DFT-Based Quantum Chemical Studies on Conformational, Electronic and Antioxidant Properties of Isobavachalcone and 4-Hydroxyderricin

Isobavachalcone and 4-hydroxyderricin which exhibit numerous biological activities are two major chalcone constituents isolated from the roots of Angelica keiskei KOIDZUMI. The conformational and antioxidant activity properties have been investigated by quantum chemical calculations based on the density functional theory, with the aim of verifying dominant antioxidant mechanisms. Three parameters of the O-H bond dissociation enthalpy (BDE), ionization potential (IP) and acidity in the presence of an implicit solvent for methanol are computed to estimate the antioxidant capacities. Results reveal that the order of antioxidant efficacies predicted by BDE and IP, different from that predicted by acidity, is in agreement with that obtained by experimental data. This demonstrates the importance of the hydrogen atom transfer and single electron transfer mechanisms to explain their capacities to scavenge 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical.     

Quantitative elucidation of the molecular mechanisms of hydroxyl radical quenching reactivity of phenolic compounds

Reported discrepancies have confused the understanding of the molecular mechanisms of antioxidant reactivity somewhat. The consequent problems necessitate systematic investigations on the molecular orbital features of antioxidants and their correlation with antioxidant potentials. In the present work, phenolic compounds as typical antioxidants were selected to investigate their hydroxyl radical-scavenging properties, and the related mechanisms of action were studied theoretically by computational chemistry. A good correlation was observed between antioxidant activity and theoretical parameters, such as O-H bond dissociation energy (BDE), ionization potential (IP), enthalpy of electron transfer (E(a)), chemical hardness (HOMO-LUMO gap), and spin delocalization of the phenoxyl radicals (D(s)(r)). The results demonstrate that the molecular mechanisms regulating the antioxidant action were more complex than hydrogen or electron-transfer processes and explain previous contradictions. Meanwhile, a satisfactory quantitative structure-activity relationship (QSAR) model was established which should be of predictive value in evaluating or screening hydroxyl radical-scavenging antioxidants.     

Exploring a possible way to synthesize novel better antioxidants based on vitamin E: a DFT study

The promoting effect of heterocyclic ring and heteroatom on the antioxidant properties of vitamin E has been investigated systemically by using density functional theory. The calculated results show that the heteroatom plays a more important role in promoting the antioxidant properties than the heterocyclic ring, indicating that replacing O atom by S or Se is impossible to synthesize the novel better antioxidants. Furthermore, the bond dissociation enthalpy (BDE) and ionization potential (IP) of the corresponding molecules are decreased dramatically when the O atom is replaced by NH. In addition, the calculated results also reveal that reducing the atom number of heterocyclic ring is an ideal way to synthesize novel antioxidants with better antioxidant activity than vitamin E.     

Effect of different C3-aryl substituents on the antioxidant activity of 4-hydroxycoumarin derivatives

The antioxidant activity of 4-hydroxycoumarin synthetic derivatives and 4-methylumbelliferone were determined taking 4-hydroxycoumarin as the reference compound. Six 3-aryl-4-hydroxycoumarin derivatives were synthesized from 4-hydroxycoumarin as precursor in order to evaluate changes in their antioxidant properties due to C3-aryl substituent nature. Free radical scavenging capacities of these compounds against two different species DPPH(·) and ABTS(·+) and the protecting ability towards the β-carotene-linoleic acid co-oxidation enzymatically induced by lipoxygenase were measured. In addition, the relationship between the activities of these molecules against DPPH radical and the bond dissociation energy of O-H (BDE) calculated using methods of computational chemistry was evaluated.     

Free radical production by hydroxy-salen manganese complexes studied by ESR and XANES

Three salen-Mn(II) complexes bearing hydroxyl groups in either the ortho, para or meta positions have been synthesized and the structures of the metal complexes and their potential to produce free radicals investigated by electron spin resonance (ESR) and X-ray absorption near edge structures (XANES) spectroscopy. All three compounds were shown to generate a high level of superoxide anions in dimethyl sulfoxide (DMSO) solution. The production of oxygen radicals results from a one electron process oxidation of Mn(II) species leading to the formation Mn(III) redox state species, as revealed by a higher XANES edge energy of 2.7 eV. The formation of superoxide anion was characterized by ESR, both directly and via the use of a spin-trapping method. Under reductive condition in the presence of ascorbic acid, the reduction of Mn(III) to Mn(II) leads to the production of hydroxyl radicals by the ortho and para compounds. The efficient production O(2)*- by such salen-Mn complexes could be useful to evaluate the scavenging properties of antioxidant molecules.     

Theoretical study on the antioxidant properties of 2′-hydroxychalcones: H-atom vs. electron transfer mechanism

The free radical scavenging activity of six 2′-hydroxychalcones has been studied in gas phase and solvents using the density functional theory (DFT) method. The three main working mechanisms, hydrogen atom transfer (HAT), stepwise electron-transfer-proton-transfer (ET-PT) and sequential-proton-loss-electron-transfer (SPLET) have been considered. The O-H bond dissociation enthalpy (BDE), ionization potential (IP), proton affinity (PA) and electron transfer energy (ETE) parameters have been computed in gas phase and solvents. The theoretical results confirmed the important role of the B ring in the antioxidant properties of hydroxychalcones. In addition, the calculated results matched well with experimental values. The results suggested that HAT would be the most favorable mechanism for explaining the radical-scavenging activity of hydroxychalcone in gas phase, whereas SPLET mechanism is thermodynamically preferred pathway in aqueous solution.     

A DFT Study on the Structural and Antioxidant Properties of Three Flavonols

The structural and antioxidant activity properties of three flavonols kaempferol, galangin and morin have been investigated at density functional level of theory with the aim of verifying experimental findings. The potentialities of antioxidant activity are highly related to their capabilities to scavenge free radicals. Two potential working mechanisms of the hydrogen-atom transfer and single-electron transfer are reported by which antioxidants can play their role. Two parameters of the O-H bond dissociation enthalpy (BDE) and ionization potential (IP) in the presence of water medium are computed to estimate the antioxidant capacities. Results indicate that the order of antioxidant efficacies predicted theoretically in this work is in agreement with that reported by experimental results of oxygen radical-scavenging capacity (ORAC) assay. This demonstrates the importance of the hydrogen-atom and single-electron transfer mechanisms to explain their capacities to scavenge peroxyl radical.     

Spin-dependent absorption of water molecules

The effects of spin state of water molecules on its absorption on lyophilized DNA, lysozyme and some inorganic sorbents were studied. It was shown that the absorption rates of ortho and para water from vapor differ noticeably. The para isomer binding with preparations is distinctly faster than that of the ortho isomer in all cases. Clear-cut distinction in the sorption kinetics is determined by the difference in quantum statistics for spin isomers, which in its turn can give rise to remarkable differences in physico-chemical properties of ortho and para water. This finding opens a wide field of activity in studying fundamental and applied problems relating to the role of the spin state of water molecules in physics, chemistry, biology and medicine.     

The influence of pH on antioxidant properties and the mechanism of antioxidant action of hydroxyflavones

The effect of the pH on antioxidant properties of a series of hydroxyflavones was investigated. The pKa of the individual hydroxyl moieties in the hydroxyflavones was compared to computer-calculated deprotonation energies. This resulted in a quantitative structure activity relationship (QSAR), which enables the estimation of pKa values of individual hydroxyl moieties, also in hydroxyflavones for which these pKa values are not available. Comparison of the pKa values to the pH-dependent antioxidant profiles, determined by the TEAC assay, reveals that for various hydroxyflavones the pH-dependent behavior is related to hydroxyl moiety deprotonation, resulting in an increase of the antioxidant potential upon formation of the deprotonated forms. Comparison of these experimental results to computer calculated O-H bond dissociation energies (BDE) and ionization potentials (IP) of the nondeprotonated and the deprotonated forms of the various hydroxyflavones indicates that especially the parameter reflecting the ease of electron donation, i.e., the IP, and not the BDE, is greatly influenced by the deprotonation. Based on these results it is concluded that upon deprotonation the TEAC value increases (radical scavenging capacity increases) because electron-, not H*-, donation becomes easier. Taking into account that the mechanism of radical scavenging antioxidant activity of the neutral form of the hydroxyflavones is generally considered to be hydrogen atom donation, this implies than not only the ease of radical scavenging, but also the mechanism of antioxidant action changes upon hydroxyflavone deprotonation.     

Evaluation of the antioxidant properties of propofol and its nitrosoderivative. comparison with homologue substituted phenols

Propofol (2,6-diisopropylphenol), some substituted phenols (2,6-dimethylphenol and 2,6-ditertbutylphenol) and their 4-nitrosoderivatives have been compared for their scavenging ability towards 1,1-diphenyl-2-picrylhydrazyl and for their inhibitory action on lipid peroxidation. These products were also compared to the classical antioxidants butylated hydroxytoluene and butylated hydroxyanisole. When measuring the reactivity of the various phenolic derivatives with 1,1-diphenyl-2-picrylhydrazyl the following order of effectiveness was observed: butylated hydroxyanisole > propofol > 2,6-dimethylphenol > 2,6-di-tertbutylphenol > butylated hydroxytoluene. In cumene hydroperoxide-dependent microsomal lipid peroxidation, propofol acts as the most effective antioxidant, while butylated hydroxyanisole, 2,6-di-tertbutylphenol and butylated hydroxytoluene exhibit a rather similar effect, although lower than propofol. In the iron/ascorbate-dependent lipid peroxidation propofol, at concentrations higher than 10 microM, exhibits antioxidant properties comparable to those of butylated hydroxytoluene and butylated hydroxyanisole, 2,6-Dimethylphenol is scarcely effective in both lipoperoxidative systems. The antioxidant properties of the various molecules depend on their hydrophobic characteristics and on the steric and electronic effects of their substituents. However, the introduction of the nitroso group in the 4-position almost completely removes the antioxidant properties of the examined compounds. The nitrosation of the aromatic ring of antioxidant molecules and the consequent loss of antioxidant capacity can be considered a condition potentially occurring in vivo since nitric oxide and its derivatives are continuously formed in biological systems.     

Evaluation of the Antioxidant Properties of Propofol and its Nitrosoderivative. Comparison with Homologue Substituted Phenols

Propofol (2,6-diisopropylphenol), some substituted phenols (2,6-dimethylphenol and 2,6-ditertbutylphenol) and their 4-nitrosoderivatives have been compared for their scavenging ability towards 1,1-diphenyl-2-picrylhydrazyl and for their inhibitory action on lipid peroxidation. These products were also compared to the classical antioxidants butylated hydroxytoluene and butylated hydroxyanisole. When measuring the reactivity of the various phenolic derivatives with 1,1-diphenyl-2-picrylhydrazyl the following order of effectiveness was observed: butylated hydroxyanisole>propofol>2,6-dimethylphenol>2,6-di-tertbutylphenol?>?butylated hydroxytoluene. In cumene hydroperoxide-dependent microsomal lipid peroxidation, propofol acts as the most effective antioxidant, while butylated hydroxyanisole, 2,6-di-tertbutylphenol and butylated hydroxytoluene exhibit a rather similar effect, although lower than propofol. In the iron/ascorbate-dependent lipid peroxidation propofol, at concentrations higher than 10?μM, exhibits antioxidant properties comparable to those of butylated hydroxytoluene and butylated hydroxyanisole. 2,6-Dimethylphenol is scarcely effective in both lipoperoxidative systems. The antioxidant properties of the various molecules depend on their hydrophobic characteristics and on the steric and electronic effects of their substituents. However, the introduction of the nitroso group in the 4-position almost completely removes the antioxidant properties of the examined compounds. The nitrosation of the aromatic ring of antioxidant molecules and the consequent loss of antioxidant capacity can be considered a condition potentially occurring in vivo since nitric oxide and its derivatives are continuously formed in biological systems.     

Density functional theory calculations for resveratrol

The calculations based on the density functional theory (DFT) have been used to study the structure-activity of resveratrol in the chain reaction of autooxidation. According to the geometry obtained by using a B3LYP/6-31G**, the HOMO, LUMO of resveratrol and the spin density, the single electron distribution of the 4'- and 5-radical of resveratrol were calculated, it was found that resveratrol is a potential antioxidant. The 4'-hydroxyl group of resveratrol is more reactive than 3- and 5-positions because of the resonance effects. The dominant structure of the resveratrol radicals is a semiquinone structure which determines the stability of radicals, and the unpaired electron is mainly distributed to the O-atom and its ortho and para positions. The antioxidant activity of resveratrol is related to the spin density and the unpaired electron distribution of the O-atom.     

A theoretical study on the structure-activity relationships of metabolites of folates as antioxidants and its implications for rational design of antioxidants

To elucidate the structure-activity relationships of metabolites of folates as antioxidants, the O-H bond dissociation enthalpies (BDEs) and ionization potentials (IPs) for these compounds were calculated by density functional theory (DFT) on B3LYP/6-31+G(,3pd) level. Accordingly, the antioxidant activity difference for metabolites of folates can be elucidated by O-H BDE and IP values and can be further explained in terms of electronic effect and intramolecular hydrogen bond effect of substituents. Furthermore, the potential of the active center of metabolites of folates, 4-hydroxypyrimidine (4-HP), as lead antioxidant, was evaluated by comparing the BDEs and IPs of 4-HP with those of 5-hydroxypyrimidine (5-HP). It was revealed that 4-HP and 5-HP held identical IPs, but the O-H BDE of the former was 22.84 kcal/mol higher than that of the latter, which meant 4-HP was inert in H-atom donation. Nevertheless, the O-H BDE of 4-HP was very sensitive to the substituents, which made NH2-derivatives of 4-HP very active as antioxidants. Therefore, 4-HP is also a potential lead antioxidant and deserves attention in rational design of antioxidants.     

Theoretical investigation of the radical scavenging activity of shikonin and acylshikonin derivatives

The radical scavenging activity of shikonin and acylshikonin derivatives was studied by using density functional theory. The hydrogen bond property of the studied structures was investigated using the atoms in molecules (AIM) theory. It turned out that the hydrogen bond is important for good radical scavenging activity. The hydrogen atom transfer for shikonin and acylshikonin derivatives is difficult to obtain because of the high bond dissociation energy (BDE). However, shikonin and acylshikonin derivatives appear to be good candidates for the one-electron-transfer. The introduction of acyl groups for shikonin decreases the ionization potential (IP) values compared with that of shikonin. The acylshikonin derivatives with 1H-pyrrole, furan, and thiophene groups are expected to be of the highest radical scavenging activity among the compounds investigated in this study. Taking this system as an example, we present an efficient method for the investigation of radical scavenging activity from theoretical point of view.     

Benchmarking the DFT methodology for assessing antioxidant-related properties: quercetin and edaravone as case studies

The overall objective was to identify an accurate computational electronic method to virtually screen phenolic compounds through their antioxidant and free-radical scavenging activity. The impact of a key parameter of the density functional theory (DFT) approach was studied. Performances of the 21 most commonly used exchange-correlation functionals are thus detailed in the evaluation of the main energetic parameters related to the activities of two prototype antioxidants, namely quercetin and edaravone, is reported. These functionals have been chosen among those belonging to three different families of hybrid functionals, namely global, range separated, and double hybrids. Other computational parameters have also been considered, such as basis set and solvent effects. The selected parameters, namely bond dissociation enthalpy (BDE), ionization potential (IP), and proton dissociation enthalpy (PDE) allow a mechanistic evaluation of the antioxidant activities of free radical scavengers. Our results show that all the selected functionals provide a coherent picture of these properties, predicting the same order of BDEs and PDEs. However, with respect to the reference values, the errors found at CBS-Q3 level significantly vary with the functional. Although it is difficult to evidence a global trend from the reported data, it clearly appears that LC-ωPBE, M05-2X, and M06-2X are the most suitable approaches for the considered properties, giving the lowest cumulative mean absolute errors. These methods are therefore suggested for an accurate and fast evaluation of energetic parameters related to an antioxidant activity via free radical scavenging.     

Spin isomeric selectivity of water molecules upon DNA hydration

Four-photon coherent scattering of laser radiation was used to study the influence of DNA on the content of quasi-free ortho and para isomers of water molecules in its aqueous solution. It was shown that the concentration of quasi-free molecules that form the rotational spectrum of spin isomers increases considerably in the hydration shell of the DNA molecule as compared with pure water. The increase in the concentration of spin isomers occurs disproportionally. In the presence of DNA, the intensity of the rotational spectrum of ortho isomers is on the average much greater than that of para isomers. It was also demonstrated that the character of hydration and the ortho/para ratio change noticeably upon DNA denaturation, which may be evidence of changes in preferable solvation of DNA during its denaturation. The data obtained allowed us to assume that the stability of different biologically important states of macromolecules can be changed by varying the relative concentration of water spin isomers in solution.     

三种黑米花色苷自由基清除能力的理论评价

用一种组合的密度泛函理论方法计算了三种黑米花色苷的O-H键解离焓和电离势,以此作为理论指标评价其自由基清除能力。计算结果发现花色苷的电离势和总抗氧化能力存在良好的线性关系,提示电离势表征的质子转移伴随电子转移的反应机制在清除自由基的过程中发挥着重要作用。     

Antioxidative and antiradical properties of plant phenolics

The plant phenolic compounds such as flavonoids, tannins and phenolic acids appeared to be strong antiradical and antioxidant compounds. The number of hydroxy groups and the presence of a 2,3-double bond and orthodiphenolic structure enhance antiradical and antioxidative activity of flavonoids. The glycosylation, blocking the 3-OH group in C-ring, lack of a hydroxy group or the presence of only a methoxy group in B-ring have a decreasing effect on antiradical or antioxidative activity of these compounds. Tannins show strong antioxidative properties. Some tannins in red wine or gallate esters were proved to have antioxidative effect in vivo. The number of hydroxy groups connected with the aromatic ring, in ortho or para position relative to each other, enhance antioxidative and antiradical activity of phenolic acids. The substitution of a methoxy group in ortho position to the OH in monophenols seems to favour the antioxidative activity of the former.     

The role of regioselective hydroxylation on toxicity of diclofenac and related derivatives

ABSTRACT

Diclofenac and related derivatives become more toxic after biotransformation reactions in the body by electron or hydrogen transfers. The structure–reactivity study on regioselective hydroxylation of diclofenac acid was elucidated by using quantum chemistry calculations at level of DFT/B3LYP/6-31G(d,p). HOMO, ionisation potential, bond dissociation energy, and spin density distributions were used as chemical reactivity parameters. Also, some properties are related to lumiracoxib and fenclofenac. The higher flexibility of lumiracoxib can be responsible for the increase of COX₂ selectivity. Diphenyl-amine moiety is responsible for their potent antioxidant capacity. Chloro atoms have a strong effect under electron transfer capacity when compared to acetic acid group. Hydroxylation for the 5-hydroxydiclofenac is more favoured in either electron or hydrogen transfers. Both hydroxylation increased the electron donation and antioxidant capacity. These properties were observed to the fenclofenac derivatives and can be related to their toxicity by redox mechanism.