Ana Amić

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.

Importance of hydrogen bonding and aromaticity indices in QSAR modeling of the antioxidative capacity of selected (poly)phenolic antioxidants

The quantitative structure-activity relationship (QSAR) models for predicting antioxidative capacity of 21 structurally similar natural and synthetic phenolic antioxidants was considered. The one-, two- and three-descriptor QSAR models were developed. For this purpose the literature data on the vitamin C equivalent antioxidative capacity (VCEAC) values were used as experimental descriptor of antioxidative capacity. Some thermodynamic and aromaticity properties, as well as the natural bond analysis (NBO) based quantities aimed at measuring the strength of intramolecular hydrogen bonds, were used as independent variables. It was examined whether a combination of these variables can yield a mathematical function that is in good correlation with the VCEAC values. It was shown that a combination of a certain thermodynamic descriptor (related to the single proton loss electron transfer mechanism) with the NBO-based quantities results in several two-descriptor models with the correlation coefficient greater than 0.950. Thus, a significant influence of internal hydrogen bonds on the antioxidative capacity of the studied molecules was confirmed. The best correlation with the VCEAC values was achieved within a three-descriptor QSAR model. This model was obtained by including a magnetic aromaticity index. It was found that aromaticity has only secondary effects on the antioxidative capacity.

Theoretical study of the thermodynamics of the mechanisms underlying antiradical activity of cinnamic acid derivatives

The role of antiradical moieties (catechol, guaiacyl and carboxyl group) and molecular conformation in antioxidative potency of dihydrocaffeic acid (DHCA) and dihydroferulic acid (DHFA) was investigated by density functional theory (DFT) method. The thermodynamic preference of different reaction paths of double (2H+/2e-) free radical scavenging mechanisms was estimated. Antiradical potency of DHCA and DHFA was compared with that exerted by their unsaturated analogs - caffeic acid (CA) and ferulic acid (FA). Cis/trans and anti-isomers of studied cinnamic acid derivatives may scavenge free radicals via double processes by involvement of catechol or guaiacyl moiety. Carboxyl group of syn-isomers may also participate in the inactivation of free radicals. Gibbs free energies of reactions with various free radicals indicate that syn-DHCA and syn-DHFA, colon catabolites that could be present in systemic circulation in low μM concentrations, have a potential to contribute to health benefits by direct free radical scavenging.

An Improved and Efficient N-acetylation of Amines Using Choline Chloride Based Deep Eutectic Solvents

An optimization of N-acetylation of various amines was performed in cholin chloride based deep eutectic solvents. First the raction was optimized regarding amine:acetic ratio and reaction time, on anthranilic acid. Then the optimizatoin was done regarding the best DES on anthranilic acid and 4-chloroaniline, where the best conditions were in combination of cholin chloride and urea or malonic acid. A series of amines was then acetylated under these conditions, in both solvents, giving an excellent results considering reaction times (10-60 min) and isolated yields up to 91%. Choline chloride based deep eutectic solvents were proven to be an excellent media for fast, selective and catalyst-free acetylation of amines.

Experimental and theoretical elucidation of structural and antioxidant properties of vanillylmandelic acid and its carboxylate anion

Vanillylmandelic acid (VMA), an important metabolite of catecholamines that is routinely screened as tumor marker, was investigated by the various spectroscopic techniques (IR, Raman, UV-Vis, antioxidant decolorization assay and NMR). Structures optimized by the employment of five common functionals (M05-2X, M06-2X, B3LYP, CAM-B3LYP, B3LYP-D3) were compared with the crystallographic data. The M05-2X functional reproduced the most reliable experimental bond lengths and angles (correlation coefficient >0.999). The importance of intramolecular hydrogen bonds for structural stability was discussed and quantified by the NBO analysis. The most prominent bands in vibrational spectrum were analyzed and compared to the experimental data. The positions of the carbon and hydrogen atoms in NMR spectra were well reproduced. The differences in UV-Vis spectrum were investigated by adding the explicit solvent and by performing NBO and QTAIM analyses. The discrepancy in the two spectra of about 50nm could be explained by the solvent effect on carboxyl group. The most probable antioxidant activity mechanism was discussed for VMA and its carboxylate anion. The Molecular Docking study with the C - reactive protein additionally proved that variety of functional groups present in VMA and its anion allowed strong hydrogen and hydrophobic interactions.

The role of guaiacyl moiety in free radical scavenging by 3,5-dihydroxy-4-methoxybenzyl alcohol: thermodynamics of 3H+/3e− mechanisms

ABSTRACT Participation of guaiacyl moiety of 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) in inactivation of free radicals was investigated using the DFT method. The thermodynamics of triple (3H+/3e−) free radical scavenging mechanisms was investigated. The Gibbs free energies of reactions of inactivation of selected 10 free radicals indicate DHMBA as a potent scavenger. Obtained results allow us to suggest that the contribution of guaiacyl moiety to antioxidant activity of phenolic compounds should be taken into account, what has been scarcely considered until now. GRAPHICAL ABSTRACT

QSAR of the free radical scavenging potency of selected hydroxyanthraquinones

It is well known that anthraquinones are molecules with moderate, but not negligible antioxidative activity. Their chemical behaviour is influenced by different parameters such as thermodynamics, orbital and structural properties, and polarity of environment. To find dependence of antioxidant activity of fourteen selected anthraquinones on the physicochemical parameters, we developed one-, two- and three-descriptor mathematical models. In all quantitative structure–activity relationship models (QSAR), experimentally obtained ABTS values were used as dependent variables. One-descriptor model indicated that in methanol the best correlation give enthalpies that describe stable radical formation following single proton loss, and then transfer of electron. Unexpectedly, the best two-descriptor model shows the best dependence of the experimental results on the combination of the orbital and structural parameters. The best two-parameter model was improved by introducing one thermodynamical parameter, such as bond dissociation enthalpy. On that way the best three-descriptor model was obtained. It indicates that the best insight into the antioxidant capacity of a molecule can be obtained by pooling all types of parameters and influences in a mathematical model.

Mechanisms of scavenging reactions of alizarin with hydroperoxyl and methylperoxyl radicals

Alizarin is anthraquinone with moderate antioxidative capacity. In this work mechanisms of antioxidative activity of alizarin with hydroperoxy and methylperoxy radicals are investigated. All calculations are carried out using B3LYP-D2 method and 6-311+G(d, p) basis set. It is affirmed based on several parameters that hydroxyl group at position 2 is predominant for antiradical activity. PCET mechanism is estimated as favorable mechanism for scavenging activity of alizarin with two selected radicals.

Free radical scavenging potency of 3-hydroxyphenylacetic acid: A DFT study

3-Hydroxyphenylacetic acid (3-HPA) is one of the colon microbial metabolites of flavonoids produced in high concentrations (~300 μM). In this work potency of direct inactivating of selected set of free radicals by 3-HPA was computationally investigated. All calculations were carried out using M05-2X functional with 6-311++G(d, p) basis set coupled with the SMD solvation model. Thermodynamics of three free radical scavenging mechanisms were studied considering electronic properties of 3-HPA and scavenged free radicals. On the basis of obtained results it can be safety predicted that 3-HPA is able to at least in situ effectively scavenge free radicals of different nature, thus contributing to protection from diseases mediated by oxidative stress.