Sequential Proton Loss Electron Transfer 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.

Flavonoid Oxidation Potentials and Antioxidant Activities-Theoretical Models Based on Oxidation Mechanisms and Related Changes in Electronic Structure.

Herein, I will review our efforts to develop a comprehensive and robust model for the estimation of the first oxidation potential, Ep1, and antioxidant activity, AA, of flavonoids that would, besides enabling fast and cheap prediction of Ep1 and AA for a flavonoid of interest, help us explain the relationship between Ep1, AA and electronic structure. The model development went forward with enlarging the set of flavonoids and, that way, we had to learn how to deal with the structural peculiarities of some of the 35 flavonoids from the final calibration set, for which the Ep1 measurements were all made in our laboratory. The developed models were simple quadratic models based either on atomic spin densities or differences in the atomic charges of the species involved in any of the three main oxidation mechanisms. The best model takes into account all three mechanisms of oxidation, single electron transfer-proton transfer (SET-PT), sequential proton loss electron transfer (SPLET) and hydrogen atom transfer (HAT), yielding excellent statistics (R2 = 0.970, S.E. = 0.043).

Theoretical Study of Radical Scavenging Antioxidant Activity of Coumarin Derivatives in Licorice Using DFT

Nowdays, much research is focused on exploring antioxidant activity based on natural compounds. Licorice, a traditional natural product rich in antioxidant components, has been widely used in clinical medicine. However, there is a lack of theoretical studies on the active components in licorice. In this context, the antioxidant activity of several common active components of coumarin derivatives in licorice was investigated using a density flooding theory (DFT) approach. The free radical scavenging ability of the compounds was achieved by hydrogen atom transfer (HAT), sequential electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) mechanisms. The effect of solvent on antioxidant activity was also investigated. It was found that in the gas and benzene phases, the compounds studied preferred to undergo the HAT mechanism, while SPLET was favoured in polar solvents. In addition to the above mechanism, the HOMO and LUMO energies of the compounds as well as molecular descriptors and electrostatic potential maps were calculated and applied to predict the antioxidant activity of the compounds. The above studies allow a better understanding of the mechanism of free radical scavenging activity of coumarin derivatives from licorice.

Antioxidant properties of catechin and its 3′O-α-glucoside: Insights from computational chemistry calculations

Density functional theory (DFT) calculations were used to investigate the conformational landscape of catechin and one of its main glucoside derivative (catechin-3′ O- α −glucopyranoside), and to determine the corresponding antioxidant properties. These investigations were carried out in benzene and water using the SMD universal continuum solvation model. Both properties were found to be significantly affected. The structures are characterized in both solvents by strong intramolecular hydrogen bonds (IMHB). In an apolar environment, Hydrogen Atom Transfer (HAT) is by far favored whereas in water the Sequential Proton Loss Electron Transfer (SPLET) mechanism is strongly preferred. In benzene, the catechin fragment has the best antioxidant character (from 27 kJ/mole) whereas in polar surroundings, the glucoside derivative has a slightly better antiradical activity (from 5 kJ/mole). Our results confirm the key role of the 3′-OH and 4′-OH groups of the catechole ring in these properties.

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

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. 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.

Theoretical Exploration of Enhanced Antioxidant Activity in Copper Complexes of Tetrahydroxystilbenes: Insights into Mechanisms and Molecular Interactions.

A theoretical investigation was conducted using DFT/PW91/TZP/DMSO calculations on a complete set of exhaustive lists of 18 compounds resulting from the complexation of trans-2,4,3',5'-tetrahydroxystilbene (T-OXY) and cis-2,4,1',3'-tetrahydroxystilbene (C-OXY) with copper metal cations (Cu+ and Cu2+). The ligand-binding sites are the critical points of Quantum Theory of Atoms in Molecules (QTAIM) analysis on neutral and deprotonated ligands. Various mechanisms, including hydrogen atom transfer (HAT), sequential proton loss electron transfer (SPLET), single electron transfer followed by proton transfer (SET-PT), and bond dissociation energy (BDE(E0)) calculations, were employed to quantify the antioxidant activity. The BDE(E0) mechanism emerged as the most suitable approach for such analyses to evaluate the departure of hydrogen atoms since the results show the HAT mechanism is the most likely occurring. Particularly intriguing were the anionic Cu+ complexes with ligands adopting trans configurations and deprotonated conformations, displaying superior antioxidant activity compared to their counterparts. Remarkably, a single ligand within the Cu+ complex exhibited exceptional antioxidant prowess, yielding a BDE(E0) value of 91.47 kcal/mol. Furthermore, a complex involving two deprotonated ligands demonstrated antioxidant activity of 31.12 kcal/mol, signifying its potential as a potent antiradical agent, surpassing T-OXY by a factor of 3.91 and even surpassing the antioxidant efficiency of Vitamin C.

Antioxidant Activity via Free Radical Scavenging of Pitavastatin and Its Hydroxylated Derivatives: A Quantum Chemical Attempt Aiming to Assist Drug Development

AbstractAlthough experiments have long provided empirical evidence that statins can suppress various oxidation pathways, theoretical attempts to quantify the antioxidant activity of statins (read, atorvastatin ATV, the only one studied so far) are not published until last year. Extensive results reported here for pitavastatin (PVT) and derivatives include the thermodynamic antioxidant descriptors (bond dissociation enthalpy [BDE], adiabatic ionization potential [IP], proton dissociation enthalpy [PDE], proton affinity [PA], and electron transfer enthalpy [ETE]) related to the three antioxidant mechanisms (hydrogen atom transfer [HAT], stepwise electron transfer proton transfer [SETPT], sequential proton loss electron transfer [SPLET]). The particular emphasis is on the PVT's hydroxylated derivatives wherein a hydroxy group replaces a hydrogen atom either on the quinoline core (Q‐hydroxylated metabolites) or on the fluorophenyl ring (F‐hydroxylated metabolites). The calculations indicate that both the Q‐ and F‐hydroxylated derivatives possess antioxidant properties superior to the parent PVT molecule. Given the fact that, to the best of the knowledge, no experimental data for the antioxidant potency of PVT and its hydroxylated derivatives exist, this is a theoretical prediction for the validation of which it is aimed hereby to stimulate companion experimental in vivo and in vitro investigations and inspire pharmacologists in further drug developments.

Predicting the activity of methoxyphenol derivatives antioxidants: II-Importance of the nature of the solvent on the mechanism, a DFT study.

The various mechanisms of primary antioxidant action of a series of 2-Methoxyphenols are investigated in the present work. The electronic properties have just been studied in a joint article, so that we focus here on Hydrogen Atom Transfer (HAT), Single Electron Transfer-Proton Transfer (SET-PT) and Sequential Proton-Loss Electron-Transfer (SPLET) mechanisms. The two computational approaches used in the previous study of the structure and reactivity of these compounds [Computational and Theoretical Chemistry 1229 (2023) 114287] provide identical mechanisms trends in gas phase. In gas media, hydrogen atom transfer (HAT) is more favored. On the contrary, the solvent polarity has a significant effect on the mechanism of the antioxidant activity, since the polarity of the solvent increases the contribution of the SPLET mechanism.

Investigation of novel radical scavenging mechanisms in the alkaline environment: Green, sustainable and environmentally friendly antioxidative agent(s)

Pharmaceutical and industrial utilization of synthetic chemicals has an immerse impact on the environment. In that sense, novel chemicals with potential for industrial application should be investigated for their behaviour in reactions with hydroxyl radical, simulating AOPs (Advanced Oxidation Processes). AOPs are known for being highly effective in wastewater management and natural water remediation. In this paper, exhaustive research on the radical scavenging activity of a newly synthesized coumarin derivative (4HCBH), as a representative of the series of coumarin-benzohydrazides with high antioxidative potential was conducted. This study took into consideration the pH value range significant for practically all living organisms (pH = 7.0–8.5). According to the experimentally obtained results, the 4HCBH showed an increase in radical scavenging activity, following the slight increase in pH values, which suggested that the formation of anionic form of 4HCBH is responsible for its antiradical activity. Further investigations led to the postulation of a novel mechanistic approach called Sequential Proton Loss Electron Transfer – Radical-Radical Coupling (SPLET-RRC), in which, by a series of steps, a new, stable compound was formed. Furthermore, it was demonstrated that the product generated through SPLET-RRC showed lower toxicity than the parent molecule.

Role of the Solvent and Intramolecular Hydrogen Bonds in the Antioxidative Mechanism of Prenylisoflavone from Leaves of Vatairea guianensis.

This work discusses the electron structure, antioxidative properties, and solvent contribution of two new antioxidant molecules discovered, named S10 and S11, extracted from a medicinal plant called Vatairea guianensis, found in the Amazon rain-forest. To gain a better understanding, a study using density functional theory coupled with the polarizable-continuum model and the standard 6-311++G(d,p) basis set was conducted. The results indicate that S10 has a higher antioxidant potential than S11, confirming the experimental expectations. In the gas phase, the hydrogen atom transfer route dominates the hydrogen scavenging procedure. However, in the water solvents, the antioxidant mechanism prefers the sequential proton loss electron transfer mechanism. Furthermore, the solvent plays a fundamental role in the antioxidant mechanism. The formation of an intramolecular OH···OCH3 hydrogen bond is crucial for accurately describing the hydrogen scavenging phenomenon, better aligning with the experimental data. The results suggest that the two isoflavones investigated are promising for the pharmacologic and food industries.

Synthesis, Spectroscopic Characterization, DFT, and Molecular Docking Analysis of Some Salicylideneaniline Schiff Base Derivatives as Potential Antioxidant Compounds

This study explores the synthesis and characterization of three Schiff base compounds, namely N-(2-hydroxybenzylidene)-m-chloroaniline (1), N-(2-hydroxybenzylidene)-m-nitroaniline (2), and N-(2-hydroxybenzylidene)-m-methoxyaniline (3). Comprehensive spectroscopic analyses involving FT-IR, H1NMR, and UV-Vis were employed to elucidate their molecular structures. Theoretical calculations were conducted using the DFT/B3LYP method with the 6-311 + G (d, p) basis set, elucidating electronic transitions and providing comprehensive vibrational assignments. The study identifies key electronic features of these compounds by analyzing global chemical reactivity descriptors. Density functional theory (DFT) was employed to assess the ability of these compounds to scavenge free radicals, both in the gas phase and solvent environment, focusing on three primary mechanisms: hydrogen atom transfer (HAT), stepwise electron-transfer-proton transfer (ET-PT), and sequential proton-loss-electron transfer (SPLET). Additionally, the research explores drug-likeness properties and conducts molecular docking investigations against the ubiquinol cytochrome c reductase protein (UQCRB) to gain further insights into potential biological activities.

Antiradical Activity of Lignans from Cleistanthus sumatranus: Theoretical Insights into the Mechanism, Kinetics, and Solvent Effects.

Sumatranus lignans (SL) isolated from Cleistanthus sumatranus have demonstrated bioactivities, e.g., they were shown to exhibit immunosuppressive properties in previous research. Their structure suggests potential antioxidant activity that has not attracted any attention thus far. Consistently, a comprehensive analysis of the antioxidant activity of these compounds is highly desirable with the view of prospective medical applications. In this work, the mechanism and kinetics of the antiradical properties of SL against hydroperoxyl radicals were studied by using calculations based on density functional theory (DFT). In the lipid medium, it was discovered that SL reacted with HOO• through the formal hydrogen transfer mechanism with a rate constant of 101-105 M-1 s-1, whereas in aqueous media, the activity primarily occurred through the sequential proton loss electron transfer mechanism with rate constants of 102-108 M-1 s-1. In both lipidic and aqueous environments, the antiradical activity of compounds 6 and 7 exceeds that of resveratrol, ascorbic acid, and Trolox. These substances are therefore predicted to be good radical scavengers in physiological environments.

Simultaneously regulating absorption capacities and antioxidant activities of four stilbene derivatives utilizing substitution effect: A theoretical and experimental study against UVB radiation

With the continued depletion of the ozone layer, the sun protection consciousness of humans has gradually enhanced. Long-term ultraviolet (UV) rays exposure will lead to skin tanning, even skin cancer in severe cases, and generate free radicals to cause skin aging. To better protect human skin against UV rays, this work explores the absorption capacities and antioxidant activities of four stilbene derivatives (EHDB, EDMB, EAPD, and HPTP) through the computational chemistry method and DPPH radical scavenging experiment. The research results indicate that their absorption spectra cover the entire UV region, and can effectively protect against UVB radiation. Moreover, three prevailing antioxidant mechanisms: hydrogen atom transfer, sequential proton loss electron transfer, and single electron transfer followed by proton transfer mechanisms, were used to evaluate their antioxidant activities in the ground state. It can be concluded that the O1H1 sites of EHDB and HPTP are the most active, and the SPLET mechanism is the most preferred for the four compounds in ethanol solvent. Furthermore, the DPPH radical scavenging experiment compensates for the theoretical calculation deficiency in the excited state, revealing that the EHDB and HPTP are the most suitable for sunscreen due to their excellent performance on antioxidant capacities, whether before or after sunlight. This work will facilitate EHDB and HPTP to be applied in sunscreen and provide a novel idea in sunscreen research.

Radical scavenging activity of three Scirpusins: A kinetic and mechanistic study

The strong antioxidant activity of Scirpusin, a polyphenolic compound also known as resveratrol or piceatannol dimer, toward •OH/•OOH in gas phase and solvents was investigated through systematic thermodynamics and kinetics analyses using the density functional theory method. All mechanisms, including hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT), sequential proton loss electron transfer (SPLET), and radical adduct formation (RAF), were investigated. The transition state theory was used to calculate potential energy surfaces and rate constants for HAT and RAF. The results revealed that Scirpusins exhibited considerable antioxidant activity, which followed the sequence: Scirpusin-B > Scirpusin-C ≈ Scirpusin-A, the amount of o-bisphenol is essential to enhance their antioxidant activity. Furthermore, Scirpusin-A, Scirpusin-B, and Scirpusin-C with structures of 13′-OH, 12′-OH, and 2-OH, respectively, shared the same parent nucleus but exhibited distinct strongest reactive sites. This result can provide a guidance for Scirpusin application in the future.

Understanding prominent effects of the intramolecular hydrogen bond on the photophysical properties and antiradical abilities of six flavonoids

The photophysical properties and antiradical abilities of 5-Hydroxyflavone, 3,5-Dihydroxyflavone, galangin, kaempferol, quercetin, and myricetin are explored using density functional theory and time-dependent density functional theory methods. The absorption spectra of the six flavonoids span the entire ultraviolet region, and their fluorescence peak intensities are faint, meeting the sunscreen requirements. Furthermore, their max absorption peaks are mainly affected by the hydroxyl groups in the A- and C-rings of the compounds. The hydrogen atom transfer, sequential proton loss electron transfer and single electron transfer followed by proton transfer mechanisms are used to evaluate their antiradical abilities. It can be concluded that the O4-H4 site of myricetin is the most active site to scavenge free radicals, revealing that the formation of intramolecular hydrogen bonds can significantly enhance molecular antiradical abilities. In a word, altering tactfully hydrogen group position is conducive to regulating the photophysical properties and antiradical abilities of flavonoids.

Revisiting the scavenging activity of glutathione: Free radicals diversity and reaction mechanisms

Glutathione (GSH) is the most abundant low-molecular-mass thiolated compound in plants and animals, highly relevant in humans since it is one of the principal antioxidant agents capable of scavenging reactive oxygen species (ROS). In addition, it has a function in the immune system and in cell proliferation, and most recently it was discovered that it works against COVID-19. Considering the high flexibility of glutathione, with an atomic configuration and charge state susceptible to minimal changes in its chemical environment, it is of relevance to ascertain what is the scavenging capacity of each of the most probable glutathione species under physiological conditions. In order to find the site and mechanism that contributes the most to the antioxidant activity of GSH, density functional theory (DFT) calculations on multiple species of this molecule were performed in this work. Reactivity indexes, related to hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) mechanism were calculated for glutathione. In addition, Gibbs free energies of reaction (ΔG) were obtained for the reactions of GSH with several free radicals to confirm the thermochemical viability of each antioxidant mechanism and to avoid misleading conclusions in terms of considering energetically unfavorable reactions. The results confirm that HAT is the chemical route contributing the most to the antioxidant activity of GSH. However, at least for one radical of interest, SPLET should also be considered.

Radical Scavenging Capability and Mechanism of Three Isoflavonoids Extracted from Radix Astragali: A Theoretical Study.

As a valuable traditional Chinese herbal medicine, Radix Astragali has attracted much attention due to its extensive pharmacological activities. In this study, density functional theory (DFT) was used thermodynamically and kinetically in detail to predict the antioxidant activity and reaction mechanisms involved in the free radical scavenging reactions of three representative isoflavonoids (formononetin, calycosin, and calycosin-7-glucoside) extracted from Radix Astragali. Three main mechanisms, including hydrogen atom transfer (HAT), proton transfer after electron transfer (SET-PT), and sequential proton loss electron transfer (SPLET) were examined by calculating the thermodynamic parameters. It was found that HAT is the predominant mechanism in the gas phase, while SPLET is supported in the solvent environment. The isoflavonoids' order of antioxidant activity was estimated as: calycosin > calycosin-7-glucoside > formononetin. For the calycosin compound, the result revealed the feasibility of double HAT mechanisms, which involve the formation of stable benzodioxazole with significantly reduced energy in the second H+/e- reaction. In addition, the potential energy profiles and kinetic calculations show that the reaction of •OH into the 3'-OH site of calycosin has a lower energy barrier (7.2 kcal/mol) and higher rate constant (4.55 × 109 M-1 s-1) compared with other reactions in the gas phase.

A broad assessment of Eremurus spectabilis M. Bieb: chemical and elemental composition, total phenolic and antimicrobial activity analysis, and quantum chemical calculations of radical scavenging potential

ABSTRACT Eremurus spectabilis M. Bieb was extensively investigated experimentally and theoretically, including the antioxidant properties of compounds such as flavonoids, hydroxycinnamic acid derivatives, hydroxybenzoic acid derivatives, and organic acids. Antioxidant activity was investigated using the Density Functional Theory (DFT) method based on three known mechanisms: hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET). Subcritical water extraction (SWE), soxhlet extraction (SE), and solvent extraction (SOE) techniques were applied in the extraction process. Malic acid was the major compound with an extract concentration of 38,532.84 ± 1849.58 µg analyte/kg, total phenolics, and free radical scavenging activity were 10.67 mg gallic acid/mL extract and 73.89% per mg/mL extract, respectively. P, Fe, Na, Mg, K, and Ca were the main elements. The antibacterial activity of E. spectabilis against seven bacteria was evaluated, and it was found to be higher than the commercial antibiotics P10 and AMC30.

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.

Evaluation of the radical scavenging potency and mechanism of natural phenolamides: A DFT study

Phenolamides have received increasing interest owing to their diverse pharmacological activities and health benefits. However, the structure–antioxidant activity relationship and underlying mechanism are still largely unclear. Herein, thermodynamic and kinetic calculations based on density functional theory (DFT) were carried out to clarify the antioxidant effects and mechanisms of four aromatic monoamines conjugated phenolamides (AMCPs). The results show that solvent effect plays a crucial role in modulating the action mechanisms for the studied phenolamides. In non-polar media, the studied AMCPs prefer to trap radicals via the formal hydrogen atom transfer (fHAT) mechanism, while in polar solvents the radical-scavenging reaction proceeds via mixed mechanisms with sequential proton loss electron transfer (SPLET), sequential proton loss hydrogen atom transfer (SPLHAT) and sequential double proton loss electron transfer (SdPLET) depending on the pH of environments. 4-OH in A-ring was found to be the preferred site to trap radical for CoTrp and CaTrp, while 5′–OH in C-ring for CoSer and FeSer. Moreover, the representative compound CaTrp was predicted to has excellent HOO scavenging potency (koverall = 3.15 × 108 M−1 s−1) in water at physiological pH, stronger than the two well-known antioxidants Trolox and ascorbic acid, and thus deserves to further utilization as nutraceutical or pharmaceutical candidates.