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Synthesis, antioxidant evaluation, and quantitative structure–activity relationship studies of chalcones

Abstract

Synthesis, antioxidant activity, and quantitative structure–activity relationship (QSAR) of 25 of chalcone derivatives is reported here. They were synthesized by Claisen–Schmidt reaction and were characterized by FTIR, NMR, and mass spectroscopy. Antioxidant activity is evaluated through four different methods namely, superoxide radical-scavenging, hydrogen peroxide scavenging, reducing power, and DPPH radical-scavenging assays. Generally, compounds with –SCH3 and –OCH3 in the para position of the A-ring and –OH in the B-ring were more active than others. In few cases some of the compounds were more active than ascorbic acid or butylated hydroxytoluene. QSAR was developed correlating the antioxidant activity with the structural features of the compounds and the predictive capability of the models was estimated using internal and external validation methods. All the predictions were within the 99% confidence level. Spatial, structural, and lipophilic properties of the compounds determine their antioxidant properties.

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Notes

  1. 1.

    http://www.supplementquality.com/efficacy/ashitaba.html (21.02.08).

  2. 2.

    Selected spectral data for C24: IR (KBr) 1652 cm−1(Carbonyl), 1H NMR (400 MHz, CDCl3): δ 3.84 (s, 3H), δ 6.90–6.92 (m, 2H), δ 7.14 (ddd, 1H, J = 8.0 Hz, J′ = 2.4 Hz, J″ = 0.8 Hz), δ 7.36 (dd, 1H, J = 8.4 Hz, J′ = 7.6 Hz), δ 7.38 (d, 1H, J = 15.6 Hz), δ 7.54–7.58 (m, 3H), δ 7.66 (dd, 1H, J = 2.4 Hz, J′ = 1.6 Hz), δ 7.79 (d, 1H, J = 16 Hz).13C NMR (100 MHz, CDCl3): δ 191.00, 161.84, 156.56, 145.45, 139.73, 130.41, 129.83, 127.47, 120.79, 120.33, 119.58, 115.25, 114.45, 55.424. EIMS: [M]+ 254.37.

References

  1. Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922

    PubMed  Article  CAS  Google Scholar 

  2. Beauchamp C, Fridovich I (1971) Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem 44:276–287

    PubMed  Article  CAS  Google Scholar 

  3. Bednarczyk D, Ekins S, Wikel JH, Wright SH (2003) Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1. Mol Pharmacol 63:489–498

    PubMed  Article  CAS  Google Scholar 

  4. Caballero J, Zampini FM, Collina S, Fernandez M (2007) Quantitative structure–activity relationship modeling of growth hormone secretagogues agonist activity of some tetrahydroisoquinoline 1-carboxamides. Chem Biol Drug Des 69:48–55

    PubMed  Article  CAS  Google Scholar 

  5. Cartling B, Ehrenberg A (1978) A molecular mechanism of the energetic coupling of a sequence of electron transfer reactions to endergonic reactions. Biophys J 23:451–461

    PubMed  Article  CAS  Google Scholar 

  6. Cioffi G, Escobar LM, Braca A, Tommasi ND (2003) Antioxidant chalcone glycosides and flavanones from Maclura(Chlorophora)tinctoria. J Nat Prod 66:1061–1064

    PubMed  Article  CAS  Google Scholar 

  7. Dhar DN (1981) The chemistry of chalcones and related compounds, vol 213. Wiley, New York

    Google Scholar 

  8. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    PubMed  CAS  Google Scholar 

  9. Durand AC, Farce A, Carato P, Dilly S, Yous S, Berthelot P, Chavatte P (2007) Quantitative structure–activity relationships studies of antioxidant hexahydropyridoindoles and flavonoid derivatives. J Enzyme Inhib Med Chem 22:556–562

    PubMed  Article  CAS  Google Scholar 

  10. Epsin JC, Soler-Rivas C, Wichers HJ (2000) Anthocyanin-based natural colorants: a new source of antiradical activity for foodstuff. J Agric Food Chem 48:648–656

    Article  Google Scholar 

  11. Farkas O, Jakus J, Heberger K (2004) Quantitative structure–antioxidant activity relationships of flavonoid compounds. Molecules 9:1079–1088

    PubMed  Article  CAS  Google Scholar 

  12. Flamm ES, Demopoulos HB, Seligman ML, Poser RG, Ransohoff J (1978) Free radicals in cerebral ischemia. Stroke 9:445–447

    PubMed  CAS  Google Scholar 

  13. Foti MC (2007) Antioxidant properties of phenols. J Pharm Pharmacol 59:1673–1685

    PubMed  Article  CAS  Google Scholar 

  14. Fujii J, Taniguchi N (1999) Down regulation of superoxide dismutases and glutathione peroxidase by reactive oxygen and nitrogen species. Free Radic Res 31:301–308

    PubMed  Article  CAS  Google Scholar 

  15. Green AR, Shuaib A (2006) Therapeutic strategies for the treatment of stroke. Drug Discov Today 11:681–693

    PubMed  Article  CAS  Google Scholar 

  16. Gutteridge JM (1993) Free radicals in disease processes: a compilation of cause and consequence. Free Radic Res Commun 19:141–158

    PubMed  Article  CAS  Google Scholar 

  17. Hobza P, Kabelac M, Sponer J, Mejzlik P, Vondrasek J (1997) Performance of empirical potentials (AMBER, CFF95, CVFF, CHARMM, OPLS, POLTEV), semiempirical quantum chemical methods (AM1, MNDO/M, PM3) and ab initio Hartree-Fock method for interaction of DNA bases. Comparison with nonempirical beyond-Hartree-Fock results. J Comput Chem 18:1136–1150

    Article  CAS  Google Scholar 

  18. Hu CC, Lin JT, Lu FJ, Chou FP, Yang DJ (2007) Determination of carotenoids in Dunaliella salina cultivated in Taiwan and antioxidant capacity of the algal carotenoid extract. Food Chem 109:439–446

    Article  Google Scholar 

  19. Karelson M (2000) Molecular Descriptors in QSAR/QSPR. Wiley-Interscience, New York

    Google Scholar 

  20. Kiemele MJ, Schmidt SR, Berdine RJ (1997) Basic statistics tools for continuous improvement, vol 7, 4th edn. Air academy press, Colorado springs, Colorado, p 3

    Google Scholar 

  21. Kozlowski D, Trouillas P, Calliste C, Marsal P, Lazzaroni R, Duroux JL (2007) Density functional theory study of the conformational, electronic, and antioxidant properties of natural chalcones. J Phys Chem A 111:1138–1145

    PubMed  Article  CAS  Google Scholar 

  22. Lamson DW, Brignall MS (1999) Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Altern Med Rev 4:304–329

    PubMed  CAS  Google Scholar 

  23. Lin J, Rivett DE, Wilshire JFK (1977) The preparation and photochemical properties of some 1,3-diphenyl-2-pyrazolines containing a heteroaromatic substituent. Aust J Chem 30:629–637

    Article  CAS  Google Scholar 

  24. Martinez AC, Marcelo EL, Marco AO, Moacyr M (2001) Differential responses of superoxide dismutase in freezing resistant Solanum curtibolam and freezing sensitive Solanum tuberosum subjected to oxidative and water stress. Plant Sci 160:505–515

    PubMed  Article  CAS  Google Scholar 

  25. Mattson MP (2003) Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromol Med 3:65–94

    Article  CAS  Google Scholar 

  26. Olinski R, Gackowski D, Foksinski M, Rozalski R, Roszkowski K, Jaruga P (2002) Oxidative DNA damage: assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome. Free Radic Biol Med 33:192–200

    PubMed  Article  CAS  Google Scholar 

  27. Ou B, Huang D, Woodill MH, Flanagan JA, Deemer EK (2002) Analysis of antioxidant activities of common vegetables employing oxygen radical absorbance capacity (ORAC) and ferric reducing antioxidant power (FRAP) assays: a comparative study. J Agric Food Chem 50:3122–3128

    PubMed  Article  CAS  Google Scholar 

  28. Oyaizu M (1986) Studies on product of browning reaction prepared from glucose amine. Jpn J Nutr 44:307–315

    CAS  Google Scholar 

  29. Pietta PG (2000) Flavonoids as antioxidants. J Nat Prod 63:1035–1043

    PubMed  Article  CAS  Google Scholar 

  30. Rice-Evans CA, Miller NJ, Paganga G (1997) Structure–antioxidant activity relationships of flavonoids and phenolic acids. Trends Plant Sci 2:152–159

    Article  Google Scholar 

  31. Rogers D, Hopfinger AJ (1994) Application of genetic function approximation to quantitative structure–activity relationships and quantitative structure–property relationships. J Chem Inf Comput Sci 34:854–866

    CAS  Google Scholar 

  32. Rohrbaugh RH, Jurs PC (1987) Molecular shape and the prediction of high-performance liquid chromatographic retention indexes of polycyclic aromatic hydrocarbons. Anal Chim Acta 199:99–109

    Article  CAS  Google Scholar 

  33. Ruch JR, Crist KA, Klaunig JE (1989) Effects of culture duration on hydrogen peroxide-induced hepatocyte toxicity. Toxicol Appl Pharmacol l00:45l–464

    Google Scholar 

  34. Satyanarayana K, Rao MNA (1993) Antiinflamatory, analgesic, and antipyretic activities of 3-[4-[3-(4-dimethylaminophenyl)-1-oxo]-2-propenyl]sydnone. Indian Drugs 30:313–318

    CAS  Google Scholar 

  35. Shen L, Ji HF, Zhang HY (2007) How to understand the dichotomy of antioxidants. Biochem Biophys Res Commun 362:543–545

    PubMed  Article  CAS  Google Scholar 

  36. Shibata S (1994) Anti-tumorigenic chalcones. Stem Cells 12:44–52

    PubMed  Article  CAS  Google Scholar 

  37. Sivakumar PM, Geetha Babu SK, Doble M (2007a) QSAR studies on chalcones and flavonoids as anti-tuberculosis agents using genetic function approximation (GFA) method. Chem Pharm Bull 55:44–50

    PubMed  Article  CAS  Google Scholar 

  38. Sivakumar PM, Seenivasan SP, Kumar V, Doble M (2007b) Synthesis, antimycobacterial activity evaluation, and QSAR studies of chalcone derivatives. Bioorg Med Chem Lett 17:1695–1700

    PubMed  Article  CAS  Google Scholar 

  39. Stanton DT, Jurs PC (1990) Development and use of charged partial surface area structural descriptors in computer-assisted quantitative structure–property relationship studies. Anal Chem 62:2323–2329

    Article  CAS  Google Scholar 

  40. Stavrovskaya IG, Kristal BS (2005) The powerhouse takes control of the cell: is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death? Free Radic Biol Med 38:687–697

    PubMed  Article  CAS  Google Scholar 

  41. Todeschini R, Consonni V (2000) Handbook of molecular descriptors. Wiley-VCH, Weinheim

    Book  Google Scholar 

  42. Todeschini R, Lasagni M, Marengo E (1994) New molecular descriptors for 2D- and 3D-structures. J Chemom 8:263–273

    Article  CAS  Google Scholar 

  43. Varma SD, Devamanoharan PS, Morris SM (1995) Prevention of cataracts by nutritional and metabolic antioxidants. Crit Rev Food Sci Nutr 35:111–129

    PubMed  Article  CAS  Google Scholar 

  44. Vaya J, Belinky PA, Aviram M (1997) Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med 23:302–313

    PubMed  Article  CAS  Google Scholar 

  45. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ (2003) Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 361:2017–2023

    PubMed  Article  CAS  Google Scholar 

  46. Witte P, Beuerle F, Hartnagel U, Lebovitz R, Savouchkina A, Sali S, Guldi D, Chronakis N, Hirsch A (2007) Water solubility, antioxidant activity and cytochrome C binding of four families of exohedral adducts of C60 and C70. Org Biomol Chem 5:3599–3613

    PubMed  Article  CAS  Google Scholar 

  47. Yamagami C, Akamatsu M, Motohashi N, Hamada S, Tanahashi T (2005) Quantitative structure activity relationship studies for antioxidanthydroxybenzalacetones by quantum chemicaland3-D-QSAR (CoMFA) analyses. Bioorg Med Chem Lett 15:2845–2850

    PubMed  Article  CAS  Google Scholar 

  48. Yayli N, Ucuncu O, Aydin E, Gok Y, Yasar A, Baltaci C, Yildirim N, Kucuk M (2005) Intramolecular 4π photocyclization of chalconoid-like compounds in solution and antimicrobial activities. J Photochem Photobiol A 169:229–234

    Article  CAS  Google Scholar 

  49. Yayli N, Ucuncu O, Yasar A, Kucuk M, Yayli N, Akyuz E, Karaoglu SA (2006) Synthesis and biological activities of N-alkyl derivatives of o-, m-, and p-nitro (E)-4-azachalcones and stereoselective photochemistry in solution, with theoretical calculations. Turk J Chem 30:505–514

    CAS  Google Scholar 

  50. Yu L, Haley S, Perret J, Harris M, Wilson J, Qian M (2002) Free radical scavenging properties of wheat extracts. J Agric Food Chem 50:1619–1624

    PubMed  Article  CAS  Google Scholar 

  51. Ziakas GN, Rekka EA, Gavalas AM, Eleftheriou PT, Kourounakis PN (2006) New analogues of butylated hydroxytoluene as anti-inflammatory and antioxidant agents. Bioorg Med Chem 14:5616–5624

    PubMed  Article  CAS  Google Scholar 

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Acknowledgment

Authors thank SAIF, IIT Madras for providing spectral analysis.

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Correspondence to M. Doble.

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Sivakumar, P.M., Prabhakar, P.K. & Doble, M. Synthesis, antioxidant evaluation, and quantitative structure–activity relationship studies of chalcones. Med Chem Res 20, 482–492 (2011). https://doi.org/10.1007/s00044-010-9342-1

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Keywords

  • Chalcones
  • EPR
  • Antioxidant activity
  • Quantitative structure–activity relationship