Synthesis and evaluation of antioxidant activity of some novel hydroxypyridinone derivatives: a DFT approach for explanation of their radical scavenging activity

Afshin Fassihi , Farshid Hasanzadeh, Ahmad Movahedian Attar, Lotfalah Saghaie, Mehrdad Mohammadpour


Background and purpose: Reactive oxygen species (ROSs) are continuously produced as byproducts of cell metabolism. Free radicals are an unstable form of ROSs with the tendency to react readily with biomolecules such as amino acids, lipids and DNA. These reactions lead to oxidative damages to the cell. Oxidative stress occurs when the concentration of the ROSs exceeds the capacity of antioxidative protection systems of the body. 5-Hydroxypyridin-4-one derivatives can chelate Fe2+ and Fe3+ due to their α-hydroxyketone moiety. Also, tautomerism in hydroxypyridinone ring leads to enough level of aromaticity resulting in a catechol-like behavior that provides them with good chelating and radical scavenging properties.

Experimental approach: Different compounds were synthesized with 5-hydroxypyridine-4-one moiety as the core. The antioxidant properties of molecules were evaluated experimentally by DPPH scavenging method and theoretically using DFT/B3LYP with a 6-31++G (d,p) basis set. Electronic properties were investigated using frontier molecular orbital theory calculations. Furthermore, global descriptive parameters were obtained to find the chemical reactivity of molecules. The natural bond orbital analysis was performed to investigate charge distribution and hydrogen bonding.

Findings/Results: Structures of the synthesized compounds were confirmed using IR, 1H-NMR, and 13C-NMR spectral analyses. Among all the synthesized compounds, Va and Vb showed the best antioxidant effect experimentally and computationally.

Conclusion and implications: Results of this study were valuable in terms of synthesis, in silico, and in vitro antioxidant evaluations and can be useful for future investigations about the design of novel 5-hydroxypyridin-4-one derivatives possessing iron-chelating and radical scavenging abilities.




Keywords: Antioxidant; DFT; Hydroxypyridinone; Radical scavenging.

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Snezhkina AV, Kudryavtseva AV, Kardymon OL, Savvateeva MV, Melnikova NV, Krasnov GS, et al. ROS Generation and antioxidant defense systems in normal and malignant cells. Oxid Med Cell Longev. 2019;(4):1-17.

DOI: 10.1155/2019/6175804.

Sayre LM, Perry G, Smith MA. Oxidative stress and neurotoxicity. Chem Res Toxicol. 2008;21(1):172-188.

DOI: 10.1021/tx700210j.

Sadasivam K, Kumaresan R. A comparative DFT study on the antioxidant activity of apigenin and scutellarein flavonoid compounds. Mol Physics. 2011;109(6):839-852.

DOI: 10.1080/00268976.2011.556576.

Di Meo F, Lemaur V, Cornil J, Lazzaroni R, Duroux JL, Olivier Y, et al. Free radical scavenging by natural polyphenols: atom versus electron transfer. J Phys Chem A. 2013;117(10):2082-2092.

DOI: 10.1021/jp3116319.

Leopoldini M, Marino T, Russo N, Toscano M. Antioxidant properties of phenolic compounds: H-atom versus electron transfer mechanism. J Phys Chem A. 2004;108(22):4916-4922.

DOI: 10.1021/jp037247d.

Kehrer JP. The Haber-Weiss reaction and mechanisms of toxicity. Toxicology. 2000;149(1):43-50.

DOI: 10.1016/s0300-483x(00)00231-6.

Velasco-Sánchez D, Aracil A, Montero R, Mas A, Jiménez L, O’Callaghan M, et al. Combined therapy with idebenone and deferiprone in patients with Friedreich’s ataxia. Cerebellum. 2011;10(1):1-8.

DOI: 10.1007/s12311-010-0212-7.

Foti MC. Antioxidant properties of phenols. J Pharm Pharmacol. 2007;59(12):1673-1685.

DOI: 10.1211/jpp.59.12.0010.

Alboaklah HKM, Leake DS. Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH. Free Radic. Res. 2020;16:1-12.

DOI: 10.1080/10715762.2020.1817912

Saghaie L, Pourfarzam M, Fassihi A, Sartippour B. Synthesis and tyrosinase inhibitory properties of some novel derivatives of kojic acid. Res pharm sci. 2013;8(4):233-242.

Zborowski K, Korenova A, Uher M, Proniewicz LM. Quantum chemical studies on tautomeric equilibria in chlorokojic and azidokojic acids. J Mol Struct: THEOCHEM. 2004;683(1-3):15-22.

DOI: 10.1016/j.theochem.2004.06.007.

Sadasivam K, Kumaresan R. Theoretical investigation on the antioxidant behavior of chrysoeriol and hispidulin flavonoid compounds-A DFT study. Comput Theor Chem. 2011;963(1):227-235.

DOI: 10.1016/j.comptc.2010.10.025.

Zborowski KK, Mohammadpour M, Sadeghi A, Proniewicz LM. Theoretical study on the molecular tautomerism of the 3-hydroxy-pyridin-4-one system. ‎Mol Phys. 2013;111(8):958-967.

DOI: 10.1080/00268976.2012.760052.

Streater M, Taylor PD, Hider RC, Porter j. Novel 3-hydroxy-2- (1H)-pyridinones. Synthesis. Iron (III)-chelating properties and biological activity. J Med Chem. 1990;33(6):1749-1755.

Ma Y, Luo W, Quinn PJ, Liu Z, Hider RC. Design, synthesis, physicochemical properties, and evaluation of novel iron chelators with fluorescent sensors. J Med Chem. 2004;47(25):6349-6362.

DOI: 10.1021/jm049751s.

Becker H. Conversion of kojic acid into comenaldehyde and comenic acid. Acta Chem Scand. 1962;16(1):78-82.

DOI: 10.3891/acta.chem.scand.16-0078.

Pesek JJ, Frost JH. Synthesis of imines from aromatic aldehydes and aliphatic amines in aqueous solution. Synthetic Commun. 1974;4(6):367-372.

DOI: 10.1080/00397917408064097.

Mohammadpour M, Sadeghi A, Fassihi A, Saghaei L, Movahedian A, Rostami M. Synthesis and antioxidant evaluation of some novel ortho-hydroxypyridine-4-one iron chelators. Res Pharm Sci. 2012;7(3):171-179.

Blois MS. Antioxidant determinations by the use of a stable free radical. Nature. 1958;181:1199-1200.

DOI: 10.1038/1811199a0.

Frisch M, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J, et al. Gaussian 03, Revision C. 02. Wallingford, CT: Gaussian. Inc[Google Scholar]. 2004.

Rajan VK, Muraleedharan K. A computational investigation on the structure, global parameters and antioxidant capacity of a polyphenol, gallic acid. Food Chem. 2017;220:93-99.

DOI: 10.1016/j.foodchem.2016.09.178.

Amić D, Stepanić V, Lučić B, Marković Z, Marković JMD. PM6 study of free radical scavenging mechanisms of flavonoids: why does O-H bond dissociation enthalpy effectively represent free radical scavenging activity? J Mol Model. 2013;19(6):2593-2603.

DOI: 10.1007/s00894-013-1800-5.

Dhaouadi Z, Nsangou M, Garrab N, Anouar EH, Marakchi K, Lahmar S. DFT study of the reaction of quercetin with O2-and OH radicals. J Mol Struct: THEOCHEM. 2009;904(1-3):35-42.

DOI: 10.1016/j.theochem.2009.02.034.

Samsonowicz M, Regulska E, Kowczyk-Sadowy M, Butarewicz A, Lewandowski W. The study on molecular structure and microbiological activity of alkali metal 3 hydroxyphenylycetates. J Mol Struct. 2017;1146:755-765.

DOI: 10.1016/j.molstruc.2017.06.052.

Świsłocka R, Regulska E, Karpińska J, Świderski G, Lewandowski W. Molecular structure and antioxidant properties of alkali metal salts of rosmarinic acid. Experimental and DFT studies. Molecules. 2019;24(14):2645-2667.

DOI: 10.3390/molecules24142645.

Parkinson CJ, Mayer PM, Radom L. An assessment of theoretical procedures for the calculation of reliable radical stabilization energies. J Chem Soc Perkin 2. 1999(11):2305-2313.

DOI: 10.1039/A905476F.

Trouillas P, Marsal P, Siri D, Lazzaroni R, Duroux JL. A DFT study of the reactivity of OH groups in quercetin and taxifolin antioxidants: the specificity of the 3-OH site. Food Chem. 2006;97(4):679-688.

DOI: 10.1016/j.foodchem.2005.05.042.

Benayahoum A, Amira-Guebailia H, Houache O. A DFT method for the study of the antioxidant action mechanism of resveratrol derivatives. J Mol Model. 2013;19(6):2285-2298.

DOI: 10.1007/s00894-013-1770-7.

Saqib M, Iqbal S, Naeem S, Mahmood A. DFT for exploring the antioxidant potential of homogentisic and orsellinic acids. Pak J Pharm Sci. 2013;26(6):1209-1214.

Al-Majedy YK, Al-Duhaidahawi DL, Al-Azawi KF, Al-Amiery AA, Kadhum AAH, Mohamad AB. Coumarins as potential antioxidant agents complemented with suggested mechanisms and approved by molecular modeling studies. Molecules. 2016;21(2):135-145.

DOI: 10.3390/molecules21020135.

Praveena R, Sadasivam K, Kumaresan R, Deepha V, Sivakumar R. Experimental and DFT studies on the antioxidant activity of a C-glycoside from Rhynchosia capitata. Spectrochim Acta A Mol Biomol Spectrosc. 2013;103:442-452.

DOI: 10.1016/j.saa.2012.11.001.

Johns JR, Platts JA. Theoretical insight into the antioxidant properties of melatonin and derivatives. Org Biomol Chem. 2014;12(39):7820-7827.

DOI: 10.1039/c4ob01396d.

Parr RG, Yang W. Density functional theory of atoms and molecules. New York: Oxford University Press; 1989. pp: 90-104.

Parr RG, Pearson RG. Absolute hardness: companion parameter to absolute electronegativity. J Am Chem Soc. 1983;105(26):7512-7516.

DOI: 10.1021/ja00364a005.

Al-Omary FA, Mary YS, Panicker CY, El-Emam AA, Al-Swaidan IA, Al-Saadi AA, et al. Spectroscopic investigations, NBO, HOMO-LUMO, NLO analysis and molecular docking of 5-(adamantan-1-yl)-3-anilinomethyl-2,3-dihydro-1,3,4-oxadiazole-2-thione, a potential bioactive agent. J Mol Struct. 2015;1096:1-14.

DOI: 10.1016/j.molstruc.2015.03.049.

Koparir M, Orek C, Koparir P, Sarac K. Synthesis, experimental, theoretical characterization and biological activities of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3 (4H)-thione. Spectrochim Acta A Mol Biomol Spectrosc. 2013;105:522-531.

DOI: 10.1016/j.saa.2012.12.052.

Al-Majedy YK, Al-Amiery AA, Kadhum AAH, Mohamad AB. Antioxidant activities of 4-methylumbelliferone derivatives. PLoS One. 2016;11(5):e0156625. 1-13.

DOI: 10.1371/journal.pone.0156625.

Rimarčík J, Lukeš V, Klein E, Ilčin M. Study of the solvent effect on the enthalpies of homolytic and heterolytic N-H bond cleavage in p-phenylenediamine and tetracyano-p-phenylenediamine. J Mol Struct: THEOCHEM. 2010;952(1-3):25-30.

DOI: 10.1016/j.theochem.2010.04.002.

Wright JS, Johnson ER, DiLabio GA. Predicting the activity of phenolic antioxidants: theoretical method, analysis of substituent effects, and application to major families of antioxidants. J Am Chem Soc. 2001;123(6):1173-1183.

DOI: 10.1021/ja002455u.

Foti MC, Daquino C, DiLabio GA, Ingold K. Kinetics of the oxidation of quercetin by 2, 2-diphenyl-1-picrylhydrazyl (dpph•). Org Lett. 2011;13(18):4826-4829.

DOI: 10.1021/ol2019086.


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