HAT Mechanism Research Articles

Analysis of the antioxidant activity of 4-(5-chloro-2-hydroxyphenylamino)-4-oxobut-2-enoic acid derivatives using quantum-chemistry descriptors and molecular docking.

In the present work, the molecular structure and the antioxidant activity of 4-(5-chloro-2-hydroxyphenylamino)-4-oxobut-2-enoic acid (A) and its derivatives (B-E) have been studied at the B3LYP/6-31++G(2d,2p) computational level. The obtained results indicate that the hydrogen atom transfer (HAT mechanism) is thermodynamically more favored in gas phase; whereas, the sequential proton loss-electron transfer (SPLET mechanism) is more preferred in polar solvents. The antioxidant activity of compounds A-E is also analyzed by the calculation of atomic spin densities, chemical hardnesses, dipole moments, and lipophilicity indexes. It turns out that compound E (R = t-Bu) is predicted to be more antioxidant than ascorbic acid and other derivatives A-D in both gas phase and polar solvents. The high antioxidant activity of compound E compared to other derivatives A-D is also rationalized using the molecular docking technique.

A computational investigation on the structure, global parameters and antioxidant capacity of a polyphenol, Gallic acid.

A computational DFT-B3LYP structural analysis of a poly phenol, Gallic acid (GA) has been performed by using 6-311++ G (df, p) basis set. The GA is a relatively stable molecule with considerable radical scavenging capacity. It is a well known antioxidant. The NBO analysis shows that the aromatic system is delocalized. The results reveal that the most stable radical is formed at O3-atom upon scavenging the free radicals. Global descriptive parameters show that GA acts as an acceptor center in charge transfer complex formation which is supported by ESP and contour diagrams and also by Qmax value. The GA is a good antioxidant and it can be better understood by HAT and TMC mechanisms as it has low BDE, ΔHacidity and ΔGacidity values. The ΔBDE and ΔAIP values also confirm that the antioxidant capacity of GA can be explained through HAT rather than the SET-PT mechanism.

A comparison of scytonemin and its carbon analogue in terms of antioxidant properties through free radical mechanisms and conformational analysis: a DFT investigation.

Scytonemin is a UV absorbing sheath pigment synthesized uniquely by cyanobacteria. Its biological features has attracted interest ecologically (in microbial mat systems), medically (for therapeutic activity) and astrobiologically (as a key biomarker). Recently, a carbon analogue of scytonemin, in which two nitrogen atoms are replaced by carbon atoms was synthesized to elucidate the origin of biological activity by comparison with scytonemin. In this work, their structural/conformational aspects and relative antioxidant capacity are compared making use of DFT calculations to provide insight about the similarities and differences between the two. The carbon analogue of scytonemin, isoelectronic with scytonemin, has the same structural skeleton and a similar potential energy surface but the hydrogens on the carbons that replace the nitrogens cause the phenolic rings to rotate out of the plane which is obseved for scytonemin. Thermochemically, the carbon analogue of scytonemin prefers the same radical scavenging mechanism scytonemin does, the HAT mechanism, and has a lower homolytic bond dissociation enthalpy for the OH group than that of scytonemin and other known antioxidants like ascorbic acid. The carbon analogue of scytonemin is suggested to be a novel synthetic antioxidant.

An exploratory study on the peroxyl-radical-scavenging activity of 2,6-dimethyl-5-hepten-2-ol and its heterocyclic analogues

The structural properties and radical scavenging activity of 2,6-dimethyl-5-hepten-2-ol (1) and its new heterocyclic analogues, i.e. 2-methyl-4-(5-methylfuran-2-yl)-butan-2-ol (2) and 2-methyl-4-(5-methylthiophen-2-yl)-butan-2-ol (3) and have been studied by using the experimental and theoretical methods for the first time. Activity of title compounds against the peroxyl radical was determined by using standard fluorimetric test, i.e. the Oxygen Radical Absorbance Capacity assay (ORACFL). Furthermore, the electron-donating ability of odorants has been evaluated by using colorimetric ABTS assay. According to the experimental results obtained from the ORACFL test 2,6-dimethyl-5-hepten-2-ol was characterized by the highest activity in comparison with the novel counterparts. Nevertheless, all investigated compounds exhibited pronounced anti-peroxyl radical activity comparable to that exerted by the one of the most prominent antioxidant among the monoterpene alcohols, i.e. by linalool. On the other hand, the title compounds exerted relatively low capacity to quench the radical cation of ABTS. Theoretical calculations based on the Density Functional Theory (DFT) method with the hybrid functional B3LYP were carried out in order to investigate selected structural and electronic properties including the geometrical parameters as well as the energy of frontier molecular orbitals of parent molecules and the resulting radicals. Furthermore, the possible mechanism of peroxyl-radical-scavenging has been determined by using the thermodynamic descriptors such as the bond dissociation enthalpies (BDEs) and ionization potentials (IPs). These theoretical data pointed out the relevance of HAT mechanism in the peroxyl-radical-scavenging exhibited by 2,6-dimethyl-5-hepten-2-ol and its new heterocyclic analogues in polar and non-polar medium.

Influence of structural characteristics of substituents on the antioxidant activity of some anthraquinone derivatives

The antioxidant activity of chrysophanol (CH), emodin (EM), aloe-emodin (AE), and 1,3,8-trihydroxyanthraquinone (THA) was examined in water and pentyl ethanoate by using the M052X/6-311++G(d,p) level of theory. It was shown that hydrogen bonds are of significant importance for the stability of the radical and anionic species obtained in the HAT and SPLET mechanisms. Consequently, all radicals and anions formed with retention of O9⋯H1–O1 and O9⋯H8–O8 hydrogen bonds are more stable than those where the hydrogen bonds are disturbed. The exceptions are the radical and anion of AE, the unpaired electron or negative charge is poorly delocalized.The high IP values for all investigated compounds undoubtedly discredit the SET-PT mechanism. Since the PA values are notably lower than the BDE values, one can conclude that SPLET is more favorable reaction pathway than the HAT mechanism in both solvents. In the case of CH and AE 1-OH and 8-OH are the most reactive sites for radical inactivation, while 3-OH is the most reactive site for EM and THA. The examined compounds are moderate antioxidants.

Details of the antioxidant mechanism of hydroxycinnamic acids

Antioxidant activities and free radical-mediated DNA strand breakages of five hydroxycinnamic acids were examined. Kinetic analysis of a stable galvinoxy (GO•)-scavenging reaction of hydroxycinnamic acids demonstrated that the molecular structure and the reaction medium were two important factors affecting the antioxidant mechanism and activity. In methanol, the kinetic process of the compounds, which have electron-donating groups (-OH, -OCH 3 ) in the ortho - or para -position of 4-OH, was primarily governed by the sequential proton loss electron transfer (SPLET mechanism). While, in ethyl acetate, the reaction mechanism is predominantly direct hydrogen atom transfer (HAT mechanism). But for the compounds having only one hydroxyl, both in ethyl acetate and methanol, the reaction mechanism is only HAT. At the same time, the compound bearing o-diphenoxyl is not the most active one in our tested environment.

Theoretical study of anticancer properties of indolyl-oxazole drugs and their interactions with DNA base pairs in gas phase and solvent

In this study, the anticancer properties of a series of synthesized indolyl-oxazoles drugs 1–6 and their interactions with DNA base pairs were investigated. The quantum molecular descriptors (chemical potential, hardness, and electrophilicity) for studied drugs and their complexes with DNA base pairs were calculated. The reaction enthalpies (BDE and IP) of HAT and SET-PT mechanism of anticancer action of drugs 1–6 were calculated. Results reveal that interactions of indolyl-oxazole drugs with DNA base pairs are energetically favorable and solvent increase the binding energies in comparison with gas phase. The binding energies of drugs 4–6 DNA base pairs complexes are more negative than corresponding values for drugs 1–3. The obtained binding energy and reaction enthalpy (BDE and IP) trends for drugs 1–6 confirm pervious experimental anticancer activity trends. IC50 scale has been used as a benchmark for measuring the anticancer activity. Based on theoretical and published experimental scales, drugs 4, 5, and 6 have higher anticancer activity among drugs 1–6. Finally, according to the obtained results, drugs 7–10 can consider as novel drugs with higher anticancer activity than drug 1. Results show that binding energies of drugs 7–10 with DNA base pairs were more negative than corresponding values for drugs 1–6. The BDE and IP values of drugs 4–10 were lower than corresponding values of drug 1. For drugs 1–10, results indicated that the SET-PT and HAT mechanisms represent the thermodynamically preferred mechanism in solvent and gas phase, respectively.

Energy requirements of the reactions of kaempferol and selected radical species in different media: towards the prediction of the possible radical scavenging mechanisms

Kaempferol, one of the most bioactive plant flavonoids was experimentally and theoretically (at M05-2X/6-311G(d,p) level of theory) investigated for its ability to scavenge potentially, highly damaging hydroxyl and superoxide anion radicals. Relating the obtained hydroxyl radical activity sequence with kaempferol structural features, it could be assumed that C4′-OH functional most probably renders it as hydroxyl radical scavenger, while C5-OH group has more prominent role compared to ortho-hydroxy groups in B ring. However, kaempferol’s activity toward superoxide anion radical implicates ortho-hydroxy groups in B ring as more relevant. Theoretical calculations point to HAT and SPLET mechanisms as operative for kaempferol in all solvents under investigations. The present paper aims to provide quantitative tools to thoroughly and comprehensively determine antiradical mechanisms of kaempferol in different media.

Investigation of the radical scavenging potency of hydroxybenzoic acids and their carboxylate anions

In this article, the antoxidative mechanisms HAT, SPLET, and SET-PT of the ortho-, meta-, and para-hydroxybenzoic acids and corresponding carboxylate anions with different radicals (·OO−, ·OH, ·OOH, and CH3OO·) were investigated. For this reason, the ΔH BDE, ΔH IP, and ΔH PA values of the corresponding reactions in different solvents (water, DMSO, pentylethanoate, and benzene) were examined. For this purpose, the M05-2X/6-311++G(d,p) and B3LYP-D2/6-311++G(d,p) theoretical models were applied. Although the B3LYP-D2 method produced lower reaction enthalpy values, both theoretical models exhibited the same trend. It was found that SET-PT is not a favorable reaction path for any hydroxybenzoic acids and their anions with any radicals in any solvents. No anion reacts with −·O2, whereas meta- and para-hydroxybenzoic acids react with −·O2 only in nonpolar solvents. In all other cases, the HAT and SPLET mechanisms are competitive. Which of them is dominant depends on the properties of the acids, anions, radicals, and solvents.

ANTIOXIDANT ACTIVITY OF AMINOTHIAZOL HYDROXYCOUMARIN DERIVATIVES

In this work, the antioxidant properties of the series of 10 aminothiazol hydroxyl coumarin derivatives have been investigated with DFT/B3LYP method. For these antioxidants all reaction enthalpies related to HAT, SPLET, SET-PT mechanisms were calculated in the gas phase and polar solvents. Based on calculated reaction enthalpies (BDE, IP and PA values) the derivations 2, 3 and 4 have the highest antioxidant activity among the studied compounds. Calculated results show that derivations 7, 5 and 6 have the lowest antioxidant activity. The observed theoretical trends for antioxidant activities of studied compounds were similar to trends of previous experimental studies that OH50, TAC50, IC50, CE50 values have been used as a benchmark for measuring the antioxidant properties of these compounds. These results can be useful in synthesis of novel aminothiazol hydroxycoumarin derivatives with high antioxidant activity. Calculated results show that BDE, PA and IP values of studied derivations have linear dependence with structure parameters such as R( O – H ), q( O ) and EHOMO. These observed linear dependences can be useful in synthesis of novel aminothiazol hydroxyl coumarin derivatives with high antioxidant activity. For studied compounds, results indicated that the SPLET and HAT mechanisms represent the thermodynamically preferred mechanism both, in solvent and the gas phase.

On the Antioxidant Activity of the Tryptophan Derivatives

Abstract The antioxidant activity of ortho- and meta-substituted tryptophan derivatives has been investigated in the gas phase and water. The reaction enthalpies of antioxidant activity of studied derivatives have been calculated and compared with corresponding values of tryptophan. Results show that EWG substituents increase the BDE, IP, and ETE while EDG appendages cause a rise in the PA and PDE. The tryptophan derivatives with lowest BDE, IP, and PA values were identified as the compounds with high antioxidant activity. Results show that the substituents in ortho-position have high potential for synthesis of novel tryptophan derivatives. Results show that EDG-substituted tryptophans can process their protective role via HAT mechanism in gas phase. On the other hand, SPLET mechanism represents the thermodynamically favored process for EWG-substituted tryptophans in water. The calculated reaction enthalpies of the substituted tryptophans have linear dependences with Hammett constants and EHOMO that can be utilized in the selection of suitable substituents for the synthesis novel antioxidants based on tryptophan.

Hydroxychalcones as potent antioxidants: Structure–activity relationship analysis and mechanism considerations

Hydroxychalcones (1–6) with different numbers and positions of hydroxyl groups on the two aromatic rings were synthesised, and their antioxidant activities against the stable galvinoxyl (GO) radical in ethanol and ethyl acetate, and free radical-mediated lipid peroxidation of human red blood cells and DNA strand breakage were systematically examined. Kinetic analysis of the GO-scavenging reaction and the quantum chemical calculations of O–H bond dissociation enthalpy (BDE) demonstrate that the molecular structure and the reaction medium are two important factors affecting the antioxidant mechanism and activity. In ethanol, that supports ionisation, the antioxidant reaction of the compounds (1, 2 and 3), bearing o-dihydroxyl groups, occurs primarily by sequential proton loss electron transfer (SPLET mechanism) while, in ethyl acetate, the reaction mechanism is predominantly direct hydrogen atom transfer (HAT mechanism). For the other compounds (4, 5 and 6), in both ethyl acetate and ethanol, the reaction mechanism is only HAT.

The Logic of Policy Change after Crisis: Proximity and Subsystem Interaction

AbstractWhat mechanisms link external events to policy change in a policy subsystem? This paper responds to this question by offering a nuanced re‐conceptualization of external events and by identifying the mechanisms that link disruptive crises to policy change. Building from the tenets of the advocacy coalition framework and a synthesis of the crisis management and policy change literatures, this paper (1) introduces the concept of policy and geographical proximity as a means to show how different types of crises alter the incentives for policy action within policy subsystems; (2) discusses an integrated set of proposals on how geographical and policy proximity affects the prospects of change in a policy subsystem; and (3) presents hypothesized scenarios outlining plausible intervening pathways linking a crisis to changes as contingent on policy subsystem structures.

Antioxidant activity of α-pyridoin and its derivatives: possible mechanism

alpha-Pyridoin (1, 1,2-di(2-pyridyl)-1,2-ethenediol) is a unique enediol antioxidant. To explore the detailed antioxidant mechanism of alpha-pyridoin, we synthesized alpha-pyridoin and its 5,5'- or 6,6'-bis-substituted derivatives (2-7) and compared their capacities to scavenge galvinoxyl radical (GO*) and protect human red blood cells (RBCs) from oxidative haemolysis. It was found that the compounds (5 and 6) with a methyl or methoxy group at the 5-position exhibit significantly higher GO*-scavenging and anti-haemolysis activities than other derivatives and vitamin C. Kinetic analysis of the GO*-scavenging reaction and the effect of added base on the reaction rate revealed that in ethyl acetate, the reaction occurs primarily by the direct hydrogen atom transfer (HAT mechanism). However, in ethanol that supports ionization, the kinetics of the process is mostly governed by sequential proton loss electron transfer (SPLET mechanism).

Role of the reacting free radicals on the antioxidant mechanism of curcumin

Density functional theory is used to study the antioxidant mechanism of curcumin. Five different mechanisms are considered: single electron transfer (SET), radical adduct formation (RAF), H atom transfer from neutral curcumin (HAT), H atom transfer from deprotonated curcumin (HAT-D), and sequential proton loss electron transfer (SPLET). The influence of the environment is investigated for polar and non-polar surroundings. The apparent contradictions among previous experimental results are explained by the role of the nature of the reacting free radical on the relative importance of the above mentioned mechanism. It is proposed that the curcumin + DPPH reaction actually takes place mainly through the SPLET mechanism, while the reaction with OCH 3, and likely with other alkoxyl radicals, is governed by the HAT mechanism. Branching ratios for the OCH 3 + curcumin reaction are reported for the first time. The calculated overall rate constants for this reaction are 1.16 × 10 10 (benzene) and 5.52 × 10 9 (water) L mol −1 s −1. The role of phenolic groups on the antioxidant activity of curcumin has been experimentally confirmed.

Oxidation mechanism of phenols by dicopper-dioxygen (Cu(2)/O(2)) complexes.

The first systematic studies on the oxidation of neutral phenols (ArOH) by the mu-eta(2):eta(2)-peroxo)dicopper(II) complex (A) and the bis(mu-oxo)dicopper(III) complex (B) supported by the 2-(2-pyridyl)ethylamine tridentate and didentate ligands L(Py2) and L(Py1), respectively, have been carried out in order to get insight into the phenolic O-H bond activation mechanism by metal-oxo species. In both cases (A and B), the C-C coupling dimer was obtained as a solely isolable product in approximately 50% yield base on the dicopper-dioxygen (Cu(2)/O(2)) complexes, suggesting that both A and B act as electron-transfer oxidants for the phenol oxidation. The rate-dependence in the oxidation of phenols by the Cu(2)/O(2) complexes on the one-electron oxidation potentials of the phenol substrates as well as the kinetic deuterium isotope effects obtained using ArOD have indicated that the reaction involves a proton-coupled electron transfer (PCET) mechanism. The reactivity of phenols for net hydrogen atom transfer reactions to cumylperoxyl radical (C) has also been investigated to demonstrate that the rate-dependence of the reaction on the one-electron oxidation potentials of the phenols is significantly smaller than that of the reaction with the Cu(2)O(2) complexes, indicative of the direct hydrogen atom transfer mechanism (HAT). Thus, the results unambiguously confirmed that the oxidation of phenols by the Cu(2)O(2) complex proceeds via the PCET mechanism rather than the HAT mechanism involved in the cumylperoxyl radical system. The reactivity difference between A and B has also been discussed by taking account of the existed fast equilibrium between A and B.

Fragmentation reactions of aromatic cation radicals: a tool for the detection of electron transfer mechanisms in biomimetic and enzymatic oxidations.

1. Mechanistic criteria, based on the side-chain fragmentation reactions of aromatic cation radicals, involving the cleavage of a beta bond (i.e. C-H, C-Si and C-S) have been developed for the detection of electron transfer mechanisms in oxidative processes of alkylbenzenes and aromatic sulphides. 2. For benzylic oxidations, the distinction between electron transfer (ET) and hydrogen atom transfer mechanism (HAT) has been based: (a) on studies of intramolecular selectivity, which, with appropriate substrates (5-Z-1,2,3,-trimethylbenzenes and 4-Z-1,2-dimethylbenzenes, where Z = OMe, alkyl), turns out to be much higher in ET than in HAT processes; and (b) on products studies concerning the reactions of bicumyl and benzyltrimethylsilanes since in these systems, the nature of products can be significantly different for ET and HAT mechanisms. 3. These criteria have been applied to the reactions of alkylbenzenes with an NO3 radical (shown to be an ET process) as well as to the microsomal and biomimetic (by iron porphyrins in the presence of PhIO) side-chain oxidation of the same compounds, where the mechanistic probes have suggested a HAT mechanism, with the exception of the biomimetic oxidation of 4-methoxybenzyltrimethylsilane in CH2Cl2-H2O-MeOH, which probably occurs by an ET mechanism. 4. For the enzymatic and biomimetic oxidation of aromatic sulphides an oxygen transfer is suggested, since, with cumyl phenyl sulphide and 4-methoxybenzyl phenyl sulphide, these reactions lead exclusively to the corresponding sulphoxides and sulphones, whereas the same substrates, in genuine ET reactions, form cation radicals which undergo C-H and C-S bond cleavage. 5. An oxygen transfer mechanism is also likely in the biomimetic and enzymatic oxidations of sulphoxides since in these reactions 4-methoxybenzyl phenyl sulphoxide is exclusively converted to sulphone, whereas in ET reactions it forms only C-S bond cleavage products.