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Dr. Pran Kishore Deb
Dr. Balakumar ChandrasekaranAssistant Professor
Pharmaceutical Medicinal Chemistry
Faculty of Pharmacy, Philadelphia University-Jordan
Email: [email protected]
Learning Outcomes
At the end of this lesson students will be able to
❑Define coumarins
❑Outline the botanical and family name, uses, side effects,
mechanism action of following coumarins and their glycosides:
❖Scopoletin
❖Psoralens
❖Khellin
❖Bergapten (5-methoxypsoralen)
❖Aesculin
❖ Picrotoxin
❑Explain the biosynthesis of coumarins
COUMARINS (Bitter principles)
➢Coumarin is a fragrant organic chemical compound in the
benzopyrone chemical class, which is a colourless crystalline substance
in its standard state. It is a natural substance found in many plants.
➢The name comes from a French term for the tonka bean, coumarou, one
of the sources from which coumarin was first isolated as a natural
product in 1820.
➢It has a sweet odour, readily recognised as the scent of new-mown hay,
and has been used in perfumes since 1882. Sweet woodruff,
Meadowsweet, sweet grass and sweet-clover in particular are named for
their sweet (i.e., pleasant) smell, which in turn is due to their high
coumarin content.
➢When it occurs in high concentrations in forage plants, coumarin is a
somewhat bitter-tasting appetite suppressant, and is presumed to be
produced by plants as a defence chemical to discourage predation.
➢Some coumarins are phytoalexins and are synthesized de novo by
the plant following infection by a bacterium or fungus.
➢Phytoalexins: any of a group of compounds formed in plants in
response to fungal infection, physical damage, chemical injury, or a
pathogenic process. Phytoalexins inhibit or destroy the invading
agent.
➢Coumarin is used in certain perfumes and fabric conditioners.
➢Coumarin has been used as an aroma enhancer in pipe tobaccos and
certain alcoholic drinks.
➢It is banned as a flavorant food additive, due to concerns regarding its
hepatotoxicity in animal models.
➢Coumarin was first synthesized in 1868. It is used in the
pharmaceutical industry as a precursor reagent in the synthesis of a
number of synthetic pharmaceutical agents or drugs such as
anticoagulants (similar to dicoumarol), warfarin (brand name
Coumadin) and potent rodenticides.
➢Although coumarin is widely
distributed in plants, glycosides
containing coumarin as such are
rare.
➢Several glycosides of hydroxylated
coumarin derivatives, however,
occur in plant materials, and none
of the hydroxylated coumarin
glycosides is of particular
medicinal importance.
➢Examples of these coumarin
glycosides: skimmin in Japanese
star-anise and aesculin (saponin)
in horse chestnut tree.
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Japanese star-anise
Scopoletin
• It is a phytoalexin found in the Quassia wood (Quassia is a
collective term for 2 plants: Picrasma excelsa and Quassiaamara L. Family: Simaroubaceae), stem wood of Picrasma excelsa(Picconia excelsa or Aeshrion excelsa) (Simaroubaceae).
Uses:
• It is used as antispasmodic for its uterine sedative activity.
• It also has antimicrobial activity.
Psoralens
• These are photosensitizing furocoumarins that occur in a number ofplant families like Umbelliferae (Apiaceae), where they are a commoncause of phototoxicity.
➢Methoxsalen: 8-methoxy psoralen (oxsoralen ®) or xanthotoxin, a constituent of cremocarps (a description of the fruit of fennel etc.) of Ammi majus Linne (Family: Umbelliferae). It is used to
➢facilitate repigmentation in idiopathic vitiligo (leukoderma) and
➢for symptomatic control of severe disabling psoriasis.
➢Methoxsalen may be applied topically or taken internally, and withexposure to U.V. light.
➢Risks are inherent in therapy with methoxsalen including carcinogenesis.
7Psoralens Methoxsalen
Idiopathic vitiligo (leukoderma) Psoriasis
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Cremocarp
Biosynthesis of coumarins
Khellin
➢ It is a furanochromone, an organic compound which is a derivative
of chromone (1,4-benzopyrone) and furan.
➢ It has lipophilic properties and causes vasodilation (widening ofblood vessels).
➢ It is found in the plant Ammi visnaga (Family: Apiaceae) which hasbeen used in Egyptian folk medicine.
➢ It has activity as a spasmolytic and vasodilator.
11
O
O
CH3
OCH3
OCH3
O
Khellin
➢ In Egypt, the plant "Khella" was used for renal colic. The incidence
of renal colic was mostly to due schistosomiasis (bilharzia, snail
fever) infections and stone formation.
➢ The plant mixture had diuretic properties that were seen to relieve
renal colic in Egyptian folk medicine.
➢ After the chemical compound khellin was identified, people began
to study its properties. It was found to relax the
ureter and coronary arteries.
➢ It is not used as a systemic medication because:
1. It is difficult to absorb.
2. It causes a range of undesirable side effects such as dizziness,
headache, gastrointestinal disorders and nausea.
➢ However, it has been used successfully to treat vitiligo by topical
application. 12
➢ In the early 20th century, researchers searched for khellin analogs
with lower toxicity and better efficacy.
➢ A number of drugs were discovered through this research
and amiodarone and cromolyn sodium are khellin analogs used in
current medical practice.
13
Amiodarone
Cromolyn sodium
Bergapten (5-methoxypsoralen)
➢ Is a furocoumarin found in:
➢ Bergamot essential oil (Citrus bergamia, the bergamot orange is a
fragrant fruit having the size of an orange, with a yellow color similar
to a lemon)
➢ Other citrus essential oils.
➢ In grapefruit juice.
➢ These compounds may be produced by the plant as a protection
mechanism against high doses of sunlight and some coumarins are
formulated into sunscreens and cosmetics for this purpose.
➢ Bergapten-free bergamot essential oil or synthetics are now used in
perfumery.
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Aesculin
❖ Aesculin is a coumarin glucoside that naturally occurs in the horse chestnut,
(Aesculus hippocastanum and family Hippocastanaceae).
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• Medicinal Uses: As medication, aesculin is sometimes used as a
vasoprotective agent.
• Laboratory use: Aesculin is also used in a microbiology laboratory to aid
in the identification of bacterial species.
• Aesculin is incorporated into agar with ferric citrate and bile salts (bile
aesculin agar). Hydrolysis of the aesculin forms aesculetin (6,7-
dihydroxycoumarin) and glucose. The aesculetin forms dark brown or
black complexes with ferric citrate, allowing the test to be read.
• Aesculin will fluoresce under long wave ultraviolet light (360 nm):
hydrolysis of aesculin results in loss of this fluorescence.
• A positive test can occur with Enterococcus, Aerococcus and Leuconostoc.
Aesculin Aesculetin
Picrotoxin (also known as cocculin)
➢ Is a poisonous crystalline plant compound, first isolated by PierreBoullay in 1812.
➢ The name "picrotoxin" is a combination of the Greek words"picros" (bitter) and "toxicon" (poison).
➢ Found primarily in the fruit of the climbing plant Anamirtacocculus.
➢ It has a strong physiological action.
➢ It acts as a noncompetitive antagonist for the GABAA receptorchloride channels.
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➢ It is therefore a channel blocker rather than a receptor antagonist.
➢ As GABA itself is an inhibitory neurotransmitter, infusion of
picrotoxin has stimulant and convulsant effects.
➢ As such, picrotoxin can be used to counter barbiturate poisoning
that can occur during general anesthesia or during a large intake
outside of the hospital.
18PicrotinPicrotoxin
Textbooks:
1. Fundamentals of Pharmacognosy and Phytotherapy; by Michael
Heinrich, Joanne Barnes, Simon Gibbons and Elizabeth M Williamson
(2012), Elsevier Ltd ISBN: 978-0-7020-3388-9.
2. Fundementals of Pharmacognosy and Phytotherapy. A Guide for
Health Care Professionals by Carol A. Newal, Linda A. Anderson and
J. David Phillipson. (2010). the Pharmaceutical Press, London, UK;
ISBN: 0 85369-474-5.
Supplementary books:
1. Herbal therapy for human diseases: Irfan Ali Khan and Atiya
Khanum (2007), Ukaaz publications ISBN: 81-88279-43-9.
2. Comprehensive pharmacy review; Leon Shargel Alan H. Mutnick et al;
4th Edition ISBN:0-7817-2147-4.
REFERENCES
