Call: +91-9177734525 | Email: info@opensciencepublications.com

Journal of Chemistry & Applied Biochemistry

Research Article

A DFT Computational Study of the Antioxidant Activities Exhibited by 3-aryl-4-hydroxycoumarin Derivatives

Ekta Khosla

Department of Chemistry, University of Jordan, Amman 11942, Jordan


Corresponding author: Mansour H Almatarneh, Department of Chemistry, University of Jordan, Amman 11942, Jordan, Tel.:(+962) 79 0182748, Fax: (+962) 6 5355 522; E-mail: m.almatarneh@ju.edu.jo


Citation: A DFT Computational Study of the Antioxidant Activities Exhibited by 3-aryl-4-hydroxycoumarin Derivatives.


Copyright © 2016 Muna TT, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Submission: 11/01/2016; Accepted: 27/01/2016; Published: 01/02/2016


Abstract


Density functional theory (DFT) was employed to obtain energy (E), ionization potential (IP), bond dissociation enthalpy (BDE) of O-H bond and stabilization energy (ΔEiso) in order to infer the scavenging activity of 3-phenyl-4-hydroxy coumarin derivatives. Spin density calculations were also performed for the proposed antioxidant activity mechanism. The unpaired electron formed by the hydrogen abstraction from the phenolic hydroxyl group of 3-phenyl-4-hydroxy coumarin derivatives localized on the phenolic oxygen at positions 4 and 3’, the C3 carbon, the C2’ and C6’ carbon atoms at ortho positions and C4’ carbon atom at para position. The lowest phenolic oxygen contribution corresponded to the highest scavenging activity value. It was found that antioxidant activity depends on the presence of a phenyl group at position 3 of coumarin skeleton and presence of a hydroxyl at the C4 and C3’. In addition, the presence of chlorine atom at position 6 on the coumarin skeleton leads to decrease O-H BDE and increase antioxidant activity significantly. There is a correlation between IP and O-H BDE and the capacity of scavenging peroxy radicals and the percentage of the hydroxyl radical scavenging activity.


Keywords: Hydroxycoumarin; Scavenging activity; Antioxidant activity

Introduction


Coumarins (known as 1,2-benzo pyrones) comprise an importantgroup of low molecular weight phenolics that have been widely usedfor prevention and treatment of many diseases [1], Figure 1 shows thestructure of the parent compound, coumarin.” Coumarins possessanti-inflammatory, antioxidants, anticancer, and antiviral activities.Several recent reviews summarize advances in the application ofcoumarins, particularly concentrating their antioxidant properties[1]. The hydroxy coumarins, which are derivatives of the parentcompound coumarin (Figure 1), are phenolic compounds known foracting as potent metal chelators and free radical scavengers. Hydroxycoumarins have attracted intense interest in recent years sincethey exhibit diverse pharmacological properties. Notable amongthese properties are their antioxidant effects that were extensivelyexamined [1], and 3-aryl-4-hydroxycoumarin derivatives that provedto be good antioxidants [2,3].


Figure 1: Structures of coumarin (A) and 4-hydroxycoumarin (B).


DFT calculations were used in studying the antioxidant activitiesof many phenolic compounds such as flavonoid [4,5] as well asdihydrochalcone derivatives [6]. In contrast, very few studies havebeen reported on using DFT calculations to study the antioxidantactivity of coumarins [7], and their derivatives such as 4-methylcoumarins [8] and some 4-hydroxy coumarin derivatives [9]. A briefcomputational study of the O-H bond dissociation energy of some3-aryl-4-hydroxycoumarin derivatives was recently conducted [2].


Up to our knowledge, there is no computational study onantioxidant activity of 3-aryl-4-hydroxycoumarin derivatives.In thiswork, quantum mechanical calculations at the B3LYP/6-31G (d,p)[10-24] level of theory shall be employed to obtain the energies (E),ionization potentials (IP) in the gas phase and implicit water solventusing the polarized continuum model (PCM), the bond dissociationenthalpy (BDE) of O-H bond and the stabilization energies (ΔEiso)of several 3-aryl-4-hydroxycoumarins as shown in Figure 2. The six 3-aryl-4-hydroxycoumarin derivatives (compounds I through V asshown in Figure 2) were studied, in addition to 4-hydroxycoumarin(Figure ) as a reference. The corresponding values of these wereutilized for the purpose of evaluating their relative scavengingactivities. Calculations of the spin densities of these derivatives werealso performed with the intent of exploring the stability of formedfree radicals.


Figure 2: Structures of the 3-Aryl-4-hydroxycoumarin derivatives.


Computational Methods


Geometry optimization of the coumarin derivatives was carriedout using density functional theory (DFT). It offers an excellentcompromise between computational time and description ofelectronic correlation. The calculations were performed utilizingthe Gaussian09 (G09) Quantum package [25]. Prior to any DFTcalculations, all proposed structures were submitted to PM3geometry conformational search. After the PM3 initial optimization,the conformer with the lowest electronic energy was selected. Andthen the structure was re-optimized with the B3LYP hybrid densityfunctional utilizing the 6-31G(d,p) basis set. This level of theorywas used previously to investigate antioxidant activity of variouscompounds [6,7]. The B3LYP optimized structure was ascertainedto conform to a real minimum utilizing frequency calculation (noimaginary frequency). The radicals were treated as open shell systems.The OH bond dissociation enthalpies (BDE), for hemolytic O-Hbond cleavage in the gas phase at 298.15 K was calculated using thesum of electronic and thermal enthalpies according to


BDE (OH) = Hr + H – Hp


Where Hr is the enthalpy of the radical resulting from hydrogenatom abstraction, H is the enthalpy of hydrogen atom (-0.49765Hartrees same as reference [6]), while Hp is the enthalpy of the parentmolecule.


The ionization potential (IP) in the gas phase and in implicitwater was estimated using the polarized continuum model (CPCM).It was calculated as the enthalpy difference between a radical cation(Hc) and the respective parent molecule (Hp)


IP = Hc – Hp


The radical stability was determined through the calculationsof the stabilization energy (ΔEiso) (as shown below), in which itrepresents the hydrogen transfer in the coumarin. The coumarinderivatives are represented by ArOH while the phenol molecules arerepresented by PhOH, according to


ΔEiso = [ArO˙] + [PhOH] – [ArOH] + [PhO˙]


Results and Discussions


Figure 3 shows the optimized structures of 3-Aryl-4-hydroxycoumarin derivatives at B3LYP/6-31G(d,p) level of theory.The stabilization energy (ΔEiso) is used as a simple yet very usefulmethod for predicting the ability of antioxidants to trap free radicalsof phenolic derivatives, which was previously utilized to study theability of several phenolic compounds [6]. The stabilization energiesof the phenoxy radicals were calculated and the values of ΔEiso areshown in Table 1. From this table, we conclude that the presence ofhydroxyl group on the 3’-phenyl ring increases the ΔEiso due to thefact that more oxygen atoms of the phenolic hydroxyl groups candonate electrons to stabilize the semiquinone form. In addition, thepresence of chlorine atom at position 6 on the coumarin skeleton of compound V leads to increase the stability energy significantly. ForIV-OH structure, the radical being on position 3’ is more stable thanon position 4. While for structure V-OH, the most stable radical isbeing at position 4 due to the effect of the chlorine atom on coumarinring. For V-OH(4), the ΔEiso reaches -4.43 kcal/mol. Adding phenyl group to 4-hydroxy coumarin (compound B) and adding electrondonating group such as methoxy or methyl (compounds II and III)do not seem to be important on ΔEiso values.


Figure 3: Optimized structures of 3-Aryl-4-hydroxycoumarin derivatives.


Table 1: Stabilization energies of phenoxy radicals relative to phenol. Theposition of the most stable hydroxyl radical is given in parenthesis. The energieswere calculated at B3LYP/6-31G(d,p) level of theory.


The bond dissociation energy (BDE) of a hydroxyl group involves H-atom transfer whereas the ionization potential (IP) refers to anelectron transfer process. Hence, there are two main theoreticallyaccepted physical parameters for evaluating the possible antioxidantcapacity of a molecule. In general, the weaker an O-H bond and thelower is the ionization potential of an antioxidant, the more activewould the antioxidant be in reacting with radical molecules [8].Hydroxycoumarins are believed to behave like classic phenol- orquinol-based antioxidants; in which the O-H group attached to anaromatic ring structure can take part in an H-atom transfer and/or anelectron transfer process impacting the reduction of a free radical [8].


The capacity of scavenging peroxy radicals was studiedexperimentally through the oxygen radical absorbance capacitymethod using the fluorescence-based technology of detectionmeasurements (ORAC-FL) [3]. The ORAC-FL assay depends on thefree radical damage to a fluorescein. The presence of antioxidantsresults in an inhibition of the free radical damage to the fluorescentcompound. This inhibition is observed as a preservation of thefluorescent signal. The area under the curve (AUC) from theexperimental sample is calculated to quantitate the protection. AUCcalculation indicates both the inhibition time as well inhibitionpercentage of free radical damage by the antioxidant [3]. Also, thepercentage of the hydroxyl radical scavenging activity was studiedpreviously by Perez-Cruz and coworkers [3]. The results of the bonddissociation energy (BDE), an ionization potential (IP), % scavengingand ORAC values are shown in Table 2. The 4-hydroxy coumarinis used as reference molecule. When a phenyl group is added atposition 3 in the compound I, the delocalization of semiquinoneradical increases; thus influencing ORAC values to be changed. Asseen in Table 2, both the BDE and IP in the gas and solvent phasesdecrease significantly, which means an increase the antioxidantactivity. In the compound II, in which the phenyl ring presents ap-methoxy group, and in the compound III with a p-methyl group,a decrease in BDE with respect to the compound I is observed andsubsequently ORAC and antioxidant activity increase. This fact canbe explained by the strong electron-donating effect that increases theelectron density around the hydroxyl group, favoring the hydrogenatom transfer mechanism, which is detected by decreasing BDE.For compound IV, although the BDE for hydroxyl groups is higherthan compound I, increasing the number of hydroxyl groups leads toincrease antioxidant activity. Compound V has the lowest BDE of 46.4kcal/mol. It is indicated that it has the highest antioxidant activity.These values agree with experimental results [3] since compoundV has the highest % scavenging and the highest ORAC values. Themechanism which involved in radical scavenging process for these3-aryl-4-hydroxycoumarin derivatives is mainly H-atom transfer [3].The result in Table 2 shows that BDE has a better correlation withantioxidant activity than IP values.


Table 2: Ionization potentials (IP) and bond dissociation energies (BDE) for 3-aryl-4-hydroxycoumarin derivatives.


Spin density is an important parameter for characterizing thestability of free radicals since the energy of a free radical can besubstantially lowered wherever unpaired electrons become highlydelocalized through a conjugated system, following hydrogenabstraction [6,26]. The spin densities for the semiquinone derivativesare shown in Figure 4. The calculated spin densities of hydrogenabstraction from phenolic hydroxyl group showed that the phenolic oxygen contribution O4 is between 15-27%. For phenolic oxygen O3’,the C3 carbon, the C2’, and C6’ carbon atoms at ortho positions andC4’ carbon atom at the para position are between 43-46%, 2-78%, 11-42%, and 16-35%, respectively. The lowest contribution of phenolicoxygen (being between 15-18%) showed the highest scavengingactivity values due to the electronegativity of oxygen and to the factthat their compounds have more resonance spin structure.


Figure 4: The spin densities for the semiquinone derivatives.


Conclusion


The antioxidant prediction of some 3-phenyl-4-hydroxycoumarinderivatives was investigated theoretically at B3LYP/6-31G(d,p) levelof theory. Phenyl group at position 3 of coumarin skeleton has greatimportance in the resonance stabilization. The introduction of anelectron-donating group such as methyl, methoxy, and hydroxylgroup on the 3-phenyl ring decreases the BDE when compared to4-hydroxy coumarin, resulting in better antioxidant activity. Thepresence of chlorine atom at position 6 on the coumarin skeleton is animportant structural factor that decreases the BDE (O-H) significantlyand increases the antioxidant activity. The phenolic oxygen withlowest spin density contribution has the highest scavenging activityvalues. Our results showed that hydrogen donation BDE (O-H)is more related to the scavenging activity of 3-phenyl-4-hydroxycoumarin derivatives.


Acknowledgment


The authors are grateful to the Atlantic Computational Excellence Network (ACENET) for computer time.


References

  1. Kostova I, Bhatia S, Grigorov P, Balkansky S, Parmar VS, et al. (2011) Coumarins as Antioxidants. Curr Med Chem 18: 3929-3951.
  2. Rodriguez SA, Nazareno MA, Baumgartner MT (2011) Effect of different C3-aryl substituents on the antioxidant activity of 4-hydroxycoumarin derivatives. Bioorg Med Chem 19: 6233-6238.
  3. Perez-Cruz F, Serra S, Delogu G, Lapier M, Maya JD, et al. (2012) Antitrypanosomal and antioxidant properties of 4-hydroxycoumarins derivatives. Bioorg Med Chem Lett 22: 5569-5573.
  4. Mendes APS, Borges RS, Neto AM, de Macedo LG, da Silva AB (2012) The basic antioxidant structure for flavonoid derivatives. J Mol Model 18: 4073-4080.
  5. Sadasivam K, Jayaprakasam R, Kumaresan R (2012) A DFT study on the role of different OH groups in the radical scavenging process. J Theor Comput Chem 11: 871-893.
  6. Bentes ALA, Borges RS, Monteiro WR, de Macedo LGM, Alves CN (2011) Structure of Dihydrochalcones and Related Derivatives and Their Scavenging and Antioxidant Activity against Oxygen and Nitrogen Radical Species. Molecules 16: 1749-1760.
  7. 7.Zhang H, Wang L (2004) Theoretical elucidation of structure-activity relationship for coumarins to scavenge peroxyl radical. J Mol Struct: THEOCHEM 673: 199-202.
  8. Barzegar A, Davari MD, Chaparzadeh N, Zarghami N, Pedersen JZ, et al. (2011) Theoretical and experimental studies on the structure-antioxidant activity relationship of synthetic 4-methylcoumarins. J Iran Chem Soc 8: 973-982.
  9. Mladenovic M, Mihailovic M, Bogojevic D, Matic S, Niciforovic N, et al. (2011) In vitro antioxidant activity of selected 4-hydroxy-chromene-2-one derivatives - SAR, QSAR and DFT studies. Int J Mol Sci 12: 2822-2841.
  10. Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98: 5648-5652.
  11. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B Condens Matter 37: 785-89.
  12. Miehlich B, Savin A, Stoll H, Preuss H (1989) Results obtained with the correlation-energy density functionals of Becke and Lee, Yang and Parr. Chem Phys Lett 157: 200-206.
  13. Vosko SH, Wilk L, Nusair M (1980) Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical analysis. Can J Phys 58: 1200-1211.
  14. Stephens PJ, Devlin FJ, Chabalowski CF, Frisch MJ (1994) Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force field. J Phys Chem 98: 11623-11627.
  15. Ditchfield R, Hehre WJ, Pople JA (1971) Self-Consistent Molecular Orbital Methods. 9. Extended Gaussian-type basis for molecular-orbital studies of organic molecules. J Chem Phys 54: 724-728.
  16. Hehre WJ, Ditchfield R, Pople JA (1972) Self-Consistent Molecular Orbital Methods. 12. Further extensions of Gaussian-type basis sets for use in molecular-orbital studies of organic-molecules. J Chem Phys 56: 2257-2261.
  17. Hariharan PC, Pople JA (1973) The influence of polarization functions on molecular-orbital hydrogenation energies. Theor Chem Acc 28: 213-222.
  18. Hariharan PC, Pople JA (1974) Accuracy of AH equilibrium geometries by single determinant molecular-orbital theory. Mol Phys 27: 209-214.
  19. Gordon MS (1980) The isomers of silacyclopropane. Chem Phys Lett 76: 163-168.
  20. Francl MM, Pietro WJ, Hehre, WJ, Binkley JS, DeFrees DJ, et al. (1982) Self-Consistent Molecular Orbital Methods. 23. A polarization-type basis set for 2nd-row elements. J Chem Phys 77: 3654-3665.
  21. Binning Jr RC, Curtiss LA (1990) Compact contracted basis-sets for 3rd-row atoms - GA-KR. J Comp Chem 11: 1206-1216.
  22. Blaudeau JP, McGrath MP, Curtiss LA, Radom L (1997) Extension of Gaussian-2 (G2) theory to molecules containing third-row atoms K and Ca. J Chem Phys 107: 5016-5021.
  23. Rassolov VA, Pople JA, Ratner MA, Windus TL (1998) 6-31G* basis set for atoms K through Zn. J Chem Phys 109: 1223-1229.
  24. Rassolov VA, Ratner MA, Pople JA, Redfern PC, Curtiss LA (2001) 6-31G* basis set for third-row atoms. J Comp Chem 22: 976-984.
  25. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, et al., Gaussian 09, Revision B.01, Gaussian, Inc., Wallingford CT, 2009.
  26. Borges RS, Queiroz AN, Mendes APS, Araujo SC, Franca LCS, et al. (2012) Density functional theory (DFT) study of edaravone derivatives as antioxidants. Int J Mol Sci 13: 7594-7606.