Radical scavenging activity of bromophenol analogs: analysis of kinetics and mechanisms.

CONTEXT: This theoretical study explores the antioxidant activity of five bromophenol analogs, with a particular focus on their interaction with different solvent environments of varying polarities. Key findings include the correlation between increased solvent polarity and enhanced antioxidant activity of these analogs, comparable in some instances to ascorbic acid. Notably, compound 5, developed by our research team, demonstrates superior antioxidant activity in both lipid and aqueous solutions, surpassing that of ascorbic acid and other tested analogs. This research contributes to the understanding of bromophenol analogs, presenting the first known kinetic and chemical stability data such as rate constants, pKa values, and branching ratios for reactions with the methylperoxyl radical (CH3OO•). METHODS: The computational analyses were conducted using the Gaussian 09 software suite at the M05-2X/6-31 + G(d) computational level. These analyses employed conventional transition state theory to account for various potential mechanisms and effects of solvent polarity on the antioxidant activities of bromophenol analogs. The study meticulously calculated enthalpy under standard conditions (298.15 K and 1 atm) with necessary thermodynamic corrections. Additionally, the Quantum Mechanics-based Test for Overall Radical Scavenging Activity (QMORSA) protocol guided the evaluation of radical scavenging activity, ensuring a comprehensive assessment of the antioxidant potential of the compounds.

Strategic design, theoretical insights, synthesis, and unveiling antioxidant potential in a novel ascorbic acid analog.

CONTEXT: In this study, we investigated the antioxidant potential of a novel ascorbic acid analog, DsD, assessing its interactions with the methylperoxyl (CH3OO·) radical in aqueous and lipid environments. Our focus was on understanding the acid-base equilibrium and how pH affects DsD's primary reaction mechanisms. Our findings indicate a marked preference for hydrogen atom transfer in lipid media, contrasting with sequential proton loss electron transfer (SPLET) in aqueous solutions. Remarkably, DsD's radical scavenging activity significantly outperforms ascorbic acid, being 4.05 and 9469.70 times more potent in polar and lipid contexts, respectively. This suggests DsD's superior efficacy as an antioxidant, potentially offering enhanced protection in biological systems. Additionally, we have demonstrated DsD's synthetic feasibility through a straightforward condensation reaction between ascorbic acid and 1,2-diaminoethane, followed by comprehensive physicochemical and spectroscopic characterization. METHODS: All computational analyses in this study were conducted using the Gaussian 09 software suite, employing the M05-2X functional and the 6-31 + G(d) basis set. Enthalpy calculations were executed under standard conditions (298.15 K and 1 atm), incorporating appropriate thermodynamic corrections. Rate constants were evaluated using transition state theory (TST), and the overall assessment of radical scavenging activity was guided by the Quantum Mechanics-based Test for Overall Radical Scavenging Activity (QMORSA) protocol.

Role of Imidazole and Chelate Ring Size in Copper Oxidation Catalysts: An Experimental and Theoretical Study.

In this work, the structural, solution, electrochemical, and catalytic properties of the complexes with ligands derived from imidazole and pyridines were studied. A comparative study of five bioinspired copper catalysts with or without coordinated imidazole and with different chelate ring sizes is presented. Catalytic efficiency on the oxidation of 3,5-di-tert-butylcatechol (DTBC) and ortho-aminophenol (OAP) in a MeOH/H2O medium was assessed by means of the Michaelis-Menten model. Catalysts comprising imidazole-containing ligands and/or a six-membered chelate ring proved to be more efficient in both oxidation reactions. Determination of stability constants and electrochemical parameters of the copper complexes supported the explanation of the catalytic behavior. A catalytic cycle similar for both reactions has been proposed. The results of density functional theory (DFT) free energy calculations for all five complexes and both catalytic reactions agree with the experimental results.

Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ.

Targeting the PI3K isoform p110δ against B cell malignancies is at the mainstay of PI3K inhibitor (PI3Ki) development. Therefore, we generated isogenic cell lines, which express wild type or mutant p110δ, for assessing the potency, isoform-selectivity and molecular interactions of various PI3Ki chemotypes. The affinity pocket mutation I777M maintains p110δ activity in the presence of idelalisib, as indicated by intracellular AKT phosphorylation, and rescues cell functions such as p110δ-dependent cell viability. Resistance owing to this substitution consistently affects the potency of p110δ-selective in contrast to most multi-targeted PI3Ki, thus distinguishing usually propeller-shaped and typically flat molecules. Accordingly, molecular dynamics simulations indicate that the I777M substitution disturbs conformational flexibility in the specificity or affinity pockets of p110δ that is necessary for binding idelalisib or ZSTK474, but not copanlisib. In summary, cell-based and molecular exploration provide comparative characterization of currently developed PI3Ki and structural insights for future PI3Ki design.

The Synergy between Glutathione and Phenols-Phenolic Antioxidants Repair Glutathione: Closing the Virtuous Circle-A Theoretical Insight.

Glutathione (GSH) and phenols are well-known antioxidants, and previous research has suggested that their combination can enhance antioxidant activity. In this study, we used Quantum Chemistry and computational kinetics to investigate how this synergy occurs and elucidate the underlying reaction mechanisms. Our results showed that phenolic antioxidants could repair GSH through sequential proton loss electron transfer (SPLET) in aqueous media, with rate constants ranging from 3.21 × 106 M-1 s-1 for catechol to 6.65 × 108 M-1 s-1 for piceatannol, and through proton-coupled electron transfer (PCET) in lipid media with rate constants ranging from 8.64 × 106 M-1 s-1 for catechol to 5.53 × 107 M-1 s-1 for piceatannol. Previously it was found that superoxide radical anion (O2•-) can repair phenols, thereby completing the synergistic circle. These findings shed light on the mechanism underlying the beneficial effects of combining GSH and phenols as antioxidants.

Chemical repair of damaged leucine and tryptophane by thiophenols at close to diffusion-controlled rates: Mechanisms and kinetics.

Thiophenols are chemical species with multiple desirable biological properties, including their primary and secondary antioxidant capacity. In this work, the repairing antioxidant activity of eight different thiophenols has been investigated for damaged leucine and tryptophane. The investigation was carried out employing quantum mechanical and transition state methods to calculate the thermodynamic and kinetic data of the reactions involved, while simulating the biological conditions at physiological pH and aqueous and lipidic medium. The analysis of the atomic charges and the spin densities at each of the points on the potential energy surface was the tool that allowed the elucidation of the reaction mechanisms through which thiophenols repair the oxidative damage caused to the amino acids leucine and tryptophan. It was found that thiophenols can repair leucine via a hydrogen atom transfer mechanism in a manner which is similar to the one used by glutathione to repair the carbon-centered radicals of guanosine. In addition, thiophenols can also restore tryptophane, a nitrogen-centered radical, via proton-coupled electron transfer and single electron transfer mechanisms. Moreover, both processes occur at close to diffusion-controlled rates.

Computationally Designed Sesamol Derivatives Proposed as Potent Antioxidants.

Oxidative stress has been recognized to play an important role in several diseases, such as Parkinson's and Alzheimer's disease, which justifies the beneficial effects of antioxidants in ameliorating the deleterious effects of these health disorders. Sesamol, in particular, has been investigated for the treatment of several conditions because of its antioxidant properties. This article reports a rational computational design of new sesamol derivatives. They were constructed by adding four functional groups (-OH, -NH2, -COOH, and -SH) in three different positions of the sesamol molecular framework. A total of 50 derivatives between mono-, di-, and trisubstituted compounds were obtained. All the derivatives were evaluated and compared with a reference set of commercial neuroprotective drugs. The estimated properties are absorption, distribution, metabolism, excretion, toxicity, and synthetic accessibility. Selection and elimination scores were used to choose a first set of promising candidates. Acid-based properties and reactivity indexes were then estimated using the density functional theory. Four sesamol derivatives were finally selected, which are hypothesized to be potent antioxidants, even better than sesamol and Trolox for that purpose.

The Antioxidant Capability of Higenamine: Insights from Theory.

Density functional theory was employed to highlight the antioxidant working mechanism of higenamine in aqueous and lipid-like environments. Different reaction mechanisms were considered for the reaction of higenamine with the •OOH radical. The pH values and the molar fraction at physiological pH were determined in aqueous solution. The results show that the preferred reaction mechanism was the hydrogen atom transfer from the catecholic ring. The computed kinetic constants revealed that, in order to obtain reliable results, it is important to consider all the species present in water solution derived from acid-base equilibria. From the present investigation, it emerges that at physiological pH (7.4), the scavenging activity of higenamine against the •OOH radical is higher than that of Trolox, chosen as a reference antioxidant. Furthermore, higenamine results to be more efficient for that purpose than melatonin and caffeine, whose protective action against oxidative stress is frequently associated with their reactive oxygen species (ROS) scavenging activity.

Thiophenols, Promising Scavengers of Peroxyl Radicals: Mechanisms and kinetics.

The activity of 12 thiophenols as primary antioxidants in aqueous solution has been studied using density functional theory. Twelve different substituted thiophenols were tested as peroxyl radicals scavengers. Single electron transfer (SET) and formal hydrogen transfer (FHT) were investigated. The SET mechanism was found to be the main mechanism, with rate constants that are close to the diffusion limit, which means that these thiophenolic compounds have the capacity to scavenge peroxyl radicals before they can damage biomolecules. All 12 thiophenolic compounds react faster with methylperoxyl than with hydroperoxyl radicals. In addition, it was found that pH plays an important role in the reactivity of these compounds. © 2019 Wiley Periodicals, Inc.

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.

The other side of the superoxide radical anion: its ability to chemically repair DNA oxidized sites.

The superoxide radical anion can repair oxidative damage. In particular, it was demonstrated that O2˙- can repair oxidized DNA by electron transfer, restoring the original structure of this important molecule. Acid-base equilibria have been considered, and the influence of the pH on the main reaction mechanism has been explored.

Chemical Insights into the Antioxidant Mechanisms of Alkylseleno and Alkyltelluro Phenols: Periodic Relatives Behaving Differently.

The possible antioxidant reaction mechanisms of recently synthesized and tested alkylseleno (telluro) phenols have been explored using density functional theory by considering two solvents physiologically relevant, water and pentylethanoate (PE). In addition, the possible pathway for the antioxidant regeneration with ascorbic acid has been investigated. Results show that selenium and tellurium systems follow different chemical behaviors. In particular, the alkylseleno phenol (ebselenol) antioxidant activity is justified through a sequential proton loss-electron-transfer mechanism in water media, whereas in PE the hydrogen-atom transfer process is favored. In the case of the tellurium derivative, the oxygen-transfer mechanism represents the preferential one. Furthermore, electronic properties have been analyzed to rationalize the different reactivity of the selenium- and tellurium-containing systems. To confirm the results, smaller but similar systems were also investigated. The calculated data support the different mechanism (Se vs. Te) proposals.

The role of acid-base equilibria in formal hydrogen transfer reactions: tryptophan radical repair by uric acid as a paradigmatic case.

The results presented in this work demonstrate the high complexity of chemical reactions involving species with multiple acid-base equilibria. For the case study investigated here, it was necessary to consider two radical species for tryptophan (Trp(-H)˙ and Trp˙+) and three fractions for uric acid (H3Ur, H2Ur- and HUr2-) in order to properly reproduce the experimental results. At pH = 7.4, two main reaction mechanisms were identified: proton-electron sequential transfer (PEST) and sequential proton gain-electron transfer (SPGET). Combined, they account for more than 99% of the overall reaction, despite the fact that they involve minor species, i.e., H3Ur and Trp˙+, respectively. The excellent agreement between the calculated overall rate constant and the experimental value seems to support this proposal. In addition, if only the dominant species at pH = 7.4 (H2Ur- and Trp(-H)˙) were considered, there would be a large discrepancy with the experimental value (about 4 orders of magnitude), which also supports the finding that the key species in this case are not the most abundant ones. The influence of the pH on the kinetics of the investigated reaction was explored. It was found that the maximum repairing ability of uric acid does not occur at physiological pH, but at a more acidic pH (pH = 5.0).

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.

Hydrogen Abstraction Reactions from Phenolic Compounds by Peroxyl Radicals: Multireference Character and Density Functional Theory Rate Constants.

An assessment of multireference character in transition states is considered to be an important component in establishing the expected reliability of various electronic structure methods. In the present work, the multireference characters of the transition states and the forming and breaking of bonds for a large set of hydrogen abstraction reactions from phenolic compounds by peroxyl radicals have been analyzed using the T1, M, B1, and GB1 diagnostics. The extent of multireference character depends on the system and on the conditions under which the reaction takes place, and some systematic trends are observed. In particular, the multireference character is found to be reduced by solvation, the size of the phenolic compound, and deprotonation in aqueous solution. However, the deviations of calculated rate constants from experimental ones are not correlated with the extent of multireference character. The performance of single-determinant density functional theory was investigated for the kinetics of these reactions by comparing calculated rate constants to experimental data; the results from these analyses showed that the M05 functional performs well for the task at hand.

Assessing the Protective Activity of a Recently Discovered Phenolic Compound against Oxidative Stress Using Computational Chemistry.

The protection exerted by 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), a phenolic compound recently isolated from the Pacific oyster, against oxidative stress (OS) is investigated using the density functional theory. Our results indicate that DHMBA is an outstanding peroxyl radical scavenger, being about 15 times and 4 orders of magnitude better than Trolox for that purpose in lipid and aqueous media, respectively. It was also found to react faster with HOO(•) than other known antioxidants such as resveratrol and ascorbic acid. DHMBA is also predicted to be able to sequester Cu(II) ions, consequently inhibiting the OS induced by Cu(II)-ascorbate mixtures and downgrading the (•)OH production via the Haber-Weiss reaction. However, it is proposed that DHMBA is more efficient as a primary antioxidant (free radical scavenger), than as a secondary antioxidant (metal ion chelator). In addition, it was found that DHMBA can be efficiently regenerated in aqueous solution, at physiological pH. Such regeneration is expected to contribute to increase the antioxidant protection exerted by DHMBA. These results suggest that probably synthetic routes for this compound should be pursued, because albeit its abundance in nature is rather low, its antioxidant activity is exceptional.

Free-radical scavenging by tryptophan and its metabolites through electron transfer based processes.

Free-radical scavenging by tryptophan and eight of its metabolites through electron transfer was investigated in aqueous solution at physiological pH, using density functional theory and the Marcus theory. A test set of 30 free radicals was employed. Thermochemical and kinetic data on the corresponding reactions are provided here for the first time. Two different pathways were found to be the most important: sequential proton loss electron transfer (SPLET) and sequential double proton loss electron transfer (SdPLET). Based on kinetic analyses, it is predicted that the tryptophan metabolites kynurenic acid and xanthurenic acid are the best free-radical scavengers among the tested compounds; they were estimated to be at least 24 and 12 times more efficient than Trolox for scavenging (•)OOH. These findings are in line with previous reports suggesting that the antioxidant activity that has been attributed to tryptophan is actually due to its metabolites, and they demonstrate the particular importance of phenolic metabolites to such activity. Graphical Abstract Kynurenic acid (KNA) and xanthurenic acid (XNA) are the major contributors to the free-radical scavenging activity of tryptophan.

Kinetics of radical-molecule reactions in aqueous solution: a benchmark study of the performance of density functional methods.

The performance of 18 density functional approximations has been tested for a very challenging task, the calculations of rate constants for radical-molecule reactions in aqueous solution. Despite of the many difficulties involved in such an enterprise, six of them provide high quality results, and are recommended to that purpose. They are LC-ωPBE, M06-2X, BMK, B2PLYP, M05-2X, and MN12SX, in that order. This trend was obtained using experimental data as reference. The other relevant aspects used in this benchmark are: (i) the SMD model for mimicking the solvent; (ii) the conventional transition state, the zero-curvature tunneling correction, and the limit imposed by diffusion for the calculation of the rate constants. Even though changing any of these aspects might alter the trend in performance, at least, when using them, the aforementioned functionals can be successfully used to obtain high quality kinetic data for the kind of reactions investigated in this work.

Theoretical study on the peroxyl radicals scavenging activity of esculetin and its regeneration in aqueous solution.

The study of the ˙OOH, ˙OOCH3 and ˙OOCHCH2 radicals scavenging processes by esculetin (ES) was carried out in aqueous and lipid media, using the density functional theory. Three reaction mechanisms were considered: single electron transfer (SET), hydrogen transfer (HT) and radical adduct formation (RAF). Rate constants and branching ratios for the different paths are reported. It was found that in lipid media the main mechanism of reaction is HT, while in aqueous solution it depends on the predominant acid-base form of esculetin. HT was found to be the main mechanism involved in the free radical scavenging activity of neutral esculetin (H2ES), while for anionic esculetin (HES(-)) the relative importance of the different mechanisms changes with the reacting radical. Based on the calculated rate constants, it is proposed that esculetin has moderate peroxyl scavenging activity in lipid media while in aqueous solution, at physiological pH, it is excellent for that purpose. In addition, the possible regeneration of ES, after scavenging the first radical, was investigated in aqueous solution, at physiological pH. It was found that regeneration is very likely to occur, which suggests that this compound has the ability to scavenge several radical equivalents (two per cycle), under such conditions.