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Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids

I.A. Adejoro, E. Akintemi, O.O. Adeboye and C. Ibeji
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Eight dietary flavonoids were considered for their variation in activity as antioxidants. Semi-empirical models such as MNDO, AM1, RM1 and PM3; Density functional models at B3LYP energy level with 6-31G* and 6-31G** and moller-plesset perturbation model, MP2 at 6-31G* were used for full optimization of the structures. These methods were used to calculate the parameters such as lipophilicity, ovality, polarizability, vibrational frequency and ultraviolet absorptions which account theoretically for antioxidant potential of the flavonoids. The result of the vibrational frequency showed that MP2/6-31G* compare well with experimental values but could not determine the ultraviolet absorption bands. Myrcetin, of all the flavonoids under study, showed the highest antioxidant activity as well as antigen (stimulates an immune response in the body, especially the production of antibodies).

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I.A. Adejoro, E. Akintemi, O.O. Adeboye and C. Ibeji, 2014. Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids. Asian Journal of Applied Sciences, 7: 117-128.

DOI: 10.3923/ajaps.2014.117.128

Received: August 30, 2013; Accepted: January 22, 2014; Published: March 28, 2014


The application of computer codes to chemistry, involving approximation schemes such as Hartree-Fock, post-Hartree-Fock, density functional theory, semi-empirical methods (such as PM3) or force field methods have been widely studied. Molecular shape is the most frequently predicted property. Computers can also predict vibrational spectra and vibronic coupling but also acquire and Fourier transform Infra-red Data into frequency information. Computational chemistry and molecular modeling is a fast emerging area which is used for the modeling and simulation of small chemical and biological systems in order to understand and predict their behavior at the molecular level. It has a wide range of applications in various disciplines of engineering sciences, such as materials science, chemical engineering, biomedical engineering, etc. (Ramachandran et al., 2008). The most important natural pigments are carotenoids which are tetrapyrrole derivatives of naturally occurring phenolic compounds ubiquitously distributed in plant kingdom. Among these compounds, flavonoids constitute one of the most ubiquitous groups of all plant phenolics. So far, over 8,000 varieties of flavonoids have been identified (De Groot and Raven, 1998). The flavonoids are aromatic secondary plant metabolites which belong to the class of plant polyphenolics. Structurally they are heterocyclic π-electron systems built upon a C6H5(A)-C3-C6H5(B) flavone skeleton in which oxygen is the heteroatom. A group of flavonoids is differentiated in several classes according to the degrees of oxidation and unsaturation of the heterocyclic C ring (Swain, 1976; Harborne and Williams, 2000; Cody et al., 1986). The antioxidant action of flavonoids is due to the combination of its chelating activity, via ortho-dihydroxy structures and its ability to sequester free radicals (Moridani et al., 2003).

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Fig. 1(a-h):
Structures of the flavonoids under study, (a) Apigenin flavon), (b) Catchin flavon), (c) Fisetin flavonol), (d) Galagin flavonol), (e) Kaemferol flavonol), (f) Morin flavonol), (g) Myricetin flavonol) and (h) Quercetin flavonol)

This occurs in three stages: formation of the superoxide ion and hydroxy radicals by Fenton's reaction and formation of lipid radicals and mechanisms that decrease lipid peroxidation (Rice-Evans et al., 1996).

Although, cells have mechanisms to protect themselves against toxic agents; some of these systems suffer a decline in their activities in some physiological and environmental conditions that lead to an increased production of Reactive Oxygen Species (ROS). Thus, dietary supplementation with nutrients that contain antioxidants may be important for additional protection against oxidative stress and prevention of diseases such as atherosclerosis, cancer, ischemia, inflammation and cardiovascular and neurological diseases (Lopez-Revuelta et al., 2006). The objective of this study is to theoretically investigate the structure-activity relationship, infrared and ultraviolet absorptions of some dietary flavonoids in the light of parameters such as lipophilicity, specific-prostrate antigen (PSA) and ovality.


MMFFaq Molecular Mechanics Conformational Distribution was used to obtain the different conformers. These gave rise to different conformers for each of the eight dietary flavonoids studied with their corresponding energies. The most stable conformer (i.e., the conformer with the lowest energy) obtained for each molecule (Fig. 1) was fully optimized. Gas phase optimization was carried out for all the molecules with SPARTAN’10 using all available semiempirical molecular orbital theory models (MNDO, AM1, RM1 and PM3), density functional theory model with Becke three Lee Yang Parr with 6-31G*, 6-31G** basis sets; and Moller-Plesset theory at 6-31G* level.


Lipophilicity: Lipophilicity is a fundamental physicochemical property that plays a pivotal role in the absorption, distribution, metabolism and elimination of therapeutic drugs. Lipophilicity is expressed in several different ways, including terms such as log p, clogp, delta log p and log D. Often a parabolic relationship exists between measured lipophilicity and in vivo brain penetration of drugs, where those moderate in lipophilicity often exhibit highest uptake. Reduced brain extraction of more lipophilic compounds is associated with increased non-specific binding to plasma proteins. More lipophilic compounds can also be more vulnerable to P450 metabolism, leading to faster clearance (Waterhouse, 2003).

Mori et al. (1987) reported that the lipophilic compound 7,8-dihydroxyflavone exhibited weak activity against S. aureus and no activity against P. vulgaris. These results may be related to the high lipid content of the cell wall of P. vulgaris which may have trapped the 7,8-dihydroxyflavone. The cell wall of S. aureus, lacking a lipid layer, could be penetrated. The flavonoids exhibited a stronger effect on DNA synthesis in P. vulgaris, while exhibiting a stronger effect on RNA synthesis in S. aureus (Mori et al., 1987).

The lipophilicity, log p values above indicate that the order in which the flavonoids have affinity for lipid is apigenin = galagin>catechin>fisetin = kaempferol>morin = quercetin>myrcetin. Negative and large value of log p corresponds to lower affinity for lipids and increased reactivity against oxidants. The relationship between log p values and the flavonoids antioxidant effectiveness are in inverse proportional. That is, the lower the value of log p, the higher the antioxidant effectiveness and vice-versa as shown in Fig. 2.

This relationship between log p and antioxidant effectiveness is in agreement with the work of Xu and Lee (2001). Xu and Lee (2001) noted that the wide range of myricetin activity, both against Gram-positive and Gram-negative bacteria, was related to its inhibition of protein synthesis. They reported that only polyhydroxylated derivatives of flavonoids, except for flavone which contains no hydroxyl groups, were active against MRSA. The presence of at least one hydroxyl group in rings A or B at C-3, C-5 and C-7 was important for activity.

All the flavonols examined, except galagin which lacks hydroxyl substituent on its B ring, have higher reactivity than other flavonoids (catechin, a flavanol and apigenin, a flavone). Asides the contribution of the C-3, C-5 and C-7 hydroxyl substituent to reactivity, the presence of one or more of this on the B rings, especially at C-3’, C-4’ and C-5’, also contribute to high antioxidant activity.

Image for - Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids
Fig. 2:
Relationship between lipophilicity and antioxidant effectiveness of the studied flavonoids (A, G, C, F, K, Mo, Q and My represent apigenin, galagin, catechin, fisetin, kaempferol, morin, quercetin and myrcetin, respectively)

Table 1: Calculated hydrophobicity (log p) and haemoglobin delta (HBD) and haemoglobin alpha (HBA) counts
Image for - Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids
Dimensionless unit

This is in line with the results of Mori et al. (1987). They observed a relationship between the structures of the flavonoids and their activity against P. vulgaris and S. aureus. Most of the activity was related to the presence of hydroxyl groups C-3’, C-4’ and C-5’ in ring B and at C-3. Epigallocatechin and dihydrorobinetin exhibited weak activity indicating that the C2-C3 double bond was not crucial for antibacterial activity (Mori et al., 1987). Schinazi reported that quercetin, myricetin and quercetagetin were shown to inhibit cellular DNA polymerase-β and DNA polymerase-I and that quercetin and queretagetin were strong inhibitors (Lin et al., 1997).

Haemoglobin HbA content: Haemoglobin subumit delta is a protein in humans encoded by HDB. Two α-chains plus two β-chains constitute HbA which in adult life comprises about 97% of the total haemoglobin. As given in Table 1, a molecule with two HBA counts and two HBD counts can be said to have 1 HbA. From the computed values for all the molecules, the order of increasing HbA property of the flavonoids is apigenin = galagin<catechin = kaempferol = fisetin<quercetin = morin = myrcetin.

Prostate-specific antigen: Prostate-specific antigen, or PSA, is a protein produced by cells of the prostate gland. The blood level of PSA is often elevated in men with prostate cancer and a number of benign (not cancerous) conditions can cause a man’s PSA level to rise. The most frequent benign prostate conditions that cause an elevation in PSA level are prostatitis (inflammation of the prostate) and benign prostatic hyperplasia (BPH) (enlargement of the prostate). The more a man’s PSA level, the more likely it is that he has prostate cancer (Thompson et al., 2004). Flavonoids are now also being evaluated in terms of prostate cancer prevention (Strom et al., 1999). The full impact of these compounds, found in fruits, vegetables, tea and others on prostate disease development and treatment has yet to be determined. In vitro studies have demonstrated the partial estrogen/anti-estrogen activities of soy isoflavones and other flavonoids (Le Bail et al., 1998; Zava et al., 1997), as well as their antioxidant effects (Noroozi et al., 1998; Ng et al., 2000). In this study, the value of PSA is a measure of how much a flavonoid can inhibit the production of postrate cancer. High PSA value connotes high effectiveness of the flavonoids. That is, high antioxidant capacity of flavonoids corresponds to high calculated PSA value and great suppression of cancer growth. Hence, depending on the PSA value, (Table 2), the order of antioxidant potential of the studied flavonoids is galagin<apigenin<kaempferol<catechin<quercetin<morin<myrcetin.

Table 2: Calculated prostrate-specific antigen (PSA), ovality (dimensionless) and polarizability (in Bohr3)
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Ovality: In computational chemistry, especially in QSAR studies, ovality refers to a measure of how the shape of a molecule approaches a sphere (at one extreme) or a cigar shape (at the other):

Image for - Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids

where, O is Ovality, A is Area and V is Volume (Henre and William, 2008).

High ovality value (Table 2) suggests a flavonoid molecular structure’s proneness to deviation from its shape, thereby loosing activity as fast as possible.

Ultraviolet-visible spectroscopy: Ultraviolet-visible spectroscopy (UV = 200-400 nm, visible = 400-800 nm) corresponds to the excitations between the energy levels that correspond to the molecular orbitals of the systems. In particular, transitions involving π orbitals and lone pairs (n = nonbonding) are important a nd so UV-Visible. spectroscopy is most useful for identifying conjugated systems which tend to have stronger absorptions. The absorption of the electromagnetic radiation excites an electron to the LUMO and creates an excited state. The more highly conjugated the system, the smaller the HOMO-LUMO gap i.e., ΔE and therefore the lower the frequency and the longer the wavelength (Olajire, 2011). The ultraviolet spectra of the molecules under study calculated with DFT/B3LYP/6-31G* model chemistry are shown in Fig. 3a to h. As the HOMO-LUMO transition occurs in the ultraviolet region, near or out of the visible region, it can be predicted that these molecules will be colorless or slightly colored. All the dietary flavonoids studied except apigenin (a flavone) and catechin (a flavanol) are flavonols and they have strong absorptions close to the visible region and can be predicted to be more colored. Flavonol morin, for example, has the longest wavelength at 379.17 nm and its band encroach into the visible region than other flavonols as a result of the presence of more hydroxyl groups (auxochromes) on its B ring. It is therefore likely to be more colored than other flavonols. Catechin, a flavanol, lacks C2-C3 double bond, meaning that the hydroxyl groups at C3 and C4 has no contribution to the wavelength. Its absorption wavelength is therefore due to the A and B rings and their auxochromes (polyphenols).

Infrared spectroscopy: Characteristics infrared (IR) absorption bands such as C = Ostr, C-Hstr, C-Ostr, C=Cstr(aromatic) among others were observed for the molecules. These give information on whether or not a molecule contains some functional groups. It has been shown that the structural features are very important for high antioxidant activity of flavonoids (Cody et al., 1986). The ability of flavonoids to scavenge radicals depends on their structures and the substituents of the heterocyclic ring A. It is also known that ortho subtituents in the B ring, especially those with electron donating capabilities enhance the free radical quenching. Among major determinants are also the presences of carbonyl group at C4, a double bond between C2 and C3 conjugated with the C4-oxo group (enabling higher electron delocalization) and C3 hydroxyl group present in flavonols (Markovic et al., 2009).

Of all the model chemistry methods used for calculating the vibrational frequencies of the functional groups for all the molecules under study, MP2/6-31G* model chemistry gave the best prediction when compared with literature data. In fisetin molecule, for instance, C = Ostr in the C ring according to Olajire, 2011, is 1710 cm-1. The calculated value and the corresponding magnitude of variation from the literature value (1710cm-1) is 2089 cm-1 (379) for semi-empirical MNDO basis set, 2026 cm-1 (316) for AM1, 1949 cm-1 (239) for RM1, 1935 cm-1 (225) for PM3, 1705 cm-1 (5) for DFT/B3LYP/6-31G*, 1703 cm-1 (7) for DFT/B3LYP/6-31G** and 1711 cm-1 (1) for MP2/B3LYP/6-31G*. MP2/B3LYP/6-31G* model chemistry with the lowest magnitude of variation from the literature data best predicts the IR absorption band. Catechin molecule lacks carbonyl group at C4 and the vibrational frequencies observed from 1668-1709 cm-1 are due to the C = Cstr(aromatic) in its A and B rings. It is therefore worthy of note that the antioxidant capacity of flavanol catechin can be attributed to its possession of hydroxyl groups in the molecule.

Table 3:Calculated infrared absorption bands of functional groups in apigenin molecule (cm-1)
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Image for - Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids

Image for - Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids
Image for - Quantum Mechanical Studies of the Structure-activity Relationship and Electronic Vibration of Some Dietary Flavonoids
Fig. 3(a-h):
(a) UV of apigenin calculated with DFT/B3LYP/6-31G* (b) Catechin calculated with DFT/B3LYP/6-31G*, (c) Fisetin (d) Galagin, (e) Kaempferol, (f) Morin, (g) Myrcetin and (h) Quercetin

The infrared absorption bands of the functional groups in each of the molecules at three levels of calculations (MP2, DFT and PM3) are compared with corresponding experimental values shown in Table 3 Spectra showing the calculated IR absorption bands for the molecules under study are presented in Fig. 4a to h.

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Fig. 4(a-h):
(a) IR of the apigenin calculated with MP2/6-31G*, (b) IR catechin calculated with MP2/6-31G*, (c) Infrared spectra of the fisetin calculated with MP2/6-31G*, (d) Infrared spectra of the galagin calculated with MP2/6-31G*, (e) Infrared spectra of the kaempferol calculated with MP2/6-31G*, (f) Infrared spectra of the morin calculated with MP2/6-31G*, (g) Infrared spectra of the myrcetin calculated with MP2/6-31G* and (h) Infrared spectra of the quercetin calculated with MP2/6-31G*


The use of molecular modeling techniques via simulation of molecules has great impact on research and served as eye opener into the relevance of computational methods in scientific and non-scientific research. Antioxidant capacity of flavonoids can be attributed to their structures, as examined experimentally and also as treated theoretically in this study. Lipophilicity (logP), values showed that myrcetin has highest antioxidant effectiveness among all the studied flavonoids; which was also confirmed by the calculated PSA values. Applied theoretical approach confirms the importance of the B-ring and sheds light on the role of the C3-OH group in reactivity, influencing antioxidant properties of the molecule which is dependent upon the presence of the C2-C3 double bond (Markovic et al., 2009). Infrared absorption spectra also indicated that this bond (C2-C3 double bond) is one of the determinants of how reactive a flavonoid will be; coupled with this is the information on their ultraviolet absorption which shows the contribution of the hydroxyl substituents on both A and B rings meaning that high number of hydroxyl substituent is in direct proportion to the effectiveness of flavonoids.


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