Exp Opin Drug Dis 2009 REVIEW

Review
Advances in quantitative structureactivity relationship models of antioxidants

1. 2. 3. Introduction Quantitative structureactivity relationship Quantitative structureactivity relationship of antioxidants Expert opinion
Kunal Roy & Indrani Mitra

Jadavpur University, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Drug Theoretics and Cheminformatics Laboratory, Kolkata 700 032, India
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4.
Background: During the past decade a large number of reports described the roles of active oxygen species in the development or exacerbation of various kinds of diseases. The systemic antioxidant defense system often fails to control the excess free radicals. Such a condition necessitates external antioxidant supplementation either in the form of drugs or vitamins. Quantitative structureactivity relationship (QSAR) serves as an effective computational tool for search and design of active molecules that may eventually be synthesized and assayed. Objective/method: This review presents the current knowledge about QSAR studies of diverse groups of molecules with free radical scavenging activity. The QSAR studies summarized here would help to understand the proper mechanism underlying the interaction between the free radicals and antioxidant molecules. Conclusion: The primary determinant factors for potent antioxidant activity include the electronic distribution of the molecules together with their lipophilicity and size and orientation of the substituents attached to the parent molecules. The potency of the antioxidants depends on the degree of reactivity of these molecules with the nearby free radicals and the stability of the oxidized antioxidant molecules thus obtained. The nature of substitution at the parent moiety plays a key role in the design of antioxidant molecules.
Keywords: antioxidant, model, QSAR, validation Expert Opin. Drug Discov. (2009) 4(11):1157-1175
1.
1.1
Introduction
Free radicals and their nocive effects Free radical formation occurs continuously in the cells as a consequence of both enzymatic and nonenzymatic reactions. Oxygen molecules are indispensable for performing various systemic functions. Most of the metabolic pathways are controlled by oxidationreduction reactions [1]. Free radicals are produced constitutively during such reactions. A certain level of these free radicals is required for normal physiological processes. Within the human system, there is a constant production of free radicals as a result of the various physiological processes such as respiration, metabolism, digestion and so on. However, this amount is kept to a minimum by a number of scavenging mechanisms that detoxify these free radicals. But free radical production is increased by stresses that include inammation, infections and environmental factors (toxic pollutants, smoke etc.) [2]. Several xenobiotics (drugs and chemicals foreign to the human body) have also been implicated in the process of producing free radicals. Many xenobiotics can deplete antioxidant enzymes and glutathione stores, thus altering the redox status of the cell and making it more susceptible to oxidant-induced effects [3].
10.1517/17460440903307409 2009 Informa UK Ltd ISSN 1746-0441 All rights reserved: reproduction in whole or in part not permitted
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Two major forms of free radicals that are formed from oxygen and nitrogen include reactive oxygen species (ROS), .and reactive nitrogen species (RNS). Superoxide (O2 ) and hydroxyl (OH-) are examples of reactive oxygen radicals while nitric oxide (NO-) and nitrogen dioxide (NO2.) are nitrogen radicals [4]. Three primary reasons for the increasing free radical pathology over the past 100 years are: i) modern rened food diets, ii) increasing amounts of synthetic substances in diet and medicines and iii) the toxic environmental pollutants [5]. However, the human system possesses mechanisms for inhibiting this free radical attack. Under normal conditions, the antioxidant defense system within the body ghts the free radicals that are produced. But free radical production considerably exceeds their rate of removal during conditions of increased oxygen efux such as during exercise. When free radical production exceeds clearance, oxidative damage occurs. The resulting state that is characterized by a disturbance in the balance between ROS production on one hand and ROS removal and repair of damaged complex molecules (such as proteins or DNA) on the other is called oxidative stress [6]. Oxidative stress is a process in which normal balance between pro-oxidants and antioxidants is shifted towards the oxidant side, resulting in an increase in free radicals that cause biologic damage [1]. Such a condition thus developed is responsible for a series of deadly diseases like atherosclerosis, Alzheimers disease (AD), Parkinsons disease, rheumatoid arthritis, cancer and so on. A large-scale production of these free radicals is now believed to be the reason behind most (if not all) of the human chronic diseases, including AIDS, chronic fatigue syndrome, psoriasis and asthma (Scheme 1). Proteins, DNA and biological membranes are the targets of free radical attack within the human system. The reactive systemic oxygen-based free radicals are often associated with cell damage, mutations, malignancies and so on. Free radicals cause changes in the chemical structure of the collagen and cause breaks in the collagen strands that gradually lead to sagging of the skin resulting in early ageing [7]. Hydroxyl radical and peroxynitrite in excess can damage cell membranes and lipoproteins by a process called lipid peroxidation. This reaction leads to the formation of malondialdehyde (MDA) and conjugated diene compounds, which are cytotoxic and mutagenic. Lipid peroxidation occurs by a radical chain reaction, that is, once started, it spreads rapidly and affects more and more lipid molecules [8]. All ROS have the potential to interact with cellular components including DNA bases or the deoxyribosyl backbone of DNA to produce damaged bases or strand breaks. Oxidation of membrane lipids and proteins also produce certain intermediates that react with DNA forming adducts. Superoxide radicals are produced within the mitochondria as a result of leaking of electrons from the electron transport chain [9]. These radicals in turn cause damage to the mitochondrial DNA (mtDNA). Although the cell repairs much of the damage done to nuclearDNA, extensive mtDNA damage accumulates over
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time and shuts down mitochondria, causing cells to die and the organism to age [10]. Reactive oxygen species have been implicated as potential modulators of apoptosis. Direct exposure of various cell types to oxidants such as hydrogen peroxide or lipid hydroperoxides can directly induce apoptosis, while in many experimental models pretreatment of cells with antioxidants has been shown to protect against this form of cell death [11]. These free radicals have also been implicated in the rancidication of packaged food.
Antioxidants and their functions Antioxidants serve as the primary device in controlling the systemic free radical attack. Within the human system, the free radicals are efciently neutralized by a series of antioxidant enzymes. Antioxidants are chemical entities that break the free radical chain reaction by being oxidized themselves and also by chelating the metal ions that catalyze these free radical chain reactions [12]. Antioxidants exhibit three different action mechanisms [13-15]: hydrogen atom transfer (HAT), single-electron transferproton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). Although HAT remains the primary mechanism of antioxidant action, the other two mechanisms explain an alterative way for free radical neutralization. By using the HAT mechanism, the antioxidants interact with the free radicals according to the following reaction:
1.2
ROO + ArOH ROOH + ArO .
(1)
A high rate of hydrogen atom transfer is expected to be related to a low phenolic O-H bond dissociation enthalpy (BDE). A second possible mechanism, by which an antioxidant can deactivate a free radical, is single-electron transfer, in . which the radical cation ArOH+ is rst formed, followed by its proton transfer (SET-PT):
ROO + ArOH ROO- + ArOH+ , ArOH+ ArO + H+ , ROO- + H+ ROOH.
(2) (3) (4)
In this method both ionization potential (IP) and O-H proton dissociation enthalpy (PDE) [14,16,17] describe the energetics of the SET-PT process. However, low IP values also enhance the chance of generating a superoxide anion radical through the transfer of the electron directly to surrounding O 2. It was experimentally conrmed that vitamin E and other phenols can react with DPPH (2,2-diphenyl-1-picrylhydrazil) radical and other electron . decient radicals (ROO ) by these two mechanisms [15] . Recently, another mechanism, known as SPLET, has been
Expert Opin. Drug Discov. (2009) 4(11)
Roy & Mitra
Cigarette smoking
Atherosclerosis Alzheimers disease
Environmental pollutants
Parkinsons disease Lipid peroxidation DNA damage Cancer
Xenobiotics
Free radicals
Systemic metabolism
Oxidative damage
Early ageing Brain tumor Irritation of epithelial cells (especially bronchiolar epithelium) Malfunctioning of vital life processes
Synthetic substances in diets
Scheme 1. Free radical damage to human system.
discovered [15,18,19] . The SPLET mechanism is given by the following equations: (5)
ArOH ArO- + H+ , ArO- + ROO ArO + ROO- , ROO- + H+ ROOH.
(6) (7)
The reaction enthalpy of the SPLET rst step corresponds to the proton afnity (PA) of the phenoxide anion (ArO-). In the . second step, electron transfer from phenoxide anion to ROO occurs and the phenoxyl radical is formed. The reaction enthalpy of this step is denoted as the electron transfer enthalpy. Systemic antioxidants generally maintain a balance with the free radicals produced as a consequence of the normal metabolic processes. There are various endogenous antioxidant enzymes (superoxide dismutase, catalase, hydroxylase etc.) that play a primary role in controlling the free radical pool [12]. But this balance may be disturbed due to excessive overow of the free radicals within the system when human beings are exposed to several toxic environmental factors. Under such conditions when the systemic antioxidants fail to control the pool of free radicals, there is a need to replenish this antioxidant supply through external supplementation.
Antioxidants exhibit immense medicinal and commercial importance. Several ecological, case-control and cohort studies indicate that diets rich in plant foods provide protection against damage resulting from systemic free radical attack. Although the etiology of AD is not well understood, laboratory experiments and clinical studies revealed that ROS and RNS that are generated extracellularly and intracellularly by various mechanisms are among the major intermediary risk factors that initiate and promote neurodegeneration in idiopathic AD. Therefore, multiple antioxidant supplements could be useful in the prevention of AD, and as an adjunct to standard therapy in the treatment of AD [20]. The identication of low-density lipoprotein (LDL) oxidation as a key event in atherosclerosis suggests that it may be possible to reduce the risk of atherosclerosis by consumption of natural antioxidants through fruits and vegetables and also by antioxidant supplementation [21]. Antioxidants break free radical chain reactions by their ability to transfer the phenolic hydrogen to the peroxy free radical of peroxidized polyunsaturated fatty acid (PUFA) contained in cellular and subcellular membrane phospholipids and thus they participate in controlling PUFA peroxidation [22]. Rheumatoid arthritis is a systemic disease characterized by progressive, erosive and chronic polyarthritis. In normal physiology the endogenous free radicals produced in the body are neutralized by endogenous antioxidants. A recent study indicated that
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increased oxidative stress and defective antioxidant status contribute to the pathology of rheumatoid arthritis [23]. The study showed raised levels of malondialdehyde and low levels of endogenous antioxidants in patients of rheumatoid arthritis. Thus, antioxidants may serve as benecial tools for controlling widespread attack of rheumatoid arthritis [23]. The antioxidants have been markedly implicated in controlling aging effects [24]. Nature constitutes an abundant source of antioxidants. Fruits and vegetables serve as a surplus source of antioxidants. Vitamins and carotenoids exhibit maximum antioxidant activity. Besides these, minerals such as selenium and several phytochemicals such as avonoids, polyphenols, lucopene, luein and lignans also exert free radical scavenging activity (RSA) by varying mechanisms [25]. A proper diet rich in vegetables and fruits may serve as an efcient source of antioxidants. However, antioxidants may also be supplied in the form of drugs in order to combat fatal diseases. Very few such drugs with antioxidant property have been synthesized to date and even fewer among them are being utilized as efcient drugs (e.g., captopril, propranolol, carvedilol, probucol etc.) and food preservatives. The emerging concept is that dietary and endogenous antioxidants, endowed with different activities and characteristics, work synergistically contributing to the overall protective effect of plant foods.
2.
models developed was examined by different statistical parameters [32] such as determination coefcient (r2), explained variance (r2a), standard error of estimate (s) and variance ratio (F) at specied degrees of freedom (df). Besides these, the model predictivity and robustness are checked using various other internal and external validation parameters such as predicted residual sum of squares (PRESS), cross-validated r2 (q2), predictive r2 (r2pred), modied r2 [rm2(LOO) and rm2(test)] and overall model predictivity [rm2(overall)] (all bearing a threshold value of 0.5) [31,33-36]. Again according to Tropsha group [37,38], additional external validation parameters should also be used for judging the predictive ability of a QSAR model. These parameters include:
r 2 r02 r 2 r0 2 or < 0.1, r2 r2
(8)
Quantitative structureactivity relationship
Quantitative structure-activity relationship (QSAR) serves as a reliable tool for searching efcient antioxidant molecules with improved activity and reduced toxicity. It is a computational tool that correlates biological activity of a series of molecules with several numerical parameters called descriptors using various statistical methods [26,27]. Such numerical parameters include various physicochemical, quantum chemical and other structure related properties of the molecules under consideration. The advent of the QSAR technique can be dated back to the 1960s. The use of statistical models to predict biological and physicochemical properties started with linear regression QSAR models developed by Hansch during that period [28,29]. The basic idea is to utilize existing databases as input for a new type of structure/activity correlation methodology. A large set of new and traditional descriptors is used to create improved QSAR models that characterize and predict important biological responses. The QSAR models are developed using a variety of chemometric tools [30,31] such as stepwise multiple linear regression (MLR), partial least squares (PLS), genetic function approximation (GFA) and so on. The QSAR models thus built are then checked for their predictive ability and reproducibility using different validation techniques, namely, internal validation [leave-one-out (LOO) crossvalidation and leave-group-out cross-validation], external validation and Y-randomization. The statistical quality of the
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where k or k is close to 1, r02 is the squared correlation coefcient for the observed and predicted activity values of the of the test set compounds with the intercept set to zero, while the value of r02 is calculated by interchanging the axes. When observed and predicted activity values of the test set compounds are plotted with intercept set to zero, k gives the slope of the plot while k is the slope for the plot obtained by interchanging the axes [37]. An important step in QSAR model validation involves the approach of dening an applicability domain for the developed mode [39]. The applicability domain [40,41] is a theoretical region in chemical space, dened by the model descriptors and modeled response. It indicates that only those compounds that fall within this domain of applicability can be considered reliable for prediction. Extent of extrapolation [42] is a method of dening applicability domain calculated on the basis of the leverage (hi) value for each chemical used for the QSAR model development. Once the descriptors have been determined and a predictive model has been built and validated, thousands of new potential molecules, chemically similar to those of the benchmark dataset, are scanned from large databases and are evaluated for their chemical properties based on the predictive model. One of the aims of the QSAR approach is to target novel molecules with potential pharmaceutical activity that can eventually be tested in the traditional way in the laboratory. Being a cost effective and time saving method, QSAR helps in rapid screening of active antioxidant molecules that may further be synthesized and tested for pharmacological activity. The steps for development of a QSAR model are shown in Scheme 2. A QSAR study correlates biological activities of molecules with their molecular structure through certain numerical parameters called descriptors [26,27]. The descriptors illustrate various molecular features such as the hydrophobic, steric and electronic properties that may inuence the biological activity of the molecules under study. In a typical data table of QSAR analysis, each row represents a candidate
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Selection of the dataset
Calculation of descriptors belonging to different categories
Division of the dataset into training and test sets based on cluster analysis or activity ranking
Development of models with training set using various chemometric tools Expert Opin. Drug Discov. Downloaded from informahealthcare.com by University of Toronto on 06/14/11 For personal use only.
Maximum value of cross-validated squared correlation coefficient (Q2) (threshold value = 0.5)
Statistical validation of the developed model in order to check the robustness of the model using Y-randomization
No
Whether the model is satisfactory?
Yes Activity prediction of corresponding test set compounds using developed model
Assessment of external predictivity of the model based on the calculated value of R2 (threshold value = 0.5)
Scheme 2. Flowchart for development of a quantitative structureactivity relationship model.
compound and each column represents an experimental or computational feature. Regression analysis is applied to all or some features to create a model. A QSAR model generally takes the form of a linear equation: (9)
pC = a 0 + a1X1 + a 2 X 2 + a 3 X 3 + L,
where the parameters X1 through Xn are computed for each molecule in the series and the coefcients a1 through an are calculated by tting variations in the parameters and the biological activity [43]. The term a0 is a constant and pC indicates the biological activity of the molecules. Most commonly used QSAR studies are two-dimensional (2D; performed using different physicochemical and topological parameters) [44] and three-dimensional (3D; performed using various 3D descriptors) [45]. Recently, four-dimensional (4D; wherein conformational and alignment freedom are
incorporated in model development) [46,47], ve-dimensional (5D, which considers different induced t protocols) [48] and six-dimensional (6D, which allows simultaneous consideration of different solvation models) [49] QSAR models are also being used. In tandem with developments in molecular modeling and X-ray crystallography, QSAR has impacted drug design and development in many ways. In terms of ligand design, it shares center stage with other approaches such as structurebased ligand design and other rational drug design approaches including docking methods. Besides these, nonlinear methods such as articial neural network have also been used for activity prediction of molecules. Many bioactive compounds have emerged in agrochemistry, pesticide chemistry and medicinal chemistry with the aid of the QSAR technique. Viewing the intense medicinal as well as commercial importance of antioxidants, design and synthesis of novel antioxidant molecules is the topic of prime importance to todays medicinal chemists. Quantitative structureactivity relationship serves as an efcient approach for rapid screening
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of the potent antioxidant molecules. Using the QSAR technique, the effect of change in position of the substituents of the conventional antioxidants on the activity prole of those molecules such as lipid peroxidation inhibition capacity or ability to chelate a free radical can be determined. Thus, structurally similar as well as structurally diverse group of compounds can be studied for their activity prole using this QSAR approach. The present review gives an outline of the various QSAR models developed by different authors to date.
3. Quantitative structureactivity relationship of antioxidants
Various classes of chemical entities (including phenols, aromatic amines and other classes) have been found to exhibit antioxidant activity. A variation in the substitution pattern of these antioxidant molecules imparts a difference in their physicochemical properties, which in turn inuences their reactivity with toxic free radicals. So, during the last decade, diverse classes of such chemical entities have gained remarkable attention from different groups of medicinal chemists for their ability to scavenge free radicals and thus inhibit systemic damages such as lipid peroxidation. Depending on their chemical structure, biologically relevant antioxidants may be broadly classied into three different categories: i) phenolic antioxidants (excluding avonoids); ii) avonoid molecules with antioxidant activity; and iii) a variety of other chemical groups classied into the miscellaneous category. Quantitative structureactivity relationship studies have been reported for antioxidants from these categories by different groups of scientists.
3.1
Quantitative structureactivity relationship of phenolic antioxidants (excluding avonoids)
Zhou et al. [50] performed QSAR analysis to determine the effectiveness of the molecular structure properties on the antioxidant property of phenolic antioxidants in lubricating oils. They developed various acceptable predictive QSAR models. Finally, they inferred that some properties such as the energy of the highest occupied molecular orbital (HOMO) and molecular conformational energy are the controlling parameters for the antioxidant ability of the phenolic compounds. Cheng et al. [51] developed QSAR models for studying multiple mechanisms underlying the reaction between hydroxyl radical and phenolic compounds. They reported that the reaction rate constant (KS) bears good correlation with hydroxyl O-H bond strength, electron-donating ability (ionization potential approximated by HOMO energy level), enthalpy of single electron transfer and spin distribution of phenoxyl radicals after H-abstraction. Multilinear regression analysis indicated that, in addition to H-atom transfer, electron transfer process and stability of the resulting phenoxyl radicals also signicantly inuence the reactivity of quenching hydroxyl radicals.
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Cheng et al. [52] studied a series of phenolic compounds for their protection against lipid peroxidation (LPO) in two model experiments, pre-emulsied linoleic acid system and phosphate buffered linolenic acid system. They employed computational chemistry tools for investigating the mechanism of action and the activity determinants of the phenolic antioxidants. The descriptors used for this work included primarily the quantum chemical descriptors calculated using the AM1 method together with a few electronic and physicochemical descriptors. They obtained remarkably signicant multidescriptor QSAR models for explaining more precisely the mechanisms underlying the free RSA of these phenolic antioxidants. The models developed may serve as valuable approaches in predicting the potency of an antioxidant to inhibit oxidation of lipids using calculated physicochemical parameters. Singh et al. [53] used a quantitative topological molecular similarity (QTMS) method to develop a model for the computation of the relative substituent effects on the bond dissociation enthalpies (DBDEs) for a set of 39 phenolic derivatives displaying antioxidant activity. The QTMS method begins with the notion that each molecule serves as a collection of atomic attractors (nuclei) surrounded by a sea of charge density. A bond path exists between each pair of atoms and along this bond path there lies a saddle point. This saddle point is also known as the BCP (bond critical point). In this approach the BCP properties were correlated with the bond dissociation enthalpies of the reported series of phenolic compounds used for the work. Quantum thermochemical calculation of the O-H BDE has been known to be successful in characterizing antioxidant activity for a large number of antioxidants [54]. Substituent additivity scales based on the relative BDEs to phenol show that electron donor groups introduced on the phenol ring enhance the antioxidant activity. The advantage of this QTMS method is that it reveals the active region of the substituted phenols and identies the electronic descriptors that best explain the change of BDEs observed. A rigorous statistical treatment permits the extraction of important features that best describe the activity being modeled. A considerably signicant QSAR model was derived at the modest B3LYP/6-31+G(d,p) level of theory, although an increase in model quality was observed with increasing level of theory. By application of this QTMS methodology, they yielded a statistically robust QSAR model with r2 = 0.98 and q2 = 0.85 for the bond dissociation enthalpies of this phenolic antioxidant dataset. The variable importance in projection (VIP) plots developed by Singh et al. for both the bond length and the BCP models using the SIMCA software (Umetrics, Sweden) show that bonding between the benzene nucleus and the phenolic oxygen emerges as the most important bond. They also reported that radical stabilization plays an important role for substituents present at the para position of the phenolic moiety and proposed to include this correction factor in any of the future models developed using the phenolic derivatives.
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Quantitative structureactivity relationship analysis of phenolic antioxidants using MOLMAP (molecular maps of atom-level properties) descriptors for local properties of the molecules have been reported by Gupta et al. [55] Molecular maps of atom-level properties represent the diversity of chemical bonds existing in a molecule. In this study, Gupta et al. trained counterpropagation neural networks with the MOLMAP descriptors selected using genetic algorithms in order to predict the free RSA of a series of 47 naturally occurring phenolic antioxidants. Random forests grown in this study using the entire MOLMAP descriptor matrix gave 70% correct classications as potent, active and inactive compounds. This work shows that MOLMAPs can be successfully used for mining of structural and biological activity data. Reis et al. [56] performed a theoretical study with 41 phenolic compounds exhibiting antioxidant properties. For this purpose they calculated a series of quantum chemical descriptors at the DFT/B3LYP, HF, and AM1 and PM3 semi-empirical levels. Among the primary descriptors involved in the QSAR model development, the vertical ionization potentials (IPvs) and the charge on phenolic oxygen atom play a critical role. The IPv was calculated as the energy differences between a radical cation and the respective neutral molecule: IPv(Ecation - Eneutral)DFT and using Koopmans theorem (KT) [57] as (IPv = -eHOMO). KT, which equates the IP to the negative value of the HOMO energy, has traditionally been applied to calculate IPv using the molecular orbital theory [58]. The best regression developed by them revealed that low values of IPvHOMO(DFT) combined with negative charges on phenolic oxygen are the most signicant parameters controlling the antioxidant activity of these molecules. Modeling and statistical analysis for DPPH (1,1-diphenyl2-picrylhydrazyl) free RSA of phenolic compounds was performed by Velkov et al. [59] A set of 20 phenolic compounds and their phenoxyl radicals were investigated by them at the unrestricted B3LYP level of theory using the 6-31+G(d,p) basis set [60]. Regression analysis technique was used to correlate the relative scavenging activity (RSA) with the various descriptors used for modeling. The three descriptors used frequently in the developed QSAR models include energy of the HOMO of the compounds, C-O bond length and atomic spin density at the oxygen atoms in the radicals. Velkov et al. analyzed from the results that there existed a signicant linear correlation between the free RSA and the spin density as well as the HOMO energy of the molecules. Finally, they inferred that the RSA of the phenolic compounds is efciently inuenced by the electron donor ability of the O-H group to the aromatic ring (as indicated by the spin density delocalization), the occurrence of substituents with positive mesomeric and inductive electronic effects and the presence of hydrogen bonds involving dissociable hydroxyl group (DHG) and adjacent functional groups.
Ray et al. [61] also performed QSAR studies in order to predict the lipid peroxidation inhibition potential of some phenolic antioxidants in phosphate buffered and preemulsied linoleic acid systems. Quantitative structure activity relationship models were built in this study using stepwise regression and MLR with factor analysis (FA) as the data processing step for variable selection (FA-MLR). Among the various signicant models developed by them, the FA-MLR technique yielded the best model (r2 = 0.950, q2 = 0.914) for the rst system while for the second system the best model was obtained using stepwise MLR (r2 = 0.960, q2 = 0.949). From the eight different QSAR models developed by Ray et al., it was revealed that the bond dissociation enthalpy of the O-H bond and the MAXDP (maximal electrotopological positive variation) descriptor bear negative inuences on the lipid peroxidation inhibition potency of these molecules. Antioxidant activity of wine polyphenols was modeled by Rastija et al. [62] using QSAR technique with the descriptors calculated from 2D and 3D representation of the molecules. Four groups of 3D descriptors were used for QSAR model development, namely, geometrical, GETAWAY (geometry, topology and atom weights assembly), 3DMoRSE (3D molecule representation of structures based on electron diffraction descriptors) and RDF (radial distribution function) descriptors. The 3D descriptors possess the ability for discrimination of stereoisomers, such as catechin and epicatechin. Statistically signicant models for lipid peroxidation inhibiting effects of avonoids were obtained by polynomial and multiple regression using lipophilicity, Balaban index, Balaban-type index and 3D GETAWAY descriptor. Two different QSAR models were developed: one for the antioxidant activity of 10 wine polyphenols determined using ABTS (2,2-azinobis-(3-ethylbenzothiazoline)-6-sulfonic acid) test expressed in Trolox equivalent antioxidant capacity (TEAC; per mmol/L) values [7] against radicals generated in the aqueous phase and the other for lipid peroxidation inhibitory effects of eight avonoids expressed as the concentration for 50% inhibition of lipid peroxidation (IC50/mmol/L) [9]. The signicant models for the antioxidant activity of the polyphenols showed that the zero-order connectivity index (0c) and molar refractivity (MR) were the useful parameters for modeling free RSA of polyphenols belonging to different groups (phenolic acids and avonoids, avans, avonols and stilbene). Besides these, the models developed for the lipid peroxidation inhibitory effects of avonoids indicated that lipophilicity and van der Waals volume (Vw) were the signicant molecular descriptors for prediction of antioxidant activity of avonoids in the lipophilic phase. They also demonstrated that the number and the arrangement of free hydroxyl groups on the avonoid skeleton, or on the phenolic ring together with the shape, size, mass and steric properties of the molecules bear considerable effects on the activity prole of these molecules.
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3.2
Quantitative structureactivity relationship of avonoids exhibiting antioxidant property
Lien et al. [63] reported two QSAR models for estimating the redox potentials and antioxidant activities of substituted phenols, vitamin E derivatives and avonoids using calculated parameters such as the heat of formation (Hf), the energy of the lowest unoccupied molecular orbital of radicals (ELUMO-r), the energy of the highest occupied molecular orbital of the parent compounds (EHOMO) and the number of hydroxyl groups (OH). Models with high statistical signicance have been developed separately for the one electron redox potentials of phenols, vitamin E and its derivatives and avonoids. For the one electron redox potential of phenolic compounds, linear least squares regression analysis revealed that the two primary parameters contributing to the antioxidant activity of these compounds are the energy of electron abstraction [as calculated from the differences of the heats of formation between the parent phenols and the corresponding radicals (DHf)] and the number of hydroxyl groups. Thus, the authors [63] reported that DHf, a measure of stability of a compound or a radical, makes a positive contribution to the redox potentials of substituted phenols and DHf and other calculated parameters may be used to predict the antioxidant activity for compounds that differ from the parent structure with more than just the substituents on the phenyl ring. A highly signicant correlation (r2 = 0.845) was reported using the number of hydroxyl groups (OH) and an indicator variable (I) inferring that the equation may be useful in explaining the physicochemical contribution factors to the antioxidant activity and in estimating the TEAC values and potential biological activities of avonoids. Heijnen et al. [64] studied the peroxynitrite scavenging activity of substituted phenols and several avonoids and developed signicant predictive QSAR models with the Hammett constant and the electronic parameter, EHOMO (energy of the highest occupied molecular orbital). However, they identied two pharmacophores located on either the catechol group (3,4-diOH) in ring B or on three OH groups (3,5,7-triOH) in the A and C rings (Figure 1). As they inferred, the 3-OH group was the reactive center and the reactivity of this group was enhanced by electron donating groups at C-5 and/or C-7. Amic et al. [65] studied the relationship between the structural characteristics and antiradical activity of 29 avonoids using the QSAR technique. They developed signicant QSAR models using MLR with descriptors selected from a pool of 34 various topological and electronic parameters. The appearance of the indicator variables (I3,4-diOH or 3-OH and I5-OH) in two signicant models developed by them indicated that variations in the OH substitution pattern were responsible for variation in the RSA of the avonoids studied (Figure 1). From these signicant models they inferred that the most effective radical scavenging avonoids are those bearing the 3,4-dihydroxy substitution pattern on the B-ring and/or hydroxyl group at the C-3 position. The presence of
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hydroxy (OH) functional groups at 3 and 4 positions of the B-ring confers a higher degree of stability on the avonoid phenoxyl radicals by participating in electron delocalization and is an important feature for the antiradical potential [66]. However, they also proposed a new mechanism of action for the antiradical activity of avonoids lacking the B ring hydroxyl groups. Farkas et al. [67] studied 36 avonoids using PLS projection of latent structures method and developed signicant QSAR model with several constitutional descriptors, two dimensional topological and connectivity indices. They reported plots for PLS component scores indicating that the model provides a suitable prediction for most of the avonoids and since the model was developed for antioxidant activities of a diverse set of avonoids, the model could be used for classication of different avonoid groups. Estrada et al. [68] developed QSAR models for antioxidant activity of a series of compounds present in Brazilian propolis using the Sub-Structural Molecular Design (TOPS-MODE) approach. The TOPS-MODE descriptors account for hydrophobic, polarity/electronic and steric features of molecules on the basis of bond weights. The descriptors are based on the moment method using the topological bond matrix with the earlier mentioned weights in the main diagonal [69-71]. This TOPS-MODE approach enabled the interpretation of bond contributions of these compounds for controlling their antioxidant activity. Signicant QSAR models with high predictive ability developed by them elucidated the effects of various substituents and their positions on the antioxidant activity of these avonoids. Followed by this, they proceeded for virtual generation of compounds. With this technique, they generated 327 compounds, among which 70 were predicted to be more active than the most powerful antioxidants in the Brazilian propolis. The virtual generation of the compound analogues was carried out using two different structural frameworks. Initially, the cinnamic acid framework was chosen as the pattern structure and explored the substituents, H, OH and prenyl group at different positions of the phenyl ring. By this method they generated 243 compounds (35) and after removing identical compounds due to symmetry, 135 compounds were evaluated for antioxidant activity by the TOPS-MODE QSAR model. In the second part, 256 compounds were derived by substituting the avonoid framework with H and OH substituents at eight different positions (28) and from these 192 remained after duplications due to symmetry and were removed. They inferred that the highly hydroxylated or highly substituted compounds were predicted as the most active ones. Ghiotto et al. [72] correlated the TEAC with the electronic structures of a series of avonols isolated from natural sources such as broccoli, radishes, black tea, olive, red wine and so on. A signicant correlation was obtained using multiple regression analysis with a single descriptor DEH,H-1: the theoretically calculated energy difference between the two highest occupied molecular orbitals (HOMO and HOMO-1). The
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5 6 A 7 8 1
O
4 C 3 2 2 1 B 6 4 5 3
Chromone nucleus
Figure 1. General structure of avonoids (the chromone nucleus has been marked).
tting equation enabled the authors to predict high values of TEAC for other new avonoids, which could lead to new potent antioxidants. A series of 12 avonoids was investigated by Rackova et al. [73] in order to examine the structural parameters contributing to the antilipid peroxidative activity of the avonoids. The signicant QSAR models developed by them indicate the importance of the electronic parameters, namely, hydration energy (EHYDR) and energy of lowest unoccupied molecular orbital for the lipid peroxidation inhibitory potential of these avonoids. These parameters illustrate the hydrophilic and electrophilic properties of the molecules, respectively, and from this they inferred that the highest (absolute) values of EHYDR were obtained for most of the potent avonoids (possessing the highest number of OH groups) while the lowest (absolute) values of EHYDR were attributed to avonoids that exerted low antioxidant activity. Weber et al. [74] developed QSAR models correlating the electronic features of 25 avonoid compounds with their antioxidant activity using several chemometric tools, namely, principal component analysis (PCA), hierarchical cluster analysis (HCA) and k-nearest neighbor (KNN). Four different electronic descriptors, namely, polarizability (a), charge at carbon 3 (QC3), total charge at substituent 5 (QS5) and total charge at substituent 3 (QS3) exhibited signicant impact on the antioxidant activity of the avonoids (Figure 1). The atomic charge at C-3 reects the fact that the oxidation occurs, preferably, at ring B [75-77]. The substituent bonded to C-3 determines the planarity of the avonoid core and the stability of the avonoid phenoxyl radical. The role of position C-5 is relevant only for compounds lacking hydroxyls on ring B. Polarizability can be related to the HOMO LUMO energy gap, since the electronic distribution can be easily deformed if the LUMO is close to the HOMO. Weber et al. [78] also performed PLS regression study for a series of 19 avonoids with several electronic parameters calculated using the semi-empirical AM1 method. Among the several models developed by them, the best model exhibited signicant predictivity as indicated by the high value of the cross-validated squared correlation coefcient (r2 = 0.806, q2 = 0.730). Thus, the best model developed using the
multivariate chemometric approach revealed that the RSA of the avonoids is inuenced by some structural attributes of the avonoids moiety that include possible interactions between the hydroxyl groups, contributions of other groups for the reactivity of the compounds and importance of certain positions of the molecule for the antioxidant activity. The results obtained from the developed PLS models were well consistent with the conventional antioxidant mechanism of action of the avonoids reported earlier. Ray et al. [79] performed QSAR modeling using electrotopological state atom (E-state) parameters in order to determine the antiradical properties of avonoids as studied in a methanolic solution of DPPH (2,2-diphenyl-1-picrylhydrazil) [38] and the antioxidant activity of avonoids in a bcarotene-linoleic acid model system [39]. They developed statistically well-predictive and reproducible models for both types of activities using various chemometric tools. The electrotopological state atom parameter used by them takes into consideration the structural specicity of a drug molecule at atomic or fragmental level rather than at the molecular level. Among the several chemometric tools (factor analysis coupled with MLR, PLS method and stepwise MLR) used for model development, the best models for both the activities (measured in two different model systems) were obtained from the stepwise MLR technique. The equations obtained from all three statistical techniques indicate that S3 (E-state index of atom 3) has negative contribution for the antiradical activity. The parameter S3 indicates the importance of hydroxyl group at position 3 (Figure 1) for the antiradical activity. The equations obtained for the antioxidant activity of avonoids indicate that S3 and S1 have negative contributions for the antioxidant activity. The parameter S1 implies the effect of oxygen function at position 1 and S3 indicates the importance of hydroxyl group at position 3 (Figure 1) needed for the antioxidant activity. Moreover, the signicant presence of E-state parameters in both equations implied the importance of the substituent effect and structural changes for optimal antioxidant activity of the avonoids since E-state parameter varies with changes in structural features including branching, cyclization, homologation, heteroatom variation and changes in relative positions of different groups. The information encoded in the E-state value for an atom represents the electronic accessibility at that atom. Quantum chemical QSAR models of avones for their radical-scavenging activity were developed by Pasha et al. [80]. PM3 calculations were performed by them using MOPAC 2000 associated with CAChe Pro software. Quantitative structureactivity relationship models were constructed using molecular weight, dielectric energy (kcal/mol), total energy (Hartree), heat of formation (kcal/mole), HOMO energy (eV), lowest unoccupied molecular orbital (LUMO) energy (eV), log P, molar refractivity (MR), hardness (g), softness (S), chemical potential (l), electrophilicity index (x) and so on as descriptors. Out of the 8,192 models developed
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by them, some highly signicant models could explain 92% of internal variance. The best model (q2 = 0.92) involved heat of formation, log P, molar refractivity and molecular weight of the molecules under study, which indicated the importance of steric bulk and solvation for the antioxidant activity of the avones. Thus Pasha et al. inferred that a molecule with large steric bulk and a lower value of log P is desirable for a high RSA. Khlebnikov et al. [81] evaluated the antioxidant activity of 46 avonoids in three different assay systems of increasing complexity (chemical, enzymatic and intact phagocytes). With this series of compounds, they developed two different QSAR models using i) physicochemical and structural descriptors to generate multiparameter PLS regression equations derived from optimized molecular structures of the tested compounds and ii) a partial 3D comparison of the 46 compounds with local ngerprints obtained from fragments of the molecules by the frontal polygon (FP) method. They developed QSAR models with quite high correlation coefcients (r) for avonoid end-point antioxidant activity in all three assay systems using the FP method (0.966, 0.948 and 0.965 for datasets evaluated in the biochemical, enzymatic and whole cell assay systems, respectively) together with high LOO cross-validation coefcients (q2) of 0.907, 0.821 and 0.897 for the corresponding datasets. The advantage of using the FP method lies in the fact that in this method the biological effect of a given compound can be represented by the sum of partial contributions (weights Wjl) due to the constituent rigid submolecules [82], as given by the following equation: (10)
L
W jl =
l =1
pIC(c) . 25
Here L is the total number of rigid fragments in the jth c molecule and pIC25 is the calculated pIC25 value for each of the molecules in the dataset. The term Wjl refers to an increment of activity for the lth submolecule or fragment in a novel compound if this submolecule or fragment is surrounded by substituents similar in recognition parameters to the substituents surrounding a given submolecule or fragment in the parent compound and can be useful for the de novo design of active antioxidant substances. Using the frontal analysis method, Khlebnikov et al. developed QSAR models of very high statistical quality together with a signicantly lower number of latent variables as compared to the models obtained with physicochemical and structural descriptors. These FP-derived models were achieved by more complex and elaborate computations involving partitioning of molecules into fragments and searching for optimal superimpositions of ngerprints. Thus, using this submolecule based approach, structural molecular fragments responsible for differences in activity in the assay systems could be identied. These FP QSAR models reported may signicantly advance
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the efforts in de novo design of new avonoid analogues with potent antioxidant activity in biological systems. Calgarotto et al. [83] performed multivariate study on avonoids compounds (Figure 1) with the aim to select electronic properties responsible for their peroxynitrite scavenging activity. Various chemometric tools used for QSAR model development include PCA, HCA and KNN. The involvement of the peroxynitrites in a series of physiological processes like inammatory diseases, atherosclerosis, rheumatoid arthritis, myocardial dysfunctions and autoimmune diabetes led the authors to explore the peroxynitrite RSA of the avonoids. They carried out the nal geometry optimization of the 24 avonoids using the GAUSSIAN03 package [84] by application of the DFT methodology with the use of UB3LYP functional [85] with 6-31G* basis set [60]. From the various models developed using these techniques, they inferred that three parameters play a primary role in discriminating the active and inactive compounds, namely, HOMO energy and net charge at C3 and C4 (QC3 and QC4). They also related these ndings with previous results [86-90] obtained by different methods and found consistent results. Thus, the authors concluded that higher HOMO energy for the avonoid compounds under consideration facilitates transfer of the reducing electrons to the peroxynitrite radical while charges on C3 and C4 are associated with the hydroxyls involved in the electron transfer process between the avonoids and the peroxynitrite radical. Thus, the work proposed the prime parameters underlying the peroxynitrite RSA of this class of avonoids. Durand et al. [91] performed 2D QSAR analysis of 12 avonoids and 19 hexahydropyridoindoles in order to predict the antioxidant activity of 22 pinoline derivatives (1,2,3,4-tetrahydro-b-carbolines). Descriptors belonging to different categories (constitutional, topological, charge, empirical descriptors, aromaticity indices, functional groups and properties) were calculated using the Dragon software and were correlated with the antioxidant activity of these molecules using the PLS method implemented in the QSAR module of Sybyl. They divided the whole dataset into training and test sets paying attention to the homogeneous distribution of biological activities and structural characteristics of the compounds. The authors obtained the best model (n = 21, r2 = 0.888, q2 = 0.794, r2pred = 0.952) with the second-order connectivity index (2c), fth-order information content index (IC5), radial centric information index (ICR) and functional group parameters (total number of tertiary carbons and total number of aliphatic ketones). From these results, they inferred that these descriptors yielded equation with highly acceptable predictive correlation. It highlights that the antioxidant activity of various classes of compounds is also governed by topological and functional group parameters. The DPPH RSA of the avonoids has also been predicted using QSAR technique by Om et al. [92]. They used genetic algorithm and MLR analysis for correlating the 3D Dragon descriptors [93] and semi-empirical quantum chemical descriptors with the RSA of these molecules. They developed
Roy & Mitra
several initial monovariate, bivariate, trivariate and tetravariate models that showed signicant values of the various statistical parameters. The nal signicant multivariate model (n = 25, r2 = 0.987, q2 = 0.978) developed by them concluded that four different 3D descriptors derived using the Dragon package (Mor10u, Mor32p, G3s and R5u+.) are the primary determinants for inuencing the free RSA of the avonoids. They also inferred that besides these descriptors, the semiempirical descriptors also play an important role in controlling optimum RSA of these compounds. Parallel to these ndings, they also reported that a few of the compounds behaved as outliers in two signicant models developed by them indicating that they might act by different mechanism or imply changes in their RSA. Ray et al. [94] performed QSAR modeling for lipid peroxidation (LPO) inhibition potential of a set of 27 avonoids (Figure 1), using a variety of descriptors. The models were developed using a variety of chemometric tools, namely, stepwise regression, factor analysis followed by MLRs (FA-MLR) and PLS analysis. The series of descriptors used for QSAR model development include structural (H_bond_donor, H_bond_acceptor, Chiral centers) and topological descriptors (Balabans J index, Kappa shape index, molecular connectivity index, Wiener index, Zagreb index, subgraph count, exibility index, E-state index of common atoms of the avonoids and E-state indices for fragments). From stepwise regression and PLS analysis it was observed that the E-state values of fragments such as -CH2- were conducive for the LPO inhibition potency. The model obtained from stepwise regression analysis further indicated that the average distance sum of the connectivity among different groups was necessary for activity of these molecules. Stepwise regression analysis also indicated that E-state value of =CH2 fragment was detrimental to activity inferring that as the value of E-state index of =CH2 fragment is increased, the inhibition potency of the compounds decreased. In addition to these ndings, the PLS model indicated that the parameter S_aasC (E-state value of carbon with two aromatic bonds and one single bond) exhibited positive effect on the LPO inhibition potency of these molecules.
3.3
Quantitative structureactivity relationship of miscellaneous classes of chemicals with antioxidant activity
Nakao et al. [95] synthesized a series of hydroxyphenylureas (Figure 2) exhibiting high inhibitory activity against lipid peroxidation and developed QSAR models using those compounds in order to determine the parameters governing their antilipid peroxidative activity. In order to determine the steric and electronic effects of substituents, they calculated various physicochemical parameters such as Hammett constant, Tafts steric constant and the lipophilicity of the molecules. To assess the overall reactivity of the hydroxyl group in hydroxyphenylurea derivatives theoretically, they also performed various quantum chemical calculations. The
structures of compounds were minimized by using semi-empirical molecular orbital calculations with the PM3 Hamiltonian with the SPARTAN software [96] and the calculations were performed with restricted Hartree-Fock method for the ground-state compounds and unrestricted Hartree-Fock for the radicals. They divided the whole dataset on the basis of the common scaffold of the molecules and developed different QSAR models on the basis of the substituents present. It was revealed by Nakao et al. that among various scaffolds used for model development, the inhibitory activities of the hydroxyphenylurea derivatives were governed primarily by the electronic steric effects on the ring A and that any structural conversion around the ring B was rather tolerable. Thus, they inferred that an increase in the electron donating property of substituents towards the phenolic hydroxyl group enhanced the antioxidative activity by the stabilization of an electron-decient radical-type transition state. The steric shielding by ortho-substituents stabilized the phenoxy radicals formed following the transition state. They also inferred from these ndings that modications around the ring B might help in rational design of novel compounds with various pharmacological effects as well as high lipid peroxidation inhibitory activities. However, the fact that derivatives having the carboxyl group were only weakly active presumably because of an intermolecular ion-dipole interaction of the phenolic hydroxyl group with the carboxylate anion, which could retard the formation of the transition state, was also explained by them. Nakao et al. concluded that the primary factors contributing to improved antioxidative activity of the hydroxyphenylureas include presence of electron-donating substituents on the benzene ring near the location of the phenolic hydroxyl group, bulky substituents at the ortho-positions of the phenolic hydroxyl group and absence of any carboxylates or esters in their structures. Ancerewicz et al. [97] examined 25 compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) for their radical scavenging and antioxidant properties and their reaction with DPPH as a measure of radical scavenging capacity was assessed by two parameters, namely, EC50 (the concentration of antioxidant decreasing DPPH by 50%) and log Z, a kinetic parameter proposed by them and derived from initial second-order rate constants and antioxidant/ DPPH ratios. Molecular mechanisms responsible for the reactivity towards the DPPH radical and for the inhibition of lipid peroxidation were identied based on the developed QSAR models. The quantum chemical calculations were performed using the Unrestricted Hartree-Fock method and from these quantum chemical calculations they determined enthalpies of reactions of H-atom abstraction (DHabs) and of single electron transfer (DHox), using a-tocopherol as a reference. Additional parameters calculated by them include H-Surf (the solvent accessible surface of hydroxyl hydrogen) that describes hydroxyl hydrogen accessibility and accounts for steric hindrance, which inuences hydrogen abstraction. Besides these, virtual
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X4 X3 X5 O
OCH3 Y5 O
Y4 Y3
A
X2 X1 N H N H
B
X2
A
N H OH N H
B
Y2 Y1
Figure 2. Two common structural scaffolds of hydroxyphenylurea derivatives.
log P values (log PMLP) for the most stable conformer were also calculated by Ancerewicz et al. using the molecular lipophilicity potential (MLP) as implemented in the CLIP 1.0 package [98]. From the various signicant QSAR models developed, it was revealed that lipophilicity plays a prime role in the process of inhibition of lipid peroxidation and hydrogen abstraction was not the sole mechanism responsible for the reaction between antioxidants and radicals produced in the Fenton reaction. Thus, the QSAR analyses reported by Ancerewicz et al. could demonstrate the complexity of the molecular mechanisms governing the inhibition of lipid peroxidation. Soffers et al. [99] developed QSAR models for the antioxidant activity of a series of all trans carotenoids for their relative ability to scavenge the ABTS radical cation, their relative rate of oxidation by a range of free radicals and their capacity to inhibit lipid peroxidation in multilamellar liposomes, measured by a decrease in formation of thiobarbituric acid reactive substances (TBARS). They performed quantum chemical calculations using the semi-empirical PM3 Hamiltonian method. Two strategies were used to obtain the computer-calculated parameters representing the ease of electron donation by the carotenoids. The rst method follows from KT [57]. In a second approach, the relative differences in heat of formation (DDHf) for conversion of the parent carotenoid into its one electron oxidized radical cation was calculated as the parameter reecting the relative ease of electron donation by the antioxidant molecule, that is, the ionization potential. All the QSAR models developed exhibited excellent correlations with the three different kinds of activities. The QSAR models developed by Soffers et al. provide an insight into the quantitative description of the effect of functional groups and the number of conjugated double bonds on the capacity of the carotenoid molecule to donate electrons. Thus, the theoretical approach may be especially useful to characterize the intrinsic chemical characteristics of the antioxidants and to quantify the effect of structural features on the electron donating capacity of the molecules. Quantitative structureactivity relationship approach was utilized by Zoete et al. [100] for studying the radical-scavenging mechanism of fourteen 4-mercaptoimidazoles, derived from the natural family of ovothiols. The proposed scavenging mechanism of action of these mercaptoimidazoles involves
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hydrogen abstraction from the thiol after reacting with DPPH free radical and formation of a transient thiyl radical species. Combination of two such thiyl radicals then leads to the formation of disulde compounds. They reported that the relation between spin density on carbon 5 (ds5) and the activity [log(l/IC50)] shows a minimum whereas the relation between log(l/IC50) and spin density on the sulfur atom (dsS) is essentially linear. A 4-mercaptoimidazole compound is most active towards DPPH when the spin density on the sulfur atom is high. Since these descriptors were not intercorrelated signicantly, they used these descriptors together with the reaction enthalpy (DHr2) for disulde formation in order to develop the nal QSAR model. Three-dimensional pharmacophore generation technique and Comparative Molecular Field Analysis (CoMFA) methods were employed by Vajragupta et al. [101] in order to study the activity of 13 radical scavengers. Two statistically robust classical QSAR models developed by them bearing highly acceptable values (> 0.96) of cross-validated squared correlation coefcient indicated that the electronic parameters together with steric molar refractivity and lipophilicity are the determinant factors contributing to the antioxidant activity of the molecules. Again the 3D studies performed by them revealed that the structural properties contributing to the activity were not only lipophilic but also the optimum steric property and geometry of side-chain composition. For CoMFA studies, the sp3C(+1) probe provided the best model having q2 of 0.79 with steric and electrostatic contributions of 42.3 and 57.7%, respectively. Quantitative structureactivity relationship analysis of substituted benzylideneacetophenones as lipid peroxidation inhibitors was performed by Nagpal et al. [102] using a combination of various thermodynamic, electronic and steric descriptors. Quantitative structureactivity relationship models were built using the MLR technique. From the signicant QSAR model obtained after validation, they inferred that the electronic (total energy) and thermodynamic parameters play the critical role for controlling the antilipid peroxidative activity of this congeneric series of molecules. Beltran et al. [103] synthesized a series of di-phenyl-tinIVsalicyliden-ortho-aminophenols and performed QSAR analysis with their antioxidant activity values (IC50) calculated based on their ability to inhibit thiobarbituric acid reactive
Roy & Mitra
(CH2)nCONRR
Figure 3. Common structure shared by diphenylpropionamide derivatives.

substances (TBARS). The amount of plasma concentrations of TBARS represents lipid peroxidation and oxidative stress [104] and the TBARS assay was performed as described by Ohkawa et al. [105] with slight modications. They reported that there exists a signicant correlation between the TBARS activity (IC50) and the ortho aminophenol substitutions. Besides this, the Hammett constant (s), one bond tin coupling constants and tin chemical shift also bear a linear relationship with the activity data of these molecules. Thus, they referred to the fact that the implied molecular variables can become trackers for the calculation of TBARS inhibitory concentrations in similar systems. Using the conventional Hansch method, predictive QSAR models were developed by Zhao et al. [106] for a series of nitronyl nitroxides for their capability of trapping free radicals such as .NO, .H2O2 and .OH. The parameters used for model development using the classical Hansch approach employed the Hammett substituent parameter (s), log P and molar refractivity (MR). In some cases, a parabolic dependence of the activity on log P was observed by them, thus (logP)2 was also chosen as a parameter in performing the QSAR analysis. However, the authors used molecular descriptors belonging to four different categories (the constitutional descriptors, topological descriptors, charge descriptors and descriptors of molecular properties) generated from E-Dragon server to perform improved QSAR analysis. Finally, the models were built using the genetic algorithm and the predictive accuracy based on different parameters was evaluated using the resubstitution and LOO cross-validation tests and the optimal equation was established. In order to illustrate the quantitative relationship of the .NO, .H2O2 and .OH trapping activities, three parameters obtained from the Hansch equations and the nine molecular descriptors used in the improved QSAR models were shown to be signicantly correlated with the activity prole of these molecules. Compared with Hansch approach, the predictive results were considerably improved using the molecular descriptors calculated from the E-Dragon server. Thus, the QSAR equations developed by the authors based on these molecular descriptors can be practically used for determining the degree of structural modication needed to obtain 2-substituted phenylnitronyl nitroxides with optimum free RSA.
Urbani et al. [107] performed an extended computational and QSAR investigation on the synthetic diphenylpropionamide (Figure 3) derivatives to dene the molecular features required for high antioxidant activity. They developed QSAR models using genetic function algorithm, and generated 100 QSAR equations consisting of one four descriptors among the QSAR random models. However, the equation with best predictive power signied that the electronic descriptors are the primary controlling parameters for the antioxidant activity of these series of molecules. Samee et al. [108] performed 3D QSAR investigation for synthetic chromone derivatives (Figure 1) using molecular eld analysis (MFA). They developed signicant QSAR models for a series of 7-hydroxy, 8-hydroxy and 7, 8-dihydroxy synthetic chromone derivatives for their DPPH free radical scavenging activities using genetic PLS approach for model development. Molecular eld analysis studies performed on these molecules revealed signicant models with high values of q2 and r2pred (r2cv = 0.771, r2pred = 0.924). The MFA equation developed by them suggested that electronegative group on benzoyl ring and electropositive group on phenyl ring are the important factors controlling the antioxidant activity of these chromone derivatives. The electronegative and electropositive substituents might help in the radical stabilization throughout the chromone nucleus, which is essential for proper functioning of the antioxidant molecules within the system. In a study for predicting antioxidant activities of hydroxybenzalacetone derivatives (Figure 4) for their ability to inhibit t-BuOOH (t-butyl hydroperoxide) and G-irradiation induced lipid peroxidation and scavenge DPPH free radical, Mitra et al. [109] developed signicant QSAR models using stepwise MLR, GFA and genetic PLS (G/PLS) techniques with descriptors of different categories (quantum chemical, physicochemical, spatial and substituent constant). In this study, the quantum chemical descriptors (Mulliken charges of the common atoms) were calculated using semi-empirical AM1 method as well as the Hartree-Fock methods [HF3-21G (d) and HF6-31G(d)]. The best models for the three different kinds of activities were obtained using the genetic algorithm exhibiting signicant values of the statistical parameters q2 (> 0.9) and rm2(LOO). The QSAR models developed in that work summarized that the antioxidant activities of these molecules are primarily governed by the charge distribution over the molecule together with the charged surface areas. A comparison of the charge distribution of these molecules with that of the unsubstituted phenolic moiety indicates that optimum charges over C3, O7, C11 and C6 are necessary for effective antioxidant activity of this series of molecules. Such optimal charge requirements are achieved only through proper substitution of the parent phenolic moiety. Besides these, the shape and size of the substituents attached to the parent phenolic moiety and the lipophilicity of the molecules also play signicant role in controlling the antioxidant activity of these substituted hydroxybenzalacetones.
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4 5
3 Trans 2
CH CH
O 12 C
6 7O 8H
X
5 Trans 4 2 3
CH CH
O 12 C
Y, X
10
11
10
11
1 7
O H
13 8
13
Figure 4. Common structural scaffold of hydroxybenzalacetone (half curcumin) derivatives (X,Y indicate substituents at different positions).
H1
H1
2 8 7
R2 R1
2 8 7
R2
3
R1
3 4
4
O R3
5 6
O O
O R3
5 6
O
Figure 5. Common structural scaffold shared by substituted benzodioxoles and congeners.
In the process of design and development of antioxidant molecules with improved activity, Mitra et al. [110] developed predictive QSAR models using a series of substituted benzodioxoles with signicant lipid peroxidation inhibitory activity. In this work QSAR models were developed using two different sets of descriptors; one set comprising of MSA (molecular shape analysis) and spatial (Jurs descriptors and shadow indices) descriptors while the other set comprising of the quantum chemical (Mulliken charges of the common atoms of the molecules calculated using the semi-empirical AM1 method) and physicochemical descriptors. Signicant QSAR models were developed using GFA and G/PLS techniques. In this work, the GFA technique yielded the best model [r2 = 0.869, q2 = 0.784, rm2(LOO) = 0.823] with the MSA and spatial descriptors while the best predictive model for the charge and physicochemical descriptors [r2 = 0.887, q2 = 0.825, rm2(LOO) = 0.704] was obtained using the G/PLS technique. The models developed by Mitra et al. indicated that the ability of the benzodioxoles to inhibit lipid peroxidation is primarily inuenced by the charges on the common atoms (specially the charges on C6, C7 and C8) and the charged surface area of the molecules. Besides these, the length of the molecule along the Z direction and volume together with their lipophilicity constitute the primary determinants for the lipid peroxidation inhibitory activity of the substituted benzodioxoles (Figure 5). From these results the authors inferred that the parameters inuencing the lipid peroxidation inhibitory activity of these molecules are constituted by the charges on the carbon atoms bearing the non-phenolic oxygen and the presence of methoxy
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substituents (ortho or meta) on the phenyl ring at the R1-position of the benzodioxoles. Prouillac et al. [111] synthesized two new classes of thiol and aminothiol compounds derived from benzothiazole and thiadiazole structures exhibiting potential radioprotective (free radical scavenging) activity. These compounds were examined for their ability to scavenge free radicals (DPPH, ABTS+, OH) and subsequent QSAR studies were performed by them using descriptors obtained from DFT calculation technique. The QSAR models were developed on the basis of data from the DPPH and ABTS tests and the attack on DNA by hydroxyl radicals and articial neural network tool was used for model development. The reactivity of the compounds was judged on the basis of their reaction pathway and the corresponding reaction and activation energies obtained from DFT calculations. The network used by Prouillac et al. comprised of 12 input nodes in the input layer, 1 node in the output layer, with no nodes in the hidden layer and 30,000 learning cycles. The observation showed that by decreasing the number of input parameters while preserving the HOMO parameter (energy of highest occupied molecular orbital), the performance of the networks increased indicating that with the two parameters, HOMO and MTI (Molecular topological index), it was possible to correlate the experimental and calculated activities (IC50) with a coefcient of regression of 0.940 and 0.919 for the DPPH and ABTS tests, respectively. The results from DFT and QSAR studies thus concluded that thermodynamically, thiol derivatives may react more efciently with hydroxyl radicals than with aminothiol compounds and the importance of the HOMO energy in the structureactivity relationship strongly suggested the involvement of a hydrogen donation in the free radical scavenging process. Abreu et al. [112] developed QSAR models for predicting the free RSA of di(hetero)arylamines derivatives of benzo[b] thiophenes using the PLS projection of latent structures method with molecular descriptors, belonging to RDF (Radial Distribution Function) descriptors (RDF020e and RDF045e) and 2D autocorrelation descriptors (GATS8p and MATS5e). They developed statistically signicant QSAR models with considerably acceptable values of the various validation parameters. The models were validated using both LOO and leave-many-out (25 and 50%, respectively)
Roy & Mitra
H8
7
R3
1 2 3
10
11 12
R4
6 9 5
R2
14
13
R1
Figure 6. Common structural scaffold shared by oxazine derivatives.

cross-validation techniques in order to determine their predictivity and robustness. External validation was also performed by Abreu et al. by dividing the whole dataset into training and test sets on the basis of considerations that both the sets should represent all the benzo[b]thiophene classes present in the dataset under consideration as well as cover all the antioxidant activity scale. A plot of predicted pEC50 versus experimental pEC50 values, for both the training and test sets, gave an acceptable, nearly straight-line plot. The RDA descriptors used here can be interpreted as the probability distribution of nding an atom in a spherical volume of radius R [113]. The 2D autocorrelation descriptors explain how the values of certain functions are correlated at equal intervals. Thus they infer the appearance of the RDA descriptor in the developed QSAR model signies that the antioxidant activities of these compounds are inuenced by the presence of electronegative atoms at their inner atmosphere. Besides this, they also concluded that the 2D autocorrelation descriptors associate the presence of polarizable and electronegative pairs of atoms at specic topological distance with the compound RSA. Roy et al. [114] performed molecular shape analysis for predicting the antioxidant and squalene synthase inhibitory activities of aromatic tetrahydro-1,4-oxazine derivatives (Figure 6). Quantitative structureactivity relationship models were developed using GFA and G/PLS regression techniques with descriptors belonging to various categories, namely, molecular shape analysis descriptors, Jurs spatial descriptors, shadow indices, electronic parameters and quantum chemical descriptors [Mulliken charges of the common atoms (Figure 6) shared by the 22 oxazine derivatives]. The GFA [q2 = 0.883, rm2(LOO) = 0.761] and the G/PLS [q2 = 0.800, rm2(LOO) = 0.784] models developed for the lipid peroxidation inhibitory activity of the oxazine derivatives imply that the antioxidant activity of these molecules is governed by their electrophilicity (as indicated by the high impact of the LUMO descriptor) and volume (as signied by the noncommon overlap volume parameter). Quantitative structure activity relationship models were also developed for the ability of these compounds to inhibit the squalene synthase enzyme [115]. Here also, the GFA [q2 = 0.736, rm2(LOO) = 0.572] and G/PLS [q2 = 0.776, rm2(LOO) = 0.725] models revealed that
the ability of this series of oxazine derivatives to inhibit squalene synthase enzyme is governed primarily by the charges on the oxazine nucleus and its charged surface area together with their volume (as indicated by the shadow and density descriptors) and electrophilicity (high electrophilicity favors activity). Subsequently, external validation was also performed by Roy et al. by dividing the whole dataset (n = 22) into training and test sets (ntraining = 15, ntest = 7) by using K-means clustering technique. Acceptable internal and external validation statistics were obtained for both the responses. They observed that high activity prole was exhibited by molecules with sulfur bearing heterocyclic ring as substituent and, consequently, they concluded that the activity of these molecules can be controlled through proper substitution on the parent oxazine moiety.
4.
Expert opinion
The antioxidants exhibit potential health promoting properties resulting from their capability to decrease the risk of development of oxidative stress related diseases such as coronary heart diseases, some forms of cancer, rheumatoid arthritis and Parkinsons and Alzheimers diseases. These medicinal functions of the antioxidants can be ascribed to their free radical scavenging and metal chelation properties. Despite many efforts, the unequivocal relationships between the structural features of various chemical entities and their antioxidant activity have not been signicantly explored yet. This review presents the current knowledge about QSARs of the antioxidant activity of chemical entities belonging to a variety of classes. The results of a number of studies analyzed and discussed in the present review provide a solid rationale for continuing efforts to improve QSAR models of antioxidant activities. A variety of chemometric tools has been used by several authors for modeling the antioxidant activity of different chemicals. The outlines of the QSAR models reviewed in this context primarily conclude that besides lipophilicity, the electronic features together with the shape, size and orientation of the substituents attached at varying positions signicantly inuence their antioxidant activity of the molecules. The potency of the molecules depends on the ease of releasing the proton to the neighboring free radical and this in turn is controlled by the proper pattern of substitution around the parent nucleus. The different descriptors dominating the signicant QSAR models imply the contribution of various other topological and steric parameters to the design of molecules with notable therapeutic action. However, lack of sufcient data related to a particular class of molecules with antioxidant activity (due to very few number of antioxidant molecules of a particular class being synthesized and assayed to date) has hindered the computational modeling methods to some extent. Moreover, among the signicant number of QSAR models developed, majority have been concentrated to the development of models with phenolic derivatives. Besides this class, there
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exists a huge array of chemical compounds with signicant antioxidant activity that may be explored using QSAR technique for their improved activity and reduced toxicity in the near future. Bibliography
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Declaration of interest
The authors state no conict of interest and have received no payment in preparation of this manuscript.
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Kunal Roy & Indrani Mitra Author for correspondence Jadavpur University, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Drug Theoretics and Cheminformatics Laboratory, Kolkata 700 032, India Tel: +91 9831 5941 40; Fax: +91 33 2837 1078; E-mail: kunalroy_in@yahoo.com
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Advances in quantitative structureactivity relationship models of antioxidants

Kunal Roy & Indrani Mitra

Advances in quantitative structureactivity relationship models of antioxidants

ROO + ArOH ROOH + ArO .

(2) (3) (4)

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Atherosclerosis Alzheimers disease

Parkinsons disease Lipid peroxidation DNA damage Cancer

Synthetic substances in diets

Scheme 1. Free radical damage to human system.

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Quantitative structureactivity relationship

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Selection of the dataset

Calculation of descriptors belonging to different categories

Whether the model is satisfactory?

Scheme 2. Flowchart for development of a quantitative structureactivity relationship model.

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Quantitative structureactivity relationship of phenolic antioxidants (excluding avonoids)

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Quantitative structureactivity relationship of avonoids exhibiting antioxidant property

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Quantitative structureactivity relationship of miscellaneous classes of chemicals with antioxidant activity

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Figure 2. Two common structural scaffolds of hydroxyphenylurea derivatives.

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Figure 3. Common structure shared by diphenylpropionamide derivatives.

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Figure 5. Common structural scaffold shared by substituted benzodioxoles and congeners.

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Figure 6. Common structural scaffold shared by oxazine derivatives.

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Expert Opin. Drug Discov. (2009) 4(11)

Advances in quantitative structureactivity relationship models of antioxidants

Expert Opin. Drug Discov. (2009) 4(11)

Roy & Mitra

Expert Opin. Drug Discov. (2009) 4(11)

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