SET PT Research Articles

Synthesis, characterization, and comprehensive computational analysis of aromatic hydrazone compounds: Unveiling quantum parameters, evaluating antioxidant activity, and investigating molecular docking interactions

This study presents a synergistic approach encompassing experimental synthesis, computational analysis, and antioxidant activity evaluation of two aromatic hydrazone compounds, namely 4-[(2E)-2-(2-nitrobenzylidene) hydrazinyl] benzoic acid (NBHZ) and 4-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] benzoic acid (HBHZ). Efficient synthesis yielded impressive quantities (70 % and 58 %, respectively), and structural characterization employed IR, UV–Vis, and NMR spectroscopy. Antioxidant potential was assessed using the DPPH free radical scavenging assay, revealing distinct capabilities of NBHZ and HBHZ, each featuring a nitro (NO2) and a hydroxy (OH) group, respectively, at the ortho position. HBHZ exhibited superior efficacy (IC50 = 1.15 μg/mL) compared to NBHZ (IC50 = 2.1 μg/mL) and the standard antioxidant BHT (IC50 = 1.83 μg/mL). Computational analyses using Gaussian 09 at the B3LYP/6–311 G(d,p) level elucidated electronic characteristics, molecular electrostatic potential (MEP), HOMO-LUMO energies, and global reactivity descriptors. VEDA 4 further investigated vibrational behavior and potential energy distribution (PED), topological analyses electron localization function (ELF), localized orbital locator (LOL), average localized ionization energy (ALIE), and reduced density gradient (RDG) were identified to evaluate their interactions. Thermochemical parameters explored antioxidant mechanisms (hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT), and sequential proton loss electron transfer (SPLET)). Molecular docking via iGEMDOCK revealed binding interactions with the target NADPH oxidase. These findings not only provide insights into the compounds' antioxidant potential but also underscore the impact of specific molecular features on their properties. This integrated approach contributes to advancing the understanding of hydrazone compounds, guiding the design of materials with tailored functionalities for applications in oxidative stress mitigation.

Physicochemical Studies of Benzocaine Bearing Heterocycles as Potential Antioxidant Agents

Series of new thirteen annulated heterocyclic were prepared and screened for their antioxidant activities. The ethyl-4(2-cyanoacetamido)benzoate as a multifunctional component which possess both electrophilic and nucleophilic centers that were utilized in organic synthesis of different candidates. These new compounds studied as antioxidants at different concentrations based on DPPH and ABTS assays using ascorbic acid as a standard antioxidant. The most potent compound was 5 that recorded as the best antioxidant compound with IC50 equal 0.006 mg/ml for DPPH results. While for ABTS study, compound 4 anticipated the best result with IC50 equal 27.46 µM. Different reactive and thermodynamic descriptors were calculated as a preliminary step for a comparative thermodynamic study for antioxidant property. The results clarified that the potent compounds showed dependence on SET–PT mechanism than HAT or SPLET mechanism. These mechanisms depended on different parameters as proton affinity and electron transfer energy that were studied. SET–PT mechanism was dependent on two descriptors: IP and BDE which were studied and observed that were less-valued in site A for two potent compounds 4 and 5.

Synthesis, DFT Calculations, and In Vitro Antioxidant Study on Novel Carba-Analogs of Vitamin E.

Vitamin E is the most active natural lipophilic antioxidant with a broad spectrum of biological activity. α-Tocopherol (α-T), the main representative of the vitamin E family, is a strong inhibitor of lipid peroxidation as a chain-breaking antioxidant. Antioxidant and antiradical properties of vitamin E result from the presence of a phenolic hydroxyl group at the C-6 position. Due to stereoelectronic effects in the dihydropyranyl ring, the dissociation enthalpy for phenolic O–H bond (BDEOH) is reduced. The high chain-breaking reactivity of α-T is mainly attributed to orbital overlapping of the 2p-type lone pair on the oxygen atom (O1) in para position to the phenolic group, and the aromatic π-electron system. The influence of the O1 atom on the antioxidant activity of vitamin E was estimated quantitatively. The all-rac-1-carba-α-tocopherol was synthesized for the first time. Along with model compounds, 1-carba-analog of Trolox and its methyl ester were screened for their in vitro antioxidant activity by inhibition of styrene oxidation, and for the radical-reducing properties by means of 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) scavenging assay. To study the antioxidant activity, density functional theory (DFT) was also applied. Reaction enthalpies related to HAT (hydrogen atom transfer), SET–PT (sequential electron transfer—proton transfer), and SPLET (sequential proton loss—electron transfer) mechanisms were calculated.

Antioxidant activity and pKa calculations of 4‑mercaptostilbene and some derivatives: A theoretical approach

The radicals scavenging activity of some mercaptostilbenes and their hydroxyl analogs were investigated with the density functional theory method. The HAT, SET–PT and SPLET mechanisms were studied in vacuum and some solvents and the BDE, AIP, PDE, PA, ETE were calculated. The SPLET process represents the most thermodynamically preferred reaction pathway in water and methanol, however, the HAT mechanism is preferred in both benzene and vacuum. The SET–PT mechanism is not preferred in all media studied, because AIP values are higher than BDE and PA values. The pKa values of the studied compounds were calculated. The results revealed that the acidity of the mercaptostilbenes was higher than those of the hydroxy analogs in all models studied, as was also indicated in experimental works. These results also can be used for both food and pharmaceutical industries.

Natural language aggregate query over RDF data

Natural language question/answering over RDF (Resource Description Framework) data has received widespread attention. Although several studies can address a small number of aggregate queries, these studies have many restrictions (e.g., interactive information, controlled questions or query templates). Thus far, there has been no natural language querying mechanism that can process general aggregate queries over RDF data. Therefore, we propose a framework called NLAQ (Natural Language Aggregate Query). First, we propose a novel algorithm to automatically understand a user's query intention, which primarily contains semantic relations and aggregations. Second, to build a better bridge between the query intention and RDF data, we propose an extended paraphrase dictionary ED to obtain more candidate mappings for semantic relations, and we introduce a predicate-type adjacent set PT to filter out inappropriate candidate mapping combinations in semantic relations and basic graph patterns. Third, we design a suitable translation plan for each aggregate category and effectively distinguish whether an aggregate item is numeric, which will greatly affect the aggregate result. Finally, we conduct extensive experiments over real datasets (QALD benchmark and DBpedia). The experimental results demonstrate that our solution is effective.

Thermodynamic study of vitamin B6 antioxidant potential

For the aromatic OH group in pyridoxine, pyridoxal, pyridoxamine (vitamin B6 components) and their metabolite pyridoxic acid, reaction enthalpies related to various mechanisms of primary antioxidant action, i.e. Hydrogen Atom Transfer (HAT), Single Electron Transfer–Proton Transfer (SET–PT) and Sequential Proton-Loss Electron-Transfer (SPLET) were investigated. B3LYP, M05-2X and M06-2X functionals were employed in this study. Two solvation models were used for the solution-phase calculations in benzene and water: integral equation formalism polarized continuum model, IEF–PCM, as well as newer SMD method. All computational approaches provide identical trends. Comparison of found results with data obtained previously for phenol, α-tocopherol and flavonols indicates that vitamin B6 may show weaker antioxidant effect than naturally occurring phenolic antioxidants.

Antiradical potential of phenolic compounds fingerprints of propolis extracts: DFT approach

Phenolic compounds are the major chemical constituents of propolis extracts (PE) and are characterized by possessing antiradical activity. In this work the structure-antiradical properties relationship of flavonoids (chrysin, galangin, pinocembrin and pinostrobin) and phenolic acid (caffeic acid phenethyl ester) commonly found in PE was investigated trough M05-2X functional in conjunction with the 6-31G(d,p) and 6-31+G(d,p) basis sets, considering the structural properties, and free-radical inhibition mechanism: H-atom transfer (HAT), the stepwise electron-transfer–proton-transfer (SPLET) and the sequential proton loss electron transfer (SET–PT). To complement the ability of phenolic compounds to act as antiradical the chemical indexes and Fukui indexes were analyzed. Thermodynamically, the HAT mechanism contributes much in the antiradical activity of reactive group (O–H and C–H) of phenolic compounds. All compounds present a greater tendency to give electrons than to attract them. We found different reactive sites for nucleophilic, electrophilic and radical attack in molecules, which could mark differences in their antiradical activity.

On the role of ethylene bridge elongation in the antioxidant activity of polyhydroxylated stilbenes: A theoretical approach

Abstract The aim of this work is to investigate the elongation effect of the conjugated links of the 7–8 double bond of trans -resveratrol and its analogs on the antioxidant activity in vacuo and water using a quantum chemistry calculation by the Density Functional Theory (DFT) method. H atom transfer (HAT), single-electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) mechanisms were investigated. The highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), and the spin density were calculated. The results reveal that the elongation of the conjugated links plays an important role in promoting the antioxidant properties of molecules because of its lowering effect on BDE, spin density, AIP, and PA values. The higher antioxidant activity of 3,4 dihydroxystilbene (A 4 ) and trans , trans -3,4-dihydroxybistyryl (B 4 ) may be from the abstraction of the hydrogen atoms of the ortho-position hydroxyls. This abstraction can occur continuously to form a semiquinone structure, or even a quinone structure. On the other hand, the compounds bearing the 4,4′-DHS skeleton exhibit strong antioxidant activity due to their para-quinone structure. The results indicate correspondences between the theoretical and the experimental results. Moreover, our calculations suggest that the HAT mechanism is the most important and dominant mechanism in vacuo, the SPLET mechanism is the most thermodynamically favourable pathway in water, while the SET–PT mechanism is not preferred in all the environments studied.

DFT studies on antioxidant mechanisms, electronic properties, spectroscopic (FT-IR and UV) and NBO analysis of C-glycosyl flavone, an isoorientin

The relationship between structure and electronic properties of isoorientin, a C-glycoside flavone is investigated to relate its radical scavenging activity using molecular descriptors. To elucidate the antioxidant activity of polyphenolics, three mechanisms namely hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT) and sequential proton-loss electron-transfer (SPLET) are employed. In gas-phase, OH bond dissociation enthalpies (BDE), ionization potential (IP), proton dissociation enthalpies (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) are computed and correlated relevant to antioxidant potency of the title compound employing DFT/6-311G(d,p) protocol. The theoretically simulated FT-IR and the UV–visible absorption spectra have been compared with the experimental data. Based on the absorbed UV spectra and TD-DFT calculations, assignment of the absorption bands are carried out. In addition, formation of intramolecular hydrogen bond and most possible interaction sites are explained by using natural bond orbital (NBO) analysis.

Reaction enthalpies of O[sbnd]H bonds splitting-off in flavonoids: The role of non-polar and polar solvent

Flavonoids play important role in the scavenging of free radicals in biological systems. As the phenolic chain-breaking antioxidants they can act via three distinct mechanisms, namely hydrogen atom transfer (HAT), Single Electron Transfer–Proton Transfer (SET–PT) and Sequential Proton-Loss Electron-Transfer (SPLET). Therefore, it is inevitable to study the corresponding reaction enthalpies in solution-phase. For 10 naturally occurring flavonoids: apigenin, luteolin, fisetin, kaempferol, quercetin, epicatechin, taxifolin, tricetin, tricin and cyanidin, OH bond dissociation enthalpies, ionization potentials, proton dissociation enthalpies, proton affinities and electron transfer enthalpies were investigated using IEF-PCM B3LYP/6-311++G∗∗ method in benzene and water in order to: (i) identify the thermodynamically preferred mechanism and OH group in the two solvents and (ii) describe the solvent effect on the homolytic and heterolytic cleavage of OH groups in studied flavonoids.

Homolytic and heterolytic O–H bond cleavage in trans-resveratrol and some phenantrene analogs: A theoretical study

In this article, quantum chemical calculations based on the density functional theory (DFT) have been used to study the relationship between the structure and the antioxidant activity of trans-resveratrol (RSV) and its phenantrene analogs in the gas phase, benzene and water. Our investigation includes H-atom transfer (HAT), single electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) mechanisms. The calculated values were in good agreement with the experimental results. Like other phenolic compounds, the H-atom transfer mechanism is the thermodynamically preferred mechanism in vacuum, for the studied molecules. While, the SPLET mechanism is the thermodynamically favorable pathway in water. Our calculations suggest that, SET–PT is not the most preferred mechanism in all environments studied.

Density functional theory study of the structure–antioxidant activity of polyphenolic deoxybenzoins

Quantum chemical calculations based on the density functional theory (DFT) have been employed to study the relationship between the structure and the antioxidant activity of four polyphenolic deoxybenzoins (DOBs) in solvents and the gas phase. The three main working mechanisms, H-atom transfer (HAT), single electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) have been investigated. The calculated results closely matched experimental values. The results obtained prove that for the HAT mechanism, the most efficient system possessed ortho-dihydroxy functionality. The results suggested that HAT would be the most favourable mechanism for explaining the radical-scavenging activity of polyphenolic DOBs in the gas phase, whereas the SPLET mechanism is the thermodynamically favourable pathway in polar solvents.

Tocopheramines and tocotrienamines as antioxidants: ESR spectroscopy, rapid kinetics and DFT calculations

Tocopheramines (TNH2) and tocotrienamines (T3NH2) are analogues of tocopherols (TOH) and tocotrienols in which phenolic OH is replaced by NH2. It was shown in previous studies that TNH2 and T3NH2 act as potent antioxidants. In this study we compared the one-electron oxidation of TNH2/T3NH2 by diphenyl picryl hydrazyl (DPPH) and galvinoxyl (GOX) radicals with the one of α-TOH as a reference compound using ESR spectroscopy, stopped flow spectrophotometry and density functional theory (DFT) calculations. ESR spectroscopy revealed the presence of tocopheramine radicals during electrochemical oxidation of α-TNH2. Kinetic measurements demonstrated that in apolar n-hexane TNH2/T3NH2 derivatives reacted two to three orders of magnitude slower than α-TOH with the model radicals. DFT calculations indicated that this correlates well with the higher bond dissociation energy (BDE) for N–H in TNH2 than for O–H in α-TOH in pure H-atom transfer (HAT). In the more polar medium ethanol TNH2/T3NH2 derivatives partially reacted faster than α-TOH depending on the reaction partner. DFT calculations suggest that this is due to reaction mechanisms alternative to HAT. According to thermochemistry data sequential proton loss and electron transfer (SPLET) is more favored for α-TOH in ethanol than for TNH2. Therefore, for TNH2 a contribution of the alternative mechanism of sequential electron transfer–proton transfer (SET–PT) could be a possible explanation. These data show that the antioxidant reactivity strongly depends on the structure, reaction partners and environment. According to these findings TNH2/T3NH2 should be superior as antioxidants over α-TOH in polar head group regions of membranes but not in the apolar core of lipid bilayers.

THEORETICAL STUDY OF THE SUBSTITUENT EFFECTS ON THE REACTION ENTHALPIES OF THE ANTIOXIDANT MECHANISMS OF STOBADINE DERIVATIVES IN THE GAS-PHASE AND WATER

In this paper the reaction enthalpies of three antioxidant action mechanisms, HAT, SET–PT, and SPLET, for mono-substituted Stobadines were calculated in gas-phase and water. Results show that electron-withdrawing substituents increase the bond dissociation enthalpy (BDE), ionization potential (IP), and electron transfer enthalpy (ETE), while electron-donating ones cause a rise in the proton dissociation enthalpy (PDE) and proton affinity (PA). In comparison to gas-phase, water attenuates the substituent effect on all reaction enthalpies. Results show that IP and BDE values can be successfully correlated with the indolic N–H bond length after electron abstraction, R(N–H+•), and the partial charge on the indolyl radical nitrogen atom, q( N ). Furthermore, calculated IP and PA values for mono-substituted Stobadines show linear dependence on the energy of the highest occupied molecular orbital (E HOMO ) of studied molecules in the two environments. SPLET represents the thermodynamically preferred mechanism in water.

Theoretical investigation of the conformational, electronic and antioxidant properties of azaleatin, isorhamnetin and quercetagetin

Gas phase and solvent phase reaction enthalpies related to the individual steps of three phenolic antioxidants in the view of action mechanisms – hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) – have been calculated using DFT/B3LYP/6-311++G** method. The analysis of the theoretical bond dissociation enthalpy (BDE) values for all OH sites of studied compounds clearly shows the importance of ring B, the presence of a catechol moiety in ring A and the 3-OH group in which the C2 = C3 double bond is present. The analysis of structure–acidity and structure–activity relationships for these flavonoids clearly indicates that the hydroxyl group at position 7 to be the most acidic site except for that of azaleatin. The analysis also includes the heat of formation, highest occupied molecular orbital and spin density distribution for the radicals formed after H-removal on each OH site. The calculated ionisation potential, BDE and proton dissociation enthalpy values suggest that one-step H-atom transfer, rather than SPLET or SET–PT, would be the most favourable mechanism for explaining the antioxidant activity of considered molecules in the gas phase. From the thermodynamic point of view, SPLET mechanism represents the most probable process in water and HAT mechanism in represents the most probable process benzene. On the basis of computed reaction enthalpies, the most active system able to transfer a hydrogen atom seems to be the quercetagetin followed by azaleatin and isorhamnetin.

DFT/B3LYP Study of the Substituent Effects on the Reaction Enthalpies of the Antioxidant Mechanisms of Sesamol Derivatives in the Gas phase and water

In this paper, the study of various ortho and meta–substituted Sesamol derivatives is presented. The reaction enthalpies related to three antioxidant action mechanisms HAT, SET–PT, and SPLET for substituted Sesamols, have been calculated using the DFT/B3LYP method in gas phase and water. Calculated results show that electron-withdrawing substituents increase the bond dissociation enthalpy (BDE), ionization potential (IP), and electron transfer enthalpy (ETE), while electron-donating ones cause a rise in the proton dissociation enthalpy (PDE) and proton affinity (PA). In the ortho position, substituents show a larger effect on reaction enthalpies than in the meta position. In comparison with the gas phase, water attenuates the substituent effect on all reaction enthalpies. In the gas phase, BDEs are lower than PAs and IPs, i.e., HAT represents the thermodynamically preferred pathway. On the other hand, the SPLET mechanism represents the thermodynamically favored process in water. Results show that calculated enthalpies can be successfully correlated with Hammett constants (σm) of the substituted Sesamols. Furthermore, calculated IP and PA values for substituted Sesamols show linear dependence on the energy of the highest occupied molecular orbital (EHOMO).

On the energetics of homolytic and heterolytic O[sbnd]H bond cleavage in flavonoids

Comprehensive study of three mechanisms of phenolic chain-breaking antioxidant action, i.e. hydrogen atom transfer (HAT), Single Electron Transfer–Proton Transfer (SET–PT) and Sequential Proton-Loss Electron-Transfer (SPLET), for eight naturally occurring flavonoids (polyphenols): apigenin, luteolin, fisetin, kaempferol, quercetin, epicatechin, taxifolin and cyanidin, is presented. Gas-phase OH bond dissociation enthalpies, ionization potentials, proton dissociation enthalpies, proton affinities and electron transfer enthalpies related to these mechanisms were investigated using B3LYP/6-311++G** method. Selection of flavonoids enables to evaluate the effects of various structural features, such as hydroxy groups (3′-OH, 3-OH, 5-OH), C2C3 double bond and C4O keto group, present in the molecules on studied reaction enthalpies. Lowest OH bond dissociation enthalpies (HAT) and proton affinities (SPLET) have been found mostly for 4′-OH groups at ring B. In the second step of SET–PT mechanism, formation of radicals at 4′-OH positions is also thermodynamically favored. However, for five flavonoids, lowest values of electron transfer enthalpies were found in rings A or C.

A DFT study on the structural, electronic properties and radical scavenging mechanisms of calycosin, glycitein, pratensein and prunetin

Antioxidative properties of naturally occurring isoflavonoids calycosin, glycitein, pratensein, prunetin and their radicals were investigated through density functional theory (DFT) method employing B3LYP/6-311G(d,p) and B3LYP/6-311+G(d,p) methods.The reaction enthalpies related to the individual steps of three phenolic antioxidant action mechanisms–hydrogen atom transfer (HAT), single-electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) have been computed. The bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), electron transfer enthalpy (ETE) were determined in gas phase and in two solvents. The relative energies of each OH groups, highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO) and spin density distribution for radicals were computed and discussed. From the molecular structure and thermodynamic point of view, it was found that B-ring of isoflavonoids to be the active center and the hydrogen atom transfer (HAT) appeared as a major mechanism which contributes much in antioxidant action in gas phase. The SPLET mechanism will be the thermodynamically preferred pathway in polar solvents. On the basis of the computed IP, BDE and PA values most active system was found to be pratensein followed by calycosin, glycitein and prunetin. The analysis of structure–activity relationships for four isoflavonoids clearly indicates that hydroxyl group at position 7 to be the most acidic site.

DFT/B3LYP study of the solvent effect on the reaction enthalpies of homolytic and heterolytic O [sbnd]H bond cleavage in mono-substituted chromans

The study of various ortho and meta substituted chroman derivatives was carried out. The reaction enthalpies related to the hydrogen atom transfer (HAT) mechanism and to individual steps of two stepwise mechanisms of phenolic antioxidants action, single electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) have been calculated using DFT/B3LYP method in solution phase using Polarized Continuum Model (PCM) method. The effects of solvents with various polarities and substituent effect have been investigated. Results show that electron-donating substituents induce a rise in the proton dissociation enthalpy (PDE) and proton affinity (PA), whereas electron-withdrawing groups cause an increase in the bond dissociation enthalpy (BDE), ionization potential (IP) and electron transfer enthalpy (ETE). It has been found that substituents in ortho positions have significantly greater influence on BDE, PA and ETE in comparison with those in meta position. On the contrary, substituents in meta position show higher effect on IP and PDE than substituents in ortho positions. In comparison to gas phase, studied solvents attenuate the substituent effect on the reaction enthalpies of three studied mechanisms. From the thermodynamic point of view, entering SPLET mechanism represents the most probable process in polar solvents like water, DMSO and ethanol, where PA values of studied substituted chromans are considerably lower than BDEs and IPs. However, in benzene, BDEs are lower than PA and IP values, i.e. HAT represents the most probable pathway. Computed results reveal that all dependences of reaction enthalpies on Hammett constants of the substituents in meta position are linear in all solvents.

DFT/B3LYP study of the substituent effect on the reaction enthalpies of the individual steps of single electron transfer–proton transfer and sequential proton loss electron transfer mechanisms of chroman derivatives antioxidant action

In this paper, the study of various ortho and meta-substituted chroman-6-ol derivatives is presented. The reaction enthalpies related to the individual steps of two stepwise mechanisms of phenolic antioxidants action, single electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET), for studied compounds have been calculated using DFT/B3LYP method in gas-phase and water. Results reveal that electron-donating substituents induce rise in the proton dissociation enthalpy (PDE) and proton affinity (PA) whereas Electron withdrawing groups cause increase in the ionization potentials (IP) electron transfer enthalpy (ETE). Result indicated substituents in ortho have in comparison with the substituents in meta position significantly greater influence on PA and ETE, on the contrary, substituents in meta position cause considerable effect on IP and PDE rather than substituents in ortho positions. Results reveal that water attenuates the substituent effect on IP, PA and PDE values. Computed results indicate that all dependences of reaction enthalpies on Hammett constants of the substituents are linear. From the thermodynamic point of view, SPLET mechanism represents the most promising process in water. Furthermore, results show that calculated enthalpies can be correlated with the length of phenolic C–O and O–H + (bond length of O–H after electron abstraction) bonds and partial charge on the phenoxy radical oxygen atom q(O) of the studied molecules successfully.