.75 to 5.32 × 102  M-1 s-1 , it is expected to be fast enough to prevent propagation of the DNA damage. Melatonin metabolites 6-hydroxymelatonin (6OHM) and 4-hydroxymelatonin (4OHM) are also predicted to repair OH adducts in the imidazole ring. In particular, the rate constants corresponding to the repair of 8-OH-G adducts were found to be in the order of 104  M-1 s-1 and are assisted by a water molecule. The results presented here strongly suggest that the role of melatonin in preventing DNA damage might be mediated by its capability, combined with that of its metabolites, to directly repair oxidized sites in DNA through different chemical routes.

Comprehensive Investigation of the Antioxidant and Pro-oxidant Effects of Phenolic Compounds: A Double-Edged Sword in the Context of Oxidative Stress?

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.

Exploring Chemical Routes Relevant to the Toxicity of Paracetamol and Its meta-Analogue at a Molecular Level.

Several chemical routes related to the toxicity of paracetamol (APAP, also known as acetaminophen), its analogue N-acetyl-m-aminophenol (AMAP), and their deacetylated derivatives, were investigated using the density functional theory. It was found that AMAP is more resilient to chemical oxidation than APAP. The chemical degradation of AMAP into radical intermediates is predicted to be significant only when it is induced by strong oxidants. This might explain the apparent contradictions among experimental evidence regarding AMAP toxicity. All of the investigated species are incapable of oxidizing DNA, but they can damage lipids by H atom transfer (HAT) from the bis-allylic site, with the phenoxyl radical of AMAP being the most threatening to the lipids' chemical integrity. Regarding protein damage, Cys residues were identified as the most likely targets. The damage in this case may involve two different routes: (i) HAT from the thiol site by phenoxyl radicals and (ii) protein arylation by the quinone imine (QI) derivatives. Both are not only thermochemically viable, but also are very fast reactions. According to the mechanism identified here as the most likely one for protein arylation, a rather large concentration of QI would be necessary for this damage to be significant. This might explain why APAP is nontoxic in therapeutic doses, while overdoses can result in hepatic toxicity. In addition, the QI derived from both APAP and AMAP were found to be capable of inflicting this kind of damage. In addition, it is proposed that they might increase •OH production via the Fenton reaction, which would contribute to their toxicity.

Phenolic Melatonin-Related Compounds: Their Role as Chemical Protectors against Oxidative Stress.

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.

Empirically Fitted Parameters for Calculating pKa Values with Small Deviations from Experiments Using a Simple Computational Strategy.

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.

1,5-Diarylpyrazole and vanillin hybrids: Synthesis, biological activity and DFT studies.

Herein, we report the design and synthesis of 13 diarylpyrazole hybrids with vanillin constructed as dual compounds against oxidative stress and diabetes. Compounds were tested in two different antioxidant assays. It was found that all compounds showed an important antioxidant activity in both DPPH and ORAC models and the activity was even more remarkable than vanillin. In addition, the hypoglycemic effect of compounds 1, 2, 4 and 12 was evaluated. Interestingly, compound 1 had the most potent hypoglycemic effect with a glycemia reduction of 71%, which was higher than rimonabant. Finally, a DFT study to propose a reasonable antioxidant mechanism is detailed. Both thermodynamic and kinetic studies indicated that the most feasible mechanism consists in the HAT abstraction of the phenolic hydrogen due to the formation of an stable transition state through the most rapid and exergonic path, while the SPLET mechanism is the most significant at higher pH values.

Lipoic acid and dihydrolipoic acid. A comprehensive theoretical study of their antioxidant activity supported by available experimental kinetic data.

The free radical scavenging activity of lipoic acid (LA) and dihydrolipoic acid (DHLA) has been studied in nonpolar and aqueous solutions, using the density functional theory and several oxygen centered radicals. It was found that lipoic acid is capable of scavenging only very reactive radicals, while the dehydrogenated form is an excellent scavenger via a hydrogen transfer mechanism. The environment plays an important role in the free radical scavenging activity of DHLA because in water it is deprotonated, and this enhances its activity. In particular, the reaction rate constant of DHLA in water with an HOO(•) radical is close to the diffusion limit. This has been explained on the basis of the strong H-bonding interactions found in the transition state, which involve the carboxylate moiety, and it might have implications for other biological systems in which this group is present.