Jasmina M. Dimitrić Marković

PM6 and DFT study of free radical scavenging activity of morin

Flavonoids have long been recognised for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work, we have studied the properties of flavonoid morin using semiempirical and density functional theory (DFT) methods in order to validate the application of the recently developed parametric method 6 (PM6). Reaction enthalpies related to mechanisms of free radical scavenging by flavonoid morin were calculated by DFT and PM6 methods in gas-phase, water, DMSO and benzene. It has been shown that fast semiempirical PM6 method can mimic results obtained by means of more accurate time consuming DFT calculations. Thermodynamically favoured mechanism depends on reaction medium: SPLET (sequential proton loss electron transfer) is preferred in water and DMSO, and HAT (hydrogen atom transfer) is predominant in gas-phase. In benzene these two mechanisms are competitive.

Towards an improved prediction of the free radical scavenging potency of flavonoids: the significance of double PCET mechanisms.

The 1H(+)/1e(-) and 2H(+)/2e(-) proton-coupled electron transfer (PCET) processes of free radical scavenging by flavonoids were theoretically studied for aqueous and lipid environments using the PM6 and PM7 methods. The results reported here indicate that the significant contribution of the second PCET mechanism, resulting in the formation of a quinone/quinone methide, effectively discriminates the active from inactive flavonoids. The predictive potency of descriptors related to the energetics of second PCET mechanisms (the second O-H bond dissociation enthalpy (BDE2) related to hydrogen atom transfer (HAT) mechanism, and the second electron transfer enthalpy (ETE2) related to sequential proton loss electron transfer (SPLET) mechanism) are superior to the currently used indices, which are related to the first 1H(+)/1e(-) processes, and could serve as primary descriptors in development of the QSAR (quantitative structure-activity relationships) of flavonoids.

PM6 study of free radical scavenging mechanisms of flavonoids: why does O–H bond dissociation enthalpy effectively represent free radical scavenging activity?

AbstractIt is well known that the bond dissociation enthalpy (BDE) of the O–H group is related to the hydrogen atom transfer (HAT) mechanism of free radical scavenging that is preferred in gas-phase and non-polar solvents. The present work shows that the BDE may also be related to radical scavenging processes taking place in polar solvents, i.e., single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). This is so because the total energy requirements related to the SET-PT [sum of the ionization potential (IP) and proton dissociation enthalpy (PDE)] and the SPLET [sum of the proton affinity (PA) and electron transfer enthalpy (ETE)] are perfectly correlated with the BDE. This could explain why the published data for polyphenolic antioxidant activity measured by various assays are better correlated with the BDE than with other reaction enthalpies involved in radical scavenging mechanisms, i.e., the IP, PDE, PA and ETE. The BDE is fairly well able to rank flavonoids as antioxidants in any medium, but to conclude which radical scavenging mechanism represents the most probable reaction pathway from the thermodynamic point of view, the IP and PA (ETE) should also be considered. This is exemplified in the case of the radical scavenging activity of 25 flavonoids. FigureTotal energy requirements related to the SET-PT and SPLET mechanisms are equivalent to those of the HAT mechanism and are correlated perfectly with the BDE values.

Mechanistic study of the structure–activity relationship for the free radical scavenging activity of baicalein

AbstractDensity functional theory calculations were performed to evaluate the antioxidant activity of baicalein. The conformational behaviors of both the isolated and the aqueous-solvated species (simulated with the conductor-like polarizable continuum solvation model) were analyzed at the M052X/6-311 + G(d,p) level. The most stable tautomers of various forms of baicalein displayed three IHBs between O4 and OH5, O5 and OH6, and O6 and OH7. The most stable tautomer of the baicalein radical was obtained by dehydrogenating the hydroxyl at C6, while the most stable anion tautomer was obtained by deprotonating the C7 hydroxyl in gaseous and aqueous phases. The expected antioxidant activity of baicalein was explained by its ionization potentials (IPs) and homolytic O–H bond dissociation enthalpies (BDEs), which were obtained via the UM052X optimization level of the corresponding radical species. Heterolytic O–H bond cleavages (proton dissociation enthalpies, PDEs) were also computed. The calculated IP, BDE, and PDE values suggested that one-step H-atom transfer, rather than sequential proton loss–electron transfer or electron transfer–proton transfer, would be the most favorable mechanism for explaining the antioxidant activity of baicalein in the gas phase and in nonpolar solvents. In aqueous solution, the SPLET mechanism was more important. FigureSpin density map of the most stable baicalein radical form

Antioxidative capabilities of some organic acids and their co-pigments with malvin: Part II

Abstract Antioxidative properties of ferulic, sinapic, and tannic acids, and their co-pigment with an anthocyan molecule, malvin, were electrochemically observed by cyclic voltammetry. The values of oxidation potentials were used as a quantitative parameter in determining oxidation capabilities of the compounds. These values imply the following sequence of increasing antioxidative effect: ferulic acid

Influence of different free radicals on scavenging potency of gallic acid.

AbstractThe M05-2X/6-311++G(d,p) and B3LYP-D2/6-311++G(d,p) models are used to evaluate scavenging potency of gallic acid. The hydrogen atom transfer (HAT), sequential proton loss electron transfer (SPLET), and single electron transfer followed by proton transfer (SET-PT) mechanisms of gallic acid with some radicals (•OO−, •OH, and CH3OO•) were investigated using the corresponding thermodynamic quantities: bond dissociation enthalpy (BDE), ionization potential (IP), and proton affinity (PA). Namely, the ΔHBDE, ΔHIP, and ΔHPA values of the corresponding reactions in some solvents (water, DMSO, pentylethanoate, and benzene) are investigated using an implicit solvation model (SMD). An approach based on the reactions enthalpies related to the examined mechanisms is applied. This approach shows that a thermodynamically favored mechanism depends on the polarity of reaction media and properties of free radical reactive species. The most acidic 4-OH group of gallic acid is the active site for radical inactivation. The results of this investigation indicate that the SPLET mechanism can be a favored reaction pathway for all three radicals in all solvents, except for •OH in the aqueous solution. In water, gallic acid can inactivate •OH by the HAT mechanism. FigureInfluence of different solvents on antioxidative mechanisms of gallic acid

The preferred radical scavenging mechanisms of fisetin and baicalein towards oxygen-centred radicals in polar protic and polar aprotic solvents

Naturally occurring flavonoid molecules, i.e. fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) and baicalein (5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one), have been investigated experimentally and theoretically for their ability to scavenge hydroxyl and superoxide anion radicals. The reaction enthalpies for the reaction of fisetin and baicalein with selected radical species, related to three mechanisms of free radical scavenging activity (HAT, SET-PT and SPLET), are calculated using the M05-2X/6-311+G(d,p) model. The calculated energy requirements indicated the preferred radical scavenging mechanisms in polar protic and aprotic solvents.

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

Abstract 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.Graphical AbstractThe 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 ΔHBDE, ΔHIP, and ΔHPA 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.Graphical Abstract

A DFT and PM6 study of free radical scavenging activity of ellagic acid

Reaction enthalpies related to mechanisms of free radical scavenging activity of ellagic acid and its phenoxide anions were calculated by density functional theory and the semiempirical PM6 method. In addition to the gas phase, calculations are performed for water and benzene as the solvents, which may represent biological liquids and the membrane lipids, i.e., a natural environment for antiradical action. The thermodynamically favored mechanism depends on the polarity of reaction media, deprotonation degree of ellagic acid as well as the properties of scavenging radicals. The most acidic 3-OH group of ellagic acid is the active site for radical inactivation. The ellagate monoanions and dianions possess progressively better scavenging potency than unionized ellagic acid. The sequential proton loss electron transfer mechanism is the preferred reaction pathway for the ellagate monoanion and dianion in water. In benzene, ellagic acid inactivates free radicals by the hydrogen atom transfer mechanism. In the gas phase the latter mechanism is favored for all ellagic acid species.Graphical Abstract.