Importance of Hydrogen Bonding and Aromaticity Indices in QSAR

Journal of Molecular Graphics and Modelling 72 (2017) 240–245 Contents lists available at ScienceDirect Journal of Molecular Graphics and Modelling journal homepage: www.elsevier.com/locate/JMGM Topical Perspectives Importance of hydrogen bonding and aromaticity indices in QSAR modeling of the antioxidative capacity of selected (poly)phenolic antioxidants a,∗ b a b c Svetlana Jeremic´ , Slavko Radenkovic´ , Milosˇ Filipovic´ , Marija Antic´ , Ana Amic´ , a Zoran Markovic´ a Department of Chemical-Technological Sciences, State University of Novi Pazar, Vuka Karadziˇ ća bb, 36300 Novi Pazar, Serbia b Faculty of Science, University of Kragujevac, 12 Radoja Domanovića, P.O. Box 60, 34000 Kragujevac, Serbia c Department of Biology, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8a, 31000 Osijek, Croatia a r t i c l e i n f o a b s t r a c t Article history: The quantitative structure-activity relationship (QSAR) models for predicting antioxidative capacity of Received 24 November 2016 21 structurally similar natural and synthetic phenolic antioxidants was considered. The one-, two- and Received in revised form 5 January 2017 three-descriptor QSAR models were developed. For this purpose the literature data on the vitamin C Accepted 6 January 2017 equivalent antioxidative capacity (VCEAC) values were used as experimental descriptor of antioxidative Available online 10 January 2017 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 inde- Keywords: pendent variables. It was examined whether a combination of these variables can yield a mathematical QSAR function that is in good correlation with the VCEAC values. It was shown that a combination of a cer- Antioxidative activity tain thermodynamic descriptor (related to the single proton loss electron transfer mechanism) with the Phenolic compounds Hydrogen bond energy NBO-based quantities results in several two-descriptor models with the correlation coefficient greater Thermodynamic parameters 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. © 2017 Elsevier Inc. All rights reserved. 1. Introduction immune system significantly contributes to the prevention from harmful effects of free radicals, it is very important to protect the Oxidative stress is a phenomenon characterized with increased organism through nutrition rich in antioxidants. Natural antiox- amount of oxidizing species. These are most often reactive oxygen idants are generally polyphenolic molecules of various chemical species, such as hydroxyl and peroxyl free radicals, which can be structures. Most of these molecules can be found in the berries, overproduced under the influence of external or internal effects. roots, leaves or flowers of different fruits, vegetables, spices, and Excessive amounts of free radicals can then lead to a change in the medicinal herbs. Because of positive effects to human health, many chemical structure of proteins, nucleic acids, and lipids. Depend- of the plants containing these compounds have been used in tradi- ing on the intensity of oxidative stress, the final result may be a tional medicine [7,8]. complete destruction of the cell without a possibility for its revi- Natural antioxidants proved to be suitable additives in cosmetic talization. This can be manifested in a form of a variety of diseases, products, foods, and food supplements. In addition to investi- such as cardiovascular, coronary and neurodegenerative, as well as gations devoted to natural sources of antioxidants, much effort many types of cancer [1–6]. has been focused towards finding suitable synthetic antioxidants Organisms have their own mechanisms to detoxify reactive able to protect industrial products from decay caused by oxida- intermediates and repair the resulting damage. Although the tive stress. Synthetic antioxidant should be characterized with high scavenging potency and minor side effects. The influence of some synthetized antioxidants, such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and 2-tert-butilhydroquinone ∗ Corresponding author. (TBHQ) to human health is investigated [9]. E-mail address: [email protected] (S. Jeremic).´ http://dx.doi.org/10.1016/j.jmgm.2017.01.011 1093-3263/© 2017 Elsevier Inc. All rights reserved. S. Jeremić et al. / Journal of Molecular Graphics and Modelling 72 (2017) 240–245 241 It has been shown that experimentally obtained parameters potential, Eq. (2.1)) and PDE (proton dissociation enthalpy, Eq. related to the antioxidative capacity of the molecules mainly agree (2.2)). with their theoretically predicted behaviour. It is also known that − + −e •+−H • − → − → − biological activity and chemical reactivity of molecules depend A OH A OH A O (2) on their structure [10,11]. Among the factors that influence •+ − IP = H(A − OH ) + H(e ) − H(A − OH) (2.1) the behaviour of molecules, the number and position of differ- • + •+ = − + − − ent substituents (hydroxyl, methoxy, amino, and methyl groups, PDE H(A O ) H(H ) H(A OH ) (2.2) double bond, etc.) are of crucial significance [12–15]. These func- The third mechanism is another two-step process known as tional groups exhibit strong resonance and inductive effects, thus SPLET (sequential proton loss electron transfer). The first step is enabling spin density and charge delocalization in the radical(s) a heterolytic cleavage of hydroxyl O H bond, where the corre- issued from certain antioxidant molecule [13]. It has been shown sponding anion is formed. This anion loses an electron giving rise that the ortho and para positions of the hydroxyl groups increase to a radical in the second step of the reaction (Eq. (3)). This mecha- antioxidative capacity of the related molecule [16]. The vicinal nism is described by PA (proton affinity, Eq. (3.1)) and ETE (electron O H groups participate in the creation of intramolecular hydrogen transfer energy, Eq. (3.2)) thermodynamic quantities. bonds, stabilizing neutral molecule, as well as the corresponding − + − − reactive species [13,17–19]. H − e • A − OH → A − O → A − O (3) Many theoretical models have been used in pharmaceutical, − + = − + − − medicinal, cosmetic, food, and related industries for developing and PA H(A O ) H(H ) H(A OH) (3.1) investigating new types of antioxidants. Quantitative structure- • − − = ETE H(A − O ) + H(e ) − H(A − O ) (3.2) activity relationship (QSAR) modeling is a very useful statistical method for predicting antioxidative capacity of molecules. In our Geometries of all neutral molecules, as well as corresponding recent work it was shown that the energy based descriptors related charged and radical species, were optimized using the M05-2X to the antioxidative activity can be used to obtain reliable QSAR functional in conjugation with the 6–311 + +G(d,p) basis set, as models [20]. In the present paper we employ the same set of implemented in Gaussian 09 program package [33,34]. Combina- molecules consisting of 21 structurally similar monocyclic pheno- tion of this functional with different basis sets has been widely used. lic compounds (Fig. 1). Eighteen of them are natural benzoic acids, The method was suggested by its creators as appropriate for inves- phenylacetic acids, and phenols. These compounds are constituents tigations of thermodynamic and kinetic properties of the reactions of edible plants in both aglycone and glycoside forms [21–23], and that involve species with paired and unpaired spin [35–37]. they participate in the normal growth, development, and defence The geometries of all investigated species in water were opti- of the plants against infection and injury [24]. Their ability to react mized by using the PCM/SMD solvation model, to approximate the with other simple molecules enables esterification or conjugation solvation effects. The frequency calculations were included in all and formation of esters and polymers [25]. Synthetic antioxidants cases. The vibrational analysis has been done in order to verify that included in our model (BHA, BHT and TBHQ) are used as foodstuffs the obtained structures correspond to the structures with energy and cosmetic products to protect fats against oxidative rancid- minima. All revealed stationary points with minima of energy ity. It has been shown that they inhibit production of cancerous showed the absence of imaginary frequencies. The thermodynamic luteoskyrin [26]. They do not exert mutagenic activity, but in high parameters were calculated from the enthalpies of the optimized doses all three of them exhibit toxic effects [27]. neutral and charged species. The enthalpies of the solvated proton Apparently, all the studied molecules possess aromatic 6- and electron were taken from literature [38]. membered ring. This was our motivation to examine a possibility to relate different aromaticity indices with the antioxidative capacity 2.2. Aromaticity indices of the studied molecules. Finally, we examined how the intramolecular hydrogen bonding quantified within the NBO framework can The extent to which the electrons are delocalized within a given improve the QSAR model based on the thermodynamic descriptors ring

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