Mini-Review on Coumarins: Sources, Biosynthesis, Bioactivity, Extraction and Toxicology

Abstract

Coumarins are a class of naturally occurring compounds found in various plants, fungi, and microorganisms, each with a unique chemical profile. These compounds exhibit a broad range of bioactivities, including antithrombotic, anti-inflammatory, antioxidant, antimicrobial, antiviral, anticancer, and neuroprotective properties. The effective extraction of coumarins, facilitated by methods such as maceration and microwave-assisted extraction, is integral to unlocking their potential across various applications. Nevertheless, safety and toxicology considerations assume paramount importance, particularly in pharmaceuticals, cosmetics, and food additives. While moderate dietary consumption of coumarin-rich foods is generally safe, excessive intake, whether through foods or supplements, raises concerns linked to hepatotoxicity and photosensitivity. Notably, specific coumarin derivatives, including the widely used anticoagulant warfarin, necessitate precise dosing and vigilant monitoring to mitigate the risk of bleeding complications. In conclusion, the versatile biological activities of coumarins underscore their significance; yet, their safety and toxicity profiles are contingent on multiple factors, encompassing compound type, dosage, and individual susceptibility. This review provides a holistic understanding of coumarins, encompassing their natural origins, biosynthesis, bioactivity spectrum, extraction techniques, and insights into safety, and toxicology.

Keywords

• Coumarins
• Natural Sources
• Biosynthetic Pathway
• Extraction
• Toxicology

References

1. 1. Sharifi-Rad J, Cruz-Martins N, López-Jornet P, Lopez EPF, Harun N, Yeskaliyeva B, et al. Natural Coumarins: Exploring the Pharmacological Complexity and Underlying Molecular Mechanisms. Gil G, editor. Oxid Med Cell Longev [Internet]. 2021 Aug 23;2021:6492346. Available from: .
2. 2. Annunziata F, Pinna C, Dallavalle S, Tamborini L, Pinto A. An Overview of Coumarin as a Versatile and Readily Accessible Scaffold with Broad-Ranging Biological Activities. Int J Mol Sci [Internet]. 2020 Jun 29;21(13):4618. Available from: .
3. 3. Sharma M, Vyas VK, Bhatt S, Ghate MD. Therapeutic potential of 4-substituted coumarins: A conspectus. Eur J Med Chem Reports [Internet]. 2022 Dec 1;6:100086. Available from: .
4. 4. Hussain MI, Syed QA, Khattak MNK, Hafez B, Reigosa MJ, El-Keblawy A. Natural product coumarins: biological and pharmacological perspectives. Biologia (Bratisl) [Internet]. 2019 Jul 15;74(7):863–88. Available from: .
5. 5. Lončar M, Jakovljević M, Šubarić D, Pavlić M, Buzjak Služek V, Cindrić I, et al. Coumarins in Food and Methods of Their Determination. Foods [Internet]. 2020 May 18;9(5):645. Available from: .
6. 6. Matos MJ, Santana L, Uriarte E, Abreu OA, Molina E, Yordi EG. Coumarins — An Important Class of Phytochemicals. In: Phytochemicals - Isolation, Characterisation and Role in Human Health [Internet]. InTech; 2015. Available from: .
7. 7. Tsivileva OM, Koftin O V., Evseeva N V. Coumarins as Fungal Metabolites with Potential Medicinal Properties. Antibiotics [Internet]. 2022 Aug 26;11(9):1156. Available from: .
8. 8. Xia T, Liu Y, Lu Z, Yu H. Natural Coumarin Shows Toxicity to Spodoptera litura by Inhibiting Detoxification Enzymes and Glycometabolism. Int J Mol Sci [Internet]. 2023 Aug 24;24(17):13177. Available from: .

9. 9. Lu PH, Liao TH, Chen YH, Hsu YL, Kuo CY, Chan CC, et al. Coumarin Derivatives Inhibit ADP-Induced Platelet Activation and Aggregation. Molecules [Internet]. 2022 Jun 23;27(13):4054. Available from: .
10. 10. Ghosh R, Singha PS, Das LK, Ghosh D, Firdaus SB. Anti-inflammatory activity of natural coumarin compounds from plants of the Indo-Gangetic plain. AIMS Mol Sci [Internet]. 2023;10(2):79–98. Available from: .
11. 11. Coumarin. IARC monographs on the evaluation of carcinogenic risks to humans. 2000;77:193–225. Available from: .
12. 12. Boo YC. p-Coumaric Acid as An Active Ingredient in Cosmetics: A Review Focusing on its Antimelanogenic Effects. Antioxidants [Internet]. 2019 Aug 4;8(8):275. Available from: .
13. 13. Eggleston W. Coumarins. In: Encyclopedia of Toxicology [Internet]. Elsevier; 2024 [cited 2024 May 6]. p. 293–7. Available from: .
14. 14. Wang J, Huang S, Li C, Ding W, She Z, Li C. A New Coumarin Produced by Mixed Fermentation of Two Marine Fungi. Chem Nat Compd [Internet]. 2015 Mar 27;51(2):239–41. Available from: .
15. 15. Umashankar T, Govindappa M, Ramachandra YL, Chandrappa CP, Padmalatha RS, Channabasava R. Isolation, purification and in vitro cytotoxic activities of coumarin isolated from endophytic fungi, Alternaria species of Crotalaria pallida. Indo Am J Pharm Res [Internet]. 2015;5(2):926–36. Available from: .
16. 16. Li TX, Meng DD, Wang Y, An JL, Bai JF, Jia XW, et al. Antioxidant coumarin and pyrone derivatives from the insect-associated fungus Aspergillus Versicolor. Nat Prod Res [Internet]. 2020 May 18;34(10):1360–5. Available from: .
17. 17. Yan ZY, Lv TM, Wang YX, Shi SC, Chen JJ, Bin-Lin, et al. Terpenylated coumarins from the root bark of Ailanthus altissima (Mill.) Swingle. Phytochemistry [Internet]. 2020 Jul 1;175:112361. Available from: .
18. 18. Bai Y, Li D, Zhou T, Qin N, Li Z, Yu Z, et al. Coumarins from the roots of Angelica dahurica with antioxidant and antiproliferative activities. J Funct Foods [Internet]. 2016 Jan 1;20:453–62. Available from: .
19. 19. Wang S, Tang F, Yue Y, Yao X, Wei Q, Yu J. Simultaneous Determination of 12 Coumarins in Bamboo Leaves by HPLC. J AOAC Int [Internet]. 2013 Sep 1;96(5):942–6. Available from: .
20. 20. Joshi KR, Devkota HP, Yahara S. Chemical Analysis of Flowers of Bombax ceiba from Nepal. Nat Prod Commun [Internet]. 2013 May 1;8(5):583–4. Available from: .
21. 21. Rodríguez-Hernández KD, Martínez I, Agredano-Moreno LT, Jiménez-García LF, Reyes-Chilpa R, Espinoza B. Coumarins isolated from Calophyllum brasiliense produce ultrastructural alterations and affect in vitro infectivity of Trypanosoma cruzi. Phytomedicine [Internet]. 2019 Aug 1;61:152827. Available from: .
22. 22. Li Z lin, Li Y, Qin N bo, Li D hong, Liu Z guo, Liu Q, et al. Four new coumarins from the leaves of Calophyllum inophyllum. Phytochem Lett [Internet]. 2016 Jun 1;16:203–6. Available from: .
23. 23. Ramírez-Pelayo C, Martínez-Quiñones J, Gil J, Durango D. Coumarins from the peel of citrus grown in Colombia: composition, elicitation and antifungal activity. Heliyon [Internet]. 2019 Jun 1;5(6):e01937. Available from: .
24. 24. Dugrand A, Olry A, Duval T, Hehn A, Froelicher Y, Bourgaud F. Coumarin and Furanocoumarin Quantitation in Citrus Peel via Ultraperformance Liquid Chromatography Coupled with Mass Spectrometry (UPLC-MS). J Agric Food Chem [Internet]. 2013 Nov 13;61(45):10677–84. Available from: .
25. 25. Tian D, Wang F, Duan M, Cao L, Zhang Y, Yao X, et al. Coumarin Analogues from the Citrus grandis (L.) Osbeck and Their Hepatoprotective Activity. J Agric Food Chem [Internet]. 2019 Feb 20;67(7):1937–47. Available from: .
26. 26. Peng WW, Zheng YQ, Chen YS, Zhao SM, Ji CJ, Tan NH. Coumarins from roots of Clausena excavata. J Asian Nat Prod Res [Internet]. 2013 Mar 1;15(3):215–20. Available from: .
27. 27. Moustafa ES, Swilam NF, Ghanem OB, Hashim AN, Nawwar MA, Lindequist U, et al. A coumarin with an unusual structure from Cuphea ignea, its cytotoxicity and antioxidant activities. Pharmazie [Internet]. 2018;73(4):241–3. Available from: .
28. 28. Li G, Li X, Cao L, Zhang L, Shen L, Zhu J, et al. Sesquiterpene coumarins from seeds of Ferula sinkiangensis. Fitoterapia [Internet]. 2015 Jun 1;103:222–6. Available from: .
29. 29. Naseri M, Monsef-Esfehani HR, Saeidnia S, Dastan D, Gohari AR. Antioxidative Coumarins from the Roots of Ferulago subvelutina. Asian J Chem [Internet]. 2013;25(4):1875–8. Available from: .
30. 30. Petruľová-Poracká V, Repčák M, Vilková M, Imrich J. Coumarins of Matricaria chamomilla L.: Aglycones and glycosides. Food Chem [Internet]. 2013 Nov 1;141(1):54–9. Available from: .
31. 31. Martino E, Ramaiola I, Urbano M, Bracco F, Collina S. Microwave-assisted extraction of coumarin and related compounds from Melilotus officinalis (L.) Pallas as an alternative to Soxhlet and ultrasound-assisted extraction. J Chromatogr A [Internet]. 2006 Sep 1;1125(2):147–51. Available from: .
32. 32. Maggi F, Barboni L, Caprioli G, Papa F, Ricciutelli M, Sagratini G, et al. HPLC quantification of coumarin in bastard balm (Melittis melissophyllum L., Lamiaceae). Fitoterapia [Internet]. 2011 Dec 1;82(8):1215–21. Available from: .
33. 33. Liang H, Cao N, Zeng K, Zhao M, Tu P, Jiang Y. Coumarin and spirocyclopentenone derivatives from the leaves and stems of Murraya paniculata (L.) Jack. Phytochemistry [Internet]. 2020 Apr 1;172:112258. Available from: .
34. 34. Zhang JX, Lv JH, Zhao LQ, Shui XX, Zhang J, Wang LA. Coumarin-pi, a new antioxidant coumarin derivative from Paxillus involutus. Nat Prod Res [Internet]. 2020 May 2;34(9):1246–9. Available from: .
35. 35. Kicel A, Wolbis M. Coumarins from the flowers of Trifolium repens. Chem Nat Compd [Internet]. 2012 Mar 22;48(1):130–2. Available from: .
36. 36. Nguyen PH, Zhao BT, Kim O, Lee JH, Choi JS, Min BS, et al. Anti-inflammatory terpenylated coumarins from the leaves of Zanthoxylum schinifolium with α-glucosidase inhibitory activity. J Nat Med [Internet]. 2016 Apr 11;70(2):276–81. Available from: .
37. 37. Malla S, Koffas MAG, Kazlauskas RJ, Kim BG. Production of 7- O -Methyl Aromadendrin, a Medicinally Valuable Flavonoid, in Escherichia coli. Appl Environ Microbiol [Internet]. 2012 Feb;78(3):684–94. Available from: .
38. 38. Yang SM, Shim GY, Kim BG, Ahn JH. Biological synthesis of coumarins in Escherichia coli. Microb Cell Fact [Internet]. 2015 Dec 1;14(1):65. Available from: .
39. 39. Watts KT, Lee PC, Schmidt-Dannert C. Biosynthesis of plant-specific stilbene polyketides in metabolically engineered Escherichia coli. BMC Biotechnol [Internet]. 2006 Dec 21;6(1):22. Available from: .
40. 40. Miyahisa I, Funa N, Ohnishi Y, Martens S, Moriguchi T, Horinouchi S. Combinatorial biosynthesis of flavones and flavonols in Escherichia coli. Appl Microbiol Biotechnol [Internet]. 2006 Jun 1;71(1):53–8. Available from: .
41. 41. Comino C, Hehn A, Moglia A, Menin B, Bourgaud F, Lanteri S, et al. The isolation and mapping of a novel hydroxycinnamoyltransferase in the globe artichoke chlorogenic acid pathway. BMC Plant Biol [Internet]. 2009 Dec 18 [cited 2024 May 6];9(1):30. Available from: .
42. 42. Jiang NH, Zhang GH, Zhang JJ, Shu LP, Zhang W, Long GQ, et al. Analysis of the Transcriptome of Erigeron breviscapus Uncovers Putative Scutellarin and Chlorogenic Acids Biosynthetic Genes and Genetic Markers. Chen S, editor. PLoS One [Internet]. 2014 Jun 23;9(6):e100357. Available from: .
43. 43. Cheevarungnapakul K, Khaksar G, Panpetch P, Boonjing P, Sirikantaramas S. Identification and Functional Characterization of Genes Involved in the Biosynthesis of Caffeoylquinic Acids in Sunflower (Helianthus annuus L.). Front Plant Sci [Internet]. 2019 Jul 31;10:457795. Available from: .
44. 44. Mahesh V, Million-Rousseau R, Ullmann P, Chabrillange N, Bustamante J, Mondolot L, et al. Functional characterization of two p-coumaroyl ester 3′-hydroxylase genes from coffee tree: evidence of a candidate for chlorogenic acid biosynthesis. Plant Mol Biol [Internet]. 2007 May 27;64(1–2):145–59. Available from: .
45. 45. Riedelsheimer C, Lisec J, Czedik-Eysenberg A, Sulpice R, Flis A, Grieder C, et al. Genome-wide association mapping of leaf metabolic profiles for dissecting complex traits in maize. Proc Natl Acad Sci [Internet]. 2012 Jun 5;109(23):8872–7. Available from: .
46. 46. Shimizu BI. 2-Oxoglutarate-dependent dioxygenases in the biosynthesis of simple coumarins. Front Plant Sci [Internet]. 2014 Nov 3;5:549. Available from: .
47. 47. Wagner A, Tobimatsu Y, Phillips L, Flint H, Torr K, Donaldson L, et al. CCoAOMT suppression modifies lignin composition in Pinus radiata. Plant J [Internet]. 2011 Jul 26;67(1):119–29. Available from: .
48. 48. Bourgaud F, Hehn A, Larbat R, Doerper S, Gontier E, Kellner S, et al. Biosynthesis of coumarins in plants: a major pathway still to be unravelled for cytochrome P450 enzymes. Phytochem Rev [Internet]. 2006 Nov 29;5(2–3):293–308. Available from: .
49. 49. Zou Y, Teng Y, Li J, Yan Y. Recent advances in the biosynthesis of coumarin and its derivatives. Green Chem Eng [Internet]. 2024 Jun 1;5(2):150–4. Available from: .
50. 50. Leonard E, Lim KH, Saw PN, Koffas MAG. Engineering Central Metabolic Pathways for High-Level Flavonoid Production in Escherichia coli. Appl Environ Microbiol [Internet]. 2007 Jun 15;73(12):3877–86. Available from: .
51. 51. Tsivileva OM, Koftin O V. Fungal coumarins: biotechnological and pharmaceutical aspects. In: Studies in Natural Products Chemistry [Internet]. Elsevier; 2023. p. 441–79. Available from: .
52. 52. Gao L, Wang F, Chen Y, Li F, Han B, Liu D. The antithrombotic activity of natural and synthetic coumarins. Fitoterapia [Internet]. 2021 Oct 1;154:104947. Available from: .
53. 53. Mur J, McCartney DL, Chasman DI, Visscher PM, Muniz-Terrera G, Cox SR, et al. Variation in VKORC1 Is Associated with Vascular Dementia. Ikram MA, editor. J Alzheimer’s Dis [Internet]. 2021 Apr 6;80(3):1329–37. Available from: .
54. 54. Khan S, Shehzad O, Cheng MS, Li RJ, Kim YS. Pharmacological mechanism underlying anti-inflammatory properties of two structurally divergent coumarins through the inhibition of pro-inflammatory enzymes and cytokines. J Inflamm [Internet]. 2015 Dec 29;12(1):47. Available from: .
55. 55. Santibáñez A, Herrera-Ruiz M, González-Cortazar M, Nicasio-Torres P, Sharma A, Jiménez-Ferrer E. Dose-Effect Determination of a Neuroprotector Fraction Standardized in Coumarins of Tagetes lucida and Bioavailability. Pharmaceutics [Internet]. 2023 Mar 17;15(3):967. Available from: .
56. 56. Todorov L, Saso L, Kostova I. Antioxidant Activity of Coumarins and Their Metal Complexes. Pharmaceuticals [Internet]. 2023 Apr 26;16(5):651. Available from: .
57. 57. Kadhum AAH, Al-Amiery AA, Musa AY, Mohamad AB. The Antioxidant Activity of New Coumarin Derivatives. Int J Mol Sci [Internet]. 2011 Sep 7;12(9):5747–61. Available from: .
58. 58. Basile A, Sorbo S, Spadaro V, Bruno M, Maggio A, Faraone N, et al. Antimicrobial and Antioxidant Activities of Coumarins from the Roots of Ferulago campestris (Apiaceae). Molecules [Internet]. 2009 Feb 27;14(3):939–52. Available from: .
59. 59. Lemos ASO, Florêncio JR, Pinto NCC, Campos LM, Silva TP, Grazul RM, et al. Antifungal Activity of the Natural Coumarin Scopoletin Against Planktonic Cells and Biofilms From a Multidrug-Resistant Candida tropicalis Strain. Front Microbiol [Internet]. 2020 Jul 7;11:1525. Available from: .
60. 60. Liu GL, Liu L, Hu Y, Wang GX. Evaluation of the antiparasitic activity of coumarin derivatives against Dactylogyrus intermedius in goldfish (Carassius auratus). Aquaculture [Internet]. 2021 Feb 25;533:736069. Available from: .
61. 61. Mishra S, Pandey A, Manvati S. Coumarin: An emerging antiviral agent. Heliyon [Internet]. 2020 Jan 1;6(1):e03217. Available from: .
62. 62. Wu Y, Xu J, Liu Y, Zeng Y, Wu G. A Review on Anti-Tumor Mechanisms of Coumarins. Front Oncol [Internet]. 2020 Dec 4;10:592853. Available from: .
63. 63. Hassanein EHM, Sayed AM, Hussein OE, Mahmoud AM. Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway. Oxid Med Cell Longev [Internet]. 2020 Apr 25;2020:1675957. Available from: .
64. 64. Jameel E, Umar T, Kumar J, Hoda N. Coumarin: A Privileged Scaffold for the Design and Development of Antineurodegenerative Agents. Chem Biol Drug Des [Internet]. 2016 Jan 16;87(1):21–38. Available from: .
65. 65. Li H, Yao Y, Li L. Coumarins as potential antidiabetic agents. J Pharm Pharmacol [Internet]. 2017 Sep 5;69(10):1253–64. Available from: .
66. 66. Najmanova I, Dosedel M, Hrdina R, Anzenbacher P, Filipsky T, Riha M, et al. Cardiovascular Effects of Coumarins Besides their Antioxidant Activity. Curr Top Med Chem [Internet]. 2015;15(9):830–49. Available from: .
67. 67. Chua LS, Latiff NA, Mohamad M. Reflux extraction and cleanup process by column chromatography for high yield of andrographolide enriched extract. J Appl Res Med Aromat Plants [Internet]. 2016 May 1;3(2):64–70. Available from: .
68. 68. Abubakar A, Haque M. Preparation of medicinal plants: Basic extraction and fractionation procedures for experimental purposes. J Pharm Bioallied Sci [Internet]. 2020 Jan 1;12(1):1–10. Available from: .
69. 69. Fotsing Yannick Stéphane F, Kezetas Jean Jules B, El-Saber Batiha G, Ali I, Ndjakou Bruno L. Extraction of Bioactive Compounds from Medicinal Plants and Herbs. In: El-Shemy HA, editor. Natural Medicinal Plants [Internet]. IntechOpen; 2022. Available from: .
70. 70. Pandey A, Tripathi S. Concept of standardization, extraction and pre phytochemical screening strategies for herbal drug. J Pharmacogn Phytochem [Internet]. 2014;2(5):115–9. Available from: .
71. 71. Mukherjee PK. Extraction and Other Downstream Procedures for Evaluation of Herbal Drugs. In: Quality Control and Evaluation of Herbal Drugs [Internet]. Elsevier; 2019. p. 195–236. Available from: .
72. 72. Altemimi A, Lakhssassi N, Baharlouei A, Watson D, Lightfoot D. Phytochemicals: Extraction, Isolation, and Identification of Bioactive Compounds from Plant Extracts. Plants [Internet]. 2017 Sep 22;6(4):42. Available from: .
73. 73. Manjare SD, Dhingra K. Supercritical fluids in separation and purification: A review. Mater Sci Energy Technol [Internet]. 2019 Dec 1;2(3):463–84. Available from: .
74. 74. Rodríguez-Chanfrau JE, Robaina-Mesa M, Rodríguez-Riera Z, Jauregui-Haza U. Ultrasound-assisted extraction of coumarin from Justicia pectoralis Jacq. Rev Mex Ciencias Farm [Internet]. 2016;47(1):97–104. Available from: .
75. 75. Molnar M, Mendešević N, Šubarić D, Banjari I, Jokić S. Comparison of various techniques for the extraction of umbelliferone and herniarin in Matricaria chamomilla processing fractions. Chem Cent J [Internet]. 2017 Dec 5;11(1):78. Available from: .
76. 76. Yamada T, Katsutani N, Maruyama T, Kawamura T, Yamazaki H, Murayama N, et al. Combined Risk Assessment of Food-derived Coumarin with in Silico Approaches. Food Saf [Internet]. 2022;10(3):73–82. Available from: .
77. 77. Pitaro M, Croce N, Gallo V, Arienzo A, Salvatore G, Antonini G. Coumarin-Induced Hepatotoxicity: A Narrative Review. Molecules [Internet]. 2022 Dec 19;27(24):9063. Available from: .
78. 78. Bruni R, Barreca D, Protti M, Brighenti V, Righetti L, Anceschi L, et al. Botanical Sources, Chemistry, Analysis, and Biological Activity of Furanocoumarins of Pharmaceutical Interest. Molecules [Internet]. 2019 Jun 8;24(11):2163. Available from: .
79. 79. Ellis CR, Elston DM. Psoralen-Induced Phytophotodermatitis. Dermatitis [Internet]. 2021 May 1;32(3):140–3. Available from: .
80. 80. Verhoef TI, Redekop WK, Daly AK, van Schie RMF, de Boer A, Maitland‐van der Zee A. Pharmacogenetic‐guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. Br J Clin Pharmacol [Internet]. 2014 Apr 20;77(4):626–41. Available from: .