Skip to main content

Advertisement

SpringerLink
Log in

Synthesis, computational study and cytotoxicity of 4-hydroxycoumarin-derived imines/enamines

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

In this study, we applied a direct condensation between 3-acetyl-4-hydroxy-2H-chromen-2-one and different amines (anilines and benzyl amines) in order to synthesize some coumarin-based imines/enamines (3a–o) as cytotoxic agents. All the compounds were characterized by means of FT-IR, NMR, mass spectroscopy and elemental analyses. Since the title compounds can exist as different forms including (s-cis)-imine and (s-trans)-imine or (E and Z)-enamines, their conformational and geometrical aspects were investigated computationally by DFT method. The optimized geometry parameters, ΔE, ΔG, ΔH, Mulliken atomic charge, HOMO and LUMO energy, and NBO analysis suggested that these compounds can exist predominantly in (E)-enamine form. All the synthesized compounds (3a–o) were evaluated in vitro for their cytotoxic activities against cancer cell lines (MCF-7 and A549) and normal cell line (BEAS-2B) using the MTT assay. The 4-hydroxybenzyl derivative 3k was found to be the most potent cytotoxic agent with no selectivity, similar to doxorubicin. However, the 4-chlorobenzyl analog 3o could be considered as an equipotent compound respect to doxorubicin with higher selectivity.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. McGuire S (2016) World cancer report 2014. Geneva, Switzerland: World Health Organization, international agency for research on cancer, WHO Press, 2015. Oxford University Press

  2. Stewart B, Wild CP (2014) World cancer report 2014

  3. Kondagunta GV, Motzer RJ (2006) Chemotherapy for advanced germ cell tumors. J Clin Oncol 24(35):5493–5502

    Article  CAS  Google Scholar 

  4. Kayl AE, Meyers CA (2006) Side-effects of chemotherapy and quality of life in ovarian and breast cancer patients. Curr Opin Obstet Gynecol 18(1):24–28

    Article  Google Scholar 

  5. Oun R, Moussa YE, Wheate NJ (2018) The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans 47(19):6645–6653

    Article  CAS  Google Scholar 

  6. Thomas V, Giles D, Basavarajaswamy GPM, Das AK, Patel A (2017) Coumarin derivatives as anti-inflammatory and anticancer agents. Anticancer Agents Med Chem 17(3):415–423. https://doi.org/10.2174/1871520616666160902094739

    Article  CAS  PubMed  Google Scholar 

  7. Xi GL, Liu ZQ (2015) Coumarin-fused coumarin: antioxidant story from N, N-dimethylamino and hydroxyl groups. J Agric Food Chem 63(13):3516–3523. https://doi.org/10.1021/acs.jafc.5b00399

    Article  CAS  PubMed  Google Scholar 

  8. Alonso-Castro AJ, Guzman-Gutierrez SL, Betancourt CA, Gasca-Martinez D, Alvarez-Martinez KL, Perez-Nicolas M, Espitia-Pinzon CI, Reyes-Chilpa R (2018) Antinociceptive, anti-inflammatory, and central nervous system (CNS) effects of the natural coumarin soulattrolide. Drug Dev Res 79(7):332–338. https://doi.org/10.1002/ddr.21471

    Article  CAS  PubMed  Google Scholar 

  9. Tian D, Wang F, Duan M, Cao L, Zhang Y, Yao X, Tang J (2019) Coumarin analogues from the Citrus grandis (L.) osbeck and their hepatoprotective activity. J Agric Food Chem 67(7):1937–1947. https://doi.org/10.1021/acs.jafc.8b06489

    Article  CAS  PubMed  Google Scholar 

  10. Kasperkiewicz K, Ponczek MB, Budzisz E (2018) A biological, fluorescence and computational examination of synthetic coumarin derivatives with antithrombotic potential. Pharmacol Rep 70(6):1057–1064. https://doi.org/10.1016/j.pharep.2018.06.002

    Article  CAS  PubMed  Google Scholar 

  11. Kontogiorgis C, Nicolotti O, Mangiatordi GF, Tognolini M, Karalaki F, Giorgio C, Patsilinakos A, Carotti A, Hadjipavlou-Litina D, Barocelli E (2015) Studies on the antiplatelet and antithrombotic profile of anti-inflammatory coumarin derivatives. J Enzyme Inhib Med Chem 30(6):925–933. https://doi.org/10.3109/14756366.2014.995180

    Article  CAS  PubMed  Google Scholar 

  12. Hassan MZ, Osman H, Ali MA, Ahsan MJ (2016) Therapeutic potential of coumarins as antiviral agents. Eur J Med Chem 123:236–255. https://doi.org/10.1016/j.ejmech.2016.07.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tang ZH, Liu YB, Ma SG, Li L, Li Y, Jiang JD, Qu J, Yu SS (2016) Antiviral spirotriscoumarins A and B: two pairs of oligomeric coumarin enantiomers with a spirodienone-sesquiterpene skeleton from Toddalia asiatica. Org Lett 18(19):5146–5149. https://doi.org/10.1021/acs.orglett.6b02572

    Article  CAS  PubMed  Google Scholar 

  14. Emami S, Foroumadi A, Faramarzi MA, Samadi N (2008) Synthesis and antibacterial activity of quinolone-based compounds containing a coumarin moiety. Arch Pharm 341(1):42–48. https://doi.org/10.1002/ardp.200700090

    Article  CAS  Google Scholar 

  15. Song JL, Yuan Y, Tan HB, Huang RM, Liu HX, Xu ZF, Qiu SX (2017) Anti-inflammatory and antimicrobial coumarins from the stems of Eurya chinensis. J Asian Nat Prod Res 19(3):222–228. https://doi.org/10.1080/10286020.2016.1191474

    Article  CAS  PubMed  Google Scholar 

  16. Keri RS, Sasidhar BS, Nagaraja BM, Santos MA (2015) Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents. Eur J Med Chem 100:257–269. https://doi.org/10.1016/j.ejmech.2015.06.017

    Article  CAS  PubMed  Google Scholar 

  17. Abdel-Latif MS, Elmeleigy KM, Aly TAA, Khattab MS, Mohamed SM (2017) Pathological and biochemical evaluation of coumarin and chlorophyllin against aflatoxicosis in rat. Exp Toxicol Pathol 69(5):285–291. https://doi.org/10.1016/j.etp.2017.01.014

    Article  CAS  PubMed  Google Scholar 

  18. Tejada S, Martorell M, Capo X, Tur JA, Pons A, Sureda A (2017) Coumarin and derivates as lipid lowering agents. Curr Top Med Chem 17(4):391–398

    Article  CAS  Google Scholar 

  19. Ghanei-Nasab S, Khoobi M, Hadizadeh F, Marjani A, Moradi A, Nadri H, Emami S, Foroumadi A, Shafiee A (2016) Synthesis and anticholinesterase activity of coumarin-3-carboxamides bearing tryptamine moiety. Eur J Med Chem 121:40–46. https://doi.org/10.1016/j.ejmech.2016.05.014

    Article  CAS  PubMed  Google Scholar 

  20. Abdel Latif NA, Batran RZ, Khedr MA, Abdalla MM (2016) 3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: synthesis, molecular modeling and QSAR studies. Bioorg Chem 67:116–129. https://doi.org/10.1016/j.bioorg.2016.06.005

    Article  CAS  PubMed  Google Scholar 

  21. Li G, Zhang J, Liu Z, Wang Q, Chen Y, Liu M, Li D, Han J, Wang B (2019) Development of a series of 4-hydroxycoumarin platinum(IV) hybrids as antitumor agents: synthesis, biological evaluation and action mechanism investigation. J Inorg Biochem 194:34–43. https://doi.org/10.1016/j.jinorgbio.2019.02.011

    Article  CAS  PubMed  Google Scholar 

  22. Emami S, Dadashpour S (2015) Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur J Med Chem 102:611–630. https://doi.org/10.1016/j.ejmech.2015.08.033

    Article  CAS  PubMed  Google Scholar 

  23. Emami S, Ghanbarimasir Z (2015) Recent advances of chroman-4-one derivatives: synthetic approaches and bioactivities. Eur J Med Chem 93:539–563. https://doi.org/10.1016/j.ejmech.2015.02.048

    Article  CAS  PubMed  Google Scholar 

  24. Kotali A, Nasiopoulou DA, Tsoleridis CA, Harris PA, Kontogiorgis CA, Hadjipavlou-Litina DJ (2016) Antioxidant activity of 3-[N-(Acylhydrazono)ethyl]-4-hydroxy-coumarins. Molecules 21(2):138

    Article  Google Scholar 

  25. Batran RZ, Khedr MA, Abdel Latif NA, Abd El Aty AA, Shehata AN (2019) Synthesis, homology modeling, molecular docking, dynamics, and antifungal screening of new 4-hydroxycoumarin derivatives as potential chitinase inhibitors. J Mol Struct 1180:260–271. https://doi.org/10.1016/j.molstruc.2018.11.099

    Article  CAS  Google Scholar 

  26. Bonardi A, Falsini M, Catarzi D, Varano F, Di Cesare Mannelli L, Tenci B, Ghelardini C, Angeli A, Supuran CT, Colotta V (2018) Structural investigations on coumarins leading to chromeno[4,3-c]pyrazol-4-ones and pyrano[4,3-c]pyrazol-4-ones: new scaffolds for the design of the tumor-associated carbonic anhydrase isoforms IX and XII. Eur J Med Chem 146:47–59. https://doi.org/10.1016/j.ejmech.2018.01.033

    Article  CAS  PubMed  Google Scholar 

  27. Wang Z-C, Qin Y-J, Wang P-F, Yang Y-A, Wen Q, Zhang X, Qiu H-Y, Duan Y-T, Wang Y-T, Sang Y-L, Zhu H-L (2013) Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis. Eur J Med Chem 66:1–11. https://doi.org/10.1016/j.ejmech.2013.04.035

    Article  CAS  PubMed  Google Scholar 

  28. Nawrot-Modranka J, Nawrot E, Graczyk J (2006) In vivo antitumor, in vitro antibacterial activity and alkylating properties of phosphorohydrazine derivatives of coumarin and chromone. Eur J Med Chem 41(11):1301–1309. https://doi.org/10.1016/j.ejmech.2006.06.004

    Article  CAS  PubMed  Google Scholar 

  29. Shirodkar S (2012) Synthesis, characterization and antimicrobial activity of some new Schiff’s bases derived from 5-acetyl-2, 6-dimethylpyrimidin-4(3H)-one and primary aromatic amines. Asian J Chem 24(12):5833–5836

    CAS  Google Scholar 

  30. Darugar V, Vakili M, Afzali R, Tayyari SF (2017) Conventional and unconventional intramolecular hydrogen bonding in some beta-diketones. Org Chem Res 3(1):61–72

    Google Scholar 

  31. Grabowski SJ (2001) Ab initio calculations on conventional and unconventional hydrogen bonds study of the hydrogen bond strength. J Phys Chem A 105(47):10739–10746. https://doi.org/10.1021/jp011819h

    Article  CAS  Google Scholar 

  32. Mirzaei M, Hadipour NL (2006) An investigation of hydrogen-bonding effects on the nitrogen and hydrogen electric field gradient and chemical shielding tensors in the 9-methyladenine real crystalline structure: a density functional theory study. J Phys Chem A 110(14):4833–4838. https://doi.org/10.1021/jp0600920

    Article  CAS  PubMed  Google Scholar 

  33. Chermette H (1998) Density functional theory: a powerful tool for theoretical studies in coordination chemistry. Coord Chem Rev 178:699–721

    Article  Google Scholar 

  34. Vazquez-Rodriguez S, Matos MJ, Santana L, Uriarte E, Borges F, Kachler S, Klotz KN (2013) Chalcone-based derivatives as new scaffolds for hA3 adenosine receptor antagonists. J Pharm Pharmacol 65(5):697–703. https://doi.org/10.1111/jphp.12028

    Article  CAS  PubMed  Google Scholar 

  35. Girgaonkar M, Shirodkar S (2012) synthesis, characterization and biological studies of Cu (II) and Ni (II) complexes with new bidentate schiff’s base ligands as 4-hydroxy-3-(1-(arylimino) ethyl)(arylimino) ethyl) Chromen-2-one. Res J Recent Sci 1:110–116

    CAS  Google Scholar 

  36. van Meerloo J, Kaspers GJ, Cloos J (2011) Cell sensitivity assays: the MTT assay. Methods Mol Biol (Clifton, NJ) 731:237–245. https://doi.org/10.1007/978-1-61779-080-5_20

    Article  CAS  Google Scholar 

  37. Frisch M, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J, Scalmani G, Barone V, Mennucci B, Petersson G (2013) Gaussian 09, Revision D. 01. Gaussian. Inc, Wallingford

    Google Scholar 

  38. Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc 120(1–3):215–241

    Article  CAS  Google Scholar 

  39. Weigend F, Furche F, Ahlrichs R (2003) Gaussian basis sets of quadruple zeta valence quality for atoms H-Kr. J Chem Phys 119(24):12753–12762

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This project was related to the Ph.D. thesis of SV (Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran). We thank Dr. Nahid Hasani for her valuable comments and suggestions on the molecular modeling part of our work.

Author information

Authors and Affiliations

  1. Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Samaneh Vaseghi

  2. Department of Chemistry, Yadegar-e Imam Khomeini Shahr-e Rey Branch, Islamic Azad University, Tehran, Iran

    Mohammad Yousefi

  3. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Mohammad Shokrzadeh

  4. Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran

    Zinatossadat Hossaini

  5. Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Zahra Hosseini-khah

  6. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Saeed Emami

Authors
  1. Samaneh Vaseghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Yousefi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Shokrzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zinatossadat Hossaini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zahra Hosseini-khah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Saeed Emami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Saeed Emami.

Ethics declarations

Conflict of interest

Authors declared no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 10208 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vaseghi, S., Yousefi, M., Shokrzadeh, M. et al. Synthesis, computational study and cytotoxicity of 4-hydroxycoumarin-derived imines/enamines. Mol Divers 25, 1011–1024 (2021). https://doi.org/10.1007/s11030-020-10086-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-020-10086-2

Keywords

Search

Navigation