Skip to main content
SpringerLink
Log in

Scoparone chemical modification into semi-synthetic analogues featuring 3-substitution for their anti-inflammatory activity

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

Abstract

Natural products (NPs) continue to serve as a structural model for the development of new bioactive molecules and improve the process of identifying novel medicines. The biological effects of coumarins, one of the most researched compounds among NPs, are currently being thoroughly investigated. In the present investigation, we reported the synthesis of nineteen semi-synthetic 3-substituted scoparone analogues, followed by their characterization using analytical methods such as NMR, HPLC, and HRMS. All compounds screened for in vitro and in vivo study for their ability to reduce inflammation. The SAR study worked effectively for this particular scoparone 3-substitution, as compounds 3, 4, 9, 16, 18, and 20 displayed improved in vitro results for TNF-α than the parent molecule. Similarly, compounds 3, and 17 showed a higher percentage of IL-6 inhibition. Compounds 3, 4, and 12 have also been identified by in vivo studies as promising candidates with higher percent inhibition than the parent scoparone molecule. As evident from all in vitro and in vivo studies, compound 3 showed the most potent anti-inflammatory activity among all.

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
Scheme 1
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The supporting information including in vitro and in vivo activity tables and characterization data for all compounds (1 H, 13 C NMR, HRMS and HPLC spectra) is provided.

References

  1. Liu M, Liu J, Zhao Z, Yang G, Zhang W (2015) The Skeleton Construction and Pharmaceutical Activity of Coumarins. Atlantis Press, pp 131–134. https://doi.org/10.2991/ap3er-15.2015.32

  2. Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A (2018) Coumarin: a Natural, Privileged and Versatile Scaffold for Bioactive Compounds. Molecules 23(2):250. https://doi.org/10.3390/molecules23020250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carneiro A, Matos MJ, Uriarte E, Santana L (2021) Trending topics on Coumarin and its derivatives in 2020. Molecules 26(2):501. https://doi.org/10.3390/molecules26020501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wei L, Hou T, Li J, Zhang X, Zhou H, Wang Z, Cheng J, Xiang K, Wang J, Zhao Y, Liang X (2021) Structure–activity relationship studies of coumarin-like diacid derivatives as human G protein-coupled Receptor-35 (hGPR35) agonists and a consequent New Design Principle. J Med Chem 64(5):2634–2647. https://doi.org/10.1021/acs.jmedchem.0c01624

    Article  CAS  PubMed  Google Scholar 

  5. Cao D, Liu Z, Verwilst P, Koo S, Jangjili P, Kim JS, Lin W (2019) Coumarin-based small-molecule fluorescent chemosensors. Chem Rev 119(18):10403–10519. https://doi.org/10.1021/acs.chemrev.9b00145

    Article  CAS  PubMed  Google Scholar 

  6. Sun X, Liu T, Sun J, Wang X (2020) Synthesis and application of coumarin fluorescence probes. RSC Adv 10:10826–10847. https://doi.org/10.1039/C9RA10290F

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thakur A, Singla R, Jaitak V (2015) Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem 101:476–495. https://doi.org/10.1016/j.ejmech.2015.07.010

    Article  CAS  PubMed  Google Scholar 

  8. Bhattarai N, Kumbhar AA, Pokharel YR, Yadav PN (2021) Anticancer potential of coumarin and its derivatives. Mini-Reviews in Medicinal Chemistry 21(19):2996–3029. https://doi.org/10.2174/1389557521666210405160323

    Article  CAS  PubMed  Google Scholar 

  9. Kaur M, Kohli S, Sandhu S, Bansal Y, Bansal G (2015) Coumarin: a promising scaffold for anticancer agents. Anticancer Agents Med Chem 15(8):1032–1048. https://doi.org/10.2174/1871520615666150101125503

    Article  CAS  PubMed  Google Scholar 

  10. Stefani HA, Gueogjan K, Manarin F, Farsky SH, Zukerman-Schpector J, Caracelli I, Rodrigues SR, Muscará MN, Teixeira SA, Santin JR, Machado ID (2012) Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)-coumarin derivatives: Effect on inducible nitric oxide synthase. Eur J Med Chem 58:117–127. https://doi.org/10.1016/j.ejmech.2012.10.010

    Article  CAS  PubMed  Google Scholar 

  11. Basanagouda M, Shivashankar K, Kulkarni MV, Rasal VP, Patel H, Mutha SS, Mohite AA (2010) Synthesis and antimicrobial studies on novel sulfonamides containing 4-azidomethyl coumarin. Eur J Med Chem 45(3):1151–1157. https://doi.org/10.1016/j.ejmech.2009.12.022

    Article  CAS  PubMed  Google Scholar 

  12. Xu B, Wang L, González-Molleda L, Wang Y, Xu J, Yuan Y (2014) Antiviral activity of (+)-Rutamarin against Kaposi’s Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic activity of human topoisomerase II. Antimicrob Agents Chemother 58(1):563–573. https://doi.org/10.1128/AAC.01259-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kostova I, Bhatia S, Grigorov P, Balkansky S, Parmar V S, K Prasad A, Saso L (2011) Coumarins as antioxidants. Curr Med Chem 18(25):3929–3951. https://doi.org/10.2174/092986711803414395

    Article  CAS  PubMed  Google Scholar 

  14. Anand P, Singh B, Singh N (2012) A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease. Bioorg Med Chem 20(3):1175–1180. https://doi.org/10.1016/j.bmc.2011.12.042

    Article  CAS  PubMed  Google Scholar 

  15. Belluti F, Fontana G, Dal Bo L, Carenini N, Giommarelli C, Zunino F (2010) Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: identification of novel proapoptotic agents. Bioorg Med Chem 18(10):3543–3550. https://doi.org/10.1016/j.bmc.2010.03.069

    Article  CAS  PubMed  Google Scholar 

  16. Sánchez-Recillas A, Navarrete-Vázquez G, Hidalgo-Figueroa S, Rios MY, Ibarra-Barajas M, Estrada-Soto S (2014) Semisynthesis, ex vivo evaluation, and SAR studies of coumarin derivatives as potential antiasthmatic drugs. Eur J Med Chem 77:400–408. https://doi.org/10.1016/j.ejmech.2014.03.029

    Article  CAS  PubMed  Google Scholar 

  17. Sashidhara KV, Modukuri RK, Singh S, Rao KB, Teja GA, Gupta S, Shukla S (2015) Design and synthesis of new series of coumarin-aminopyran derivatives possessing potential anti-depressant-like activity. Bioorg Med Chem Lett 25(2):337–341. https://doi.org/10.1016/j.bmcl.2014.11.036

    Article  CAS  PubMed  Google Scholar 

  18. Kashman Y, Gustafson KR, Fuller RW, Cardellina JH, McMahon JB, Currens MJ, Buckheit RW Jr, Hughes SH, Cragg GM, Boyd MR (1992) HIV inhibitory natural products. Part 7. The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum. J Med Chem 35(15):2735–2743. https://doi.org/10.1021/jm00093a004

    Article  CAS  PubMed  Google Scholar 

  19. Manvar A, Bavishi A, Radadiya A, Patel J, Vora V, Dodia N, Rawal K, Shah A (2011) Diversity oriented design of various hydrazides and their in vitro evaluation against Mycobacterium tuberculosis H37Rv strains. Bioorg Med Chem Lett 21(16):4728–4731. https://doi.org/10.1016/j.bmcl.2011.06.074

    Article  CAS  PubMed  Google Scholar 

  20. Yeh JY, Coumar MS, Horng JT, Shiao HY, Kuo FM, Lee HL, Chen IC, Chang CW, Tang WF, Tseng SN, Chen CJ (2010) Anti-Influenza Drug Discovery: structure – activity relationship and mechanistic insight into Novel angelicin derivatives. J Med Chem 53(4):1519–1533. https://doi.org/10.1021/jm901570x

    Article  CAS  PubMed  Google Scholar 

  21. Asif M (2015) Pharmacologically potentials of different substituted coumarin derivatives. Chem Int 1(1):1–11

    CAS  Google Scholar 

  22. Olmedo D, Sancho R, Bedoya LM, López-Pérez JL, Del Olmo E, Muñoz E, Alcamí J, Gupta MP, San Feliciano A (2012) 3-Phenylcoumarins as inhibitors of HIV-1 replication. Molecules 17(8):9245–9257. https://doi.org/10.3390/molecules17089245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kabeya LM, de Marchi AA, Kanashiro A, Lopes NP, da Silva CH, Pupo MT, Lucisano-Valim YM (2007) Inhibition of horseradish peroxidase catalytic activity by new 3-phenylcoumarin derivatives: synthesis and structure-activity relationships. Bioorg Med Chem 15(3):1516–1524. https://doi.org/10.1016/j.bmc.2006.10.068

    Article  CAS  PubMed  Google Scholar 

  24. Matos MJ, Teran C, Perez-Castillo Y, Uriarte E, Santana L, Vina D (2011) Synthesis and study of a series of 3-Arylcoumarins as potent and selective Monoamine oxidase B inhibitors. J Med Chem 54(20):7127–7137. https://doi.org/10.1021/jm200716y

    Article  CAS  PubMed  Google Scholar 

  25. Serra S, Ferino G, Matos MJ, Vazquez-Rodriguez S, Delogu G, Vina D, Cadoni E, Santana L, Uriarte E (2012) Hydroxycoumarins as selective MAO-B inhibitors. Bioorg Med Chem Lett 22(1):258–261. https://doi.org/10.1016/j.bmcl.2011.11.020

    Article  CAS  PubMed  Google Scholar 

  26. Zhang Q, Miao YH, Liu T, Yun YL, Sun XY, Yang T, Sun J (2022) Natural source, bioactivity and synthesis of 3-Arylcoumarin derivatives. J Enzyme Inhib Med Chem 37(1):1023–1042. https://doi.org/10.1080/14756366.2022.2058499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu T, Zhang L, Joo D, Sun SC (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:17023

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yu H, Lin L, Zhang Z, Zhang H, Hu H (2020) Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Sig Transduct Target Ther 5:1–23. https://doi.org/10.1038/s41392-020-00312-6

    Article  CAS  Google Scholar 

  29. Barnabei L, Laplantine E, Mbongo W, Rieux-Laucat F, Weil R (2021) NF-κB: at the Borders of autoimmunity and inflammation. Front Immunol 12:716469. https://doi.org/10.3389/fimmu.2021.716469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huei-Chen H, Shu-Hsun C, Pei-Dawn Lee C (1991) Vasorelaxants from chinese herbs, emodin and scoparone, possess immunosuppressive properties. Eur J Pharmacol 198:211–213. https://doi.org/10.1016/0014-2999(91)90624-Y

    Article  Google Scholar 

  31. Huang HC, Weng YI, Lee CR, Jan TR, Chen YL, Lee YT (1993) Protection by Scoparone against the alterations of plasma lipoproteins, vascular morphology and vascular reactivity in Hyperlipidaemic Diabetic rabbit. 110(4):1508–1514. https://doi.org/10.1111/j.1476-5381.1993.tb13993.x

  32. Hoult JRS, Payá M (1996) Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen Pharmacology: Vascular Syst 27(95):713–722. https://doi.org/10.1016/0306-3623

    Article  CAS  Google Scholar 

  33. Lee YM, Hsiao G, Chang JW, Sheu JR, Yen MH (2003) Scoparone inhibits tissue factor expression in lipopolysaccharide-activated human umbilical vein endothelial cells. J Biomed Sci 10:518–525. https://doi.org/10.1007/BF02256113

    Article  CAS  PubMed  Google Scholar 

  34. Jang SI, Kim YJ, Kim HJ, Lee JC, Kim HY, Kim YC, Yun YG, Yu HH, You YO (2006) Scoparone inhibits PMA-induced IL-8 and MCP-1 production through suppression of NF-kappaB activation in U937 cells. Life Sci 78(25):2937–2943. https://doi.org/10.1016/j.lfs.2005.11.020

    Article  CAS  PubMed  Google Scholar 

  35. Lu C, Li Y, Hu S, Cai Y, Yang Z, Peng K (2018) Scoparone prevents IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through the PI3K/Akt/NF-κB pathway. Biomed Pharmacother 106:1169–1174. https://doi.org/10.1016/j.biopha.2018.07.062

    Article  CAS  PubMed  Google Scholar 

  36. Nayeli MB, Maribel HR, Enrique JF, Rafael BP, Margarita AF, Macrina FM, Ivan MD, Manasés GC (2020) Anti-inflammatory activity of coumarins isolated from Tagetes lucida Cav. Nat Prod Res 34(22):3244–3248. https://doi.org/10.1080/14786419.2018.1553172

    Article  CAS  PubMed  Google Scholar 

  37. Huang JC, Wang XR, Sun AX, Wang RX (1993) Effects of scoparone on hemodynamics in anesthetized rabbits. Zhongguo Yao Li Xue Bao 14:S18–21

    CAS  PubMed  Google Scholar 

  38. Niu N, Li B, Hu Y, Li X, Li J, Zhang H (2014) Protective effects of scoparone against lipopolysaccharide-induced acute lung injury. Int Immunopharmacol 23(1):127–133. https://doi.org/10.1016/j.intimp.2014.08.014

    Article  CAS  PubMed  Google Scholar 

  39. Phytomedicine: International Journal of Phytotherapy & Phytopharmacology 21:240–247. 10.1016/j.phymed.2013.09.001

  40. Cho D-Y, Ko HM, Kim J, Kim B-W, Yun Y-S, Park J-I, Ganesan P, Lee J-T, Choi D-K (2016) Scoparone inhibits LPS-Simulated inflammatory response by suppressing IRF3 and ERK in BV-2 microglial cells. Molecules 21(12):1718. https://doi.org/10.3390/molecules21121718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yuan JW, Yang LR, Yin QY, Mao P, Qu LB (2016) KMnO4/AcOH-mediated C3-selective direct arylation of coumarins with arylboronic acids. RSC Adv 6(42):35936–35944. https://doi.org/10.1039/C6RA04787D

    Article  CAS  Google Scholar 

  42. Chibber P, Haq SA, Kumar A, Kumar C, Gupta D, Wazir P, Singh S, Abdullah ST, Singh G (2021) Antiarthritic activity of OA-DHZ; a gastroprotective NF-κB/MAPK/ COX inhibitor. Cytokine 148:155688. https://doi.org/10.1016/j.cyto.2021.155688

    Article  CAS  PubMed  Google Scholar 

  43. Chibber P, Kumar C, Singh A, Haq SA, Ahmed I, Kumar A, Singh S, Vishwakarma R, Singh G (2020) Anti-inflammatory and analgesic potential of OA-DHZ; a novel semisynthetic derivative of dehydrozingerone. Int Immunopharmacol 83:106469. https://doi.org/10.1016/j.intimp.2020.106469

    Article  CAS  PubMed  Google Scholar 

  44. Morris CJ (2003) Carrageenan-induced paw edema in the rat and mouse. Methods Mol Biol 225:115–121. https://doi.org/10.1385/1-59259-374-7:115

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

C. K. thanks the Council of Scientific and Industrial Research for a senior research fellowship (CSIR-SRF). We also acknowledge the Director CSIR-IIIM Jammu for laboratory facilities and Dr. Sumit Gairola for plant material. IIIM Publication Number: CSIR-IIM/IPR/00596.

Author information

Authors and Affiliations

  1. Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India

    Chetan Kumar, Ritu Painuli, Ram A. Vishwakarma, Naresh K. Satti & Ravindra S. Phatake

  2. Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India

    Pankaj Chibber, Syed Assim Haq & Gurdarshan Singh

  3. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Chetan Kumar, Pankaj Chibber, Syed Assim Haq, Ram A. Vishwakarma & Ravindra S. Phatake

Authors
  1. Chetan Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pankaj Chibber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ritu Painuli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Syed Assim Haq
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ram A. Vishwakarma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gurdarshan Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naresh K. Satti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ravindra S. Phatake
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the write and reviewed the manuscript.

Corresponding authors

Correspondence to Chetan Kumar or Ravindra S. Phatake.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, C., Chibber, P., Painuli, R. et al. Scoparone chemical modification into semi-synthetic analogues featuring 3-substitution for their anti-inflammatory activity. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10687-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11030-023-10687-7

Keywords

Search

Navigation