Plan

1. Coumarins and chromones. Chemical structure.

Classification.
2. Physical and chemical properties.
3. Pathways of medicinal uses, pharmacological activity.
4. Medicinal plant materials, containing coumarins and
chromones
 COUMARINS AND CHROMONES
Coumarins are lactones derived from o-hydroxycinnamic acids, and chromones
are isomeric with coumarins. The name coumarin originates from a Caribbean name coumarou
for the tonka tree.
More than 700 different plant coumarins have been isolated, and coumarin
itself is widely distributed and has the characteristic odor of new mown hay.
Coumarins are lactones, derived from p-hydroxycinnamic acids which undergo
ortho hydroxylation, then ring closure between the ortho hydroxyl group and the
carboxylic group of the side chain, after a trans to cis isomerization of the side-chain
double bond.

9,10-benzo-a-pirone (coumarin)
cis-o-hydroxycinnamic acid (o-coumaric acid)
 COUMARINS AND CHROMONES
The principal precursors for coumarins p-hydroxycinnamic acid,
also known as p-coumaric acid in plants, arise from the aromatic amino
acid tyrosine, which in turn is synthesized via the shikimic acid pathway.
The chromones represent a small group of plant phenolics that are
isomeric with coumarins; however, technically they are not
phenylpropanoids because their biosynthetic origin is probably from acetate
via the polyketide biosynthetic pathway. The best known chromone is the
furochromone khellin, which is a potent coronary vasodilalator.
• Coumarins are natural biological active substances at the
base of which there lies a system of benzo-α-pyrone
• Coumarins owe their class name to Coumarou: the
vernacular name of the tonka bean (Dipteryx odorata
Willd., Fabaceae), from which coumarin itself was isolated
in 1820.

9,10-benzo-α-pyrone
Coumarins
 DISTRIBUTION
most of the natural coumarins in existence have been isolated from the higher plants,
some members have been discovered in microorganisms. Some important coumarin
members have been isolated from microbial sources e.g. novobiocin and coumermycin
from Streptomyces, and aflatoxins from Aspergillus species
Typical families, which contain coumarins
✓ FABACEAE,
✓ ASTERACEAE,
ESPECIALLY
✓ APIACEAE
✓ RUTACEAE
 CLASSIFICATION OF COUMARINS
1. Simple coumarins and their glycosides. The group of simple coumarins
(e.g. coumarin. 7-hydroxycoumarin and 6,7-dihydroxycoumarin) are the
hydroxylated, alkoxylated and alkylated derivatives of the parent compound,
coumarin, along with and glycosides

Сoumarin dihydrocoumarin umbelliferone

aesculetine
fraxetine
Coumarins
 CLASSIFICATION OF COUMARINS

Hydroxy-, methoxy-, methylendihydroxycoumarins. Except for a few

rare cases, including coumarin, all coumarins have substitutes a
hydroxyl group in position 7. Umbelliferone, which is 7-hydroxy-
coumarin itself, is the precursor of the 6,7-di- and 6,7,8-
trihydroxylated coumarins.

umbelliferone
 CLASSIFICATION OF COUMARINS
2. Furanocoumarins consist of a five-membered furan ring attached
to the coumarin nucleus. They can be divided into linear (psoralen
derivatives) or angular (angelicin derivatives) types with substituents: at
one or both of the ring.

psolaren angelicin

Coumarins
 CLASSIFICATION OF COUMARINS
3.Pyranocoumarins are result of condensation of coumarin
with 2’2’-dimethylpyrane in positions 5,6
(dimethylxantyletin); 6,7 or 7,8 (visnadine) and may have
substitutes in any of rings.
Pyranocoumarin members are analogous to the furanocoumarins, but
contain a six-membered ring

2,2-dimethylxantyletin
visnadine
Coumarins
 CLASSIFICATION OF COUMARINS
4. Benzocoumarins containing benzyl ring condensed with
coumarin in 3,4 positions occur in plants of Anacardiaceae and
Rosaceae.
Hydroxyderivative of 3,4-benzocoumarin is a structural component
of ellagic acid.

3,4-benzocoumarin-
hydroxyl-derivative

Coumarins
 CLASSIFICATION OF COUMARINS
5 Furobenzocoumarins containing benzofuran ring
condensed with coumarin in 3,4 positions (coumestroles) are
extracted from Trifolium spp., Fabaceae.

coumestrol

6. Complex coumarins include more complex compounds

containing the system of coumarin.
Coumarins
 PHYSICAL AND CHEMICAL
PROPERTIES OF COUMARINS
Coumarin occurs as colorless, prismatic crystals and has a characteristic fragrant odor and
a bitter, aromatic, burning taste; it is soluble in alcohol. Furano- and pyranocoumarins are
soluble in apolar and medium polar solvents such as dichloromethane, petrol, and chloroform.
Coumarins sublimate under reduced pressure and are volatile
with water vapours. Coumarins reveal strong fluorescence in UV light, which
makes their identification easy.
Solubility of coumarins depends on phenolic hydroxyls and glycoside bond. Coumarins in
the free state are soluble in alcohols and in organic solvents such as ether and chlorinated
solvents, with which they can be extracted. Their glycosides are more or less soluble in water.
Aglycones are soluble in petrol, benzene, oil ether, chloroform, diethyl ether, alcohols (methanol,
ethanol), but they are not soluble or weakly soluble in water.

Coumarins
 EXTRACTION
Because coumarins have differentiated chemical structures and various
hydrophilic and hydrophobic properties in classical extraction methods
(Soxhlet extraction, maceration, percolation, ultrasonic-aided extraction)
many solvents with increasing polarity and elution strength are used. Oil
ether, petrol, diethyl ether, acetone, methanol, or their mixtures are mostly
applied. Chloroform was chosen as the most efficient solvent in the extraction
of coumarins from plant material.
For purification purposes, it is possible to take advantage of the
properties specific to the lactone: opening and solubilization in alkaline
conditions, closing in acidic medium.

Coumarins
 DETECTION
Coumarins being heated in alkaline medium form yellow water-soluble
salts (lactone reaction); after acidification of solution is formed coumarinic acid,
that after cyclization is converted into water insoluble coumarins.

NaOH O
O -H2O
HCl
O C ONa O O O
O C OH OH

Coumarins are slowly hydrolyzed under the action of dilute alkali to form a
yellow solution of coumaric (cis-o- hydroxy) cinnamic acid salts. Acidification of
alkaline solutions of cis-o-hydroxycyclic acid cyclizes to form coumarin (lactone
sample).
Coumarins
 DETECTION
Reaction with dinitroreagents (nitrified sulphanilic acid, n-nitroaniline or
sulphanilamide) in alkaline medium is based on the properties of coumarins to form
colored compounds with aromatic amino-derivatives; solution develops reddish-
brown colour.
It is also possible, in some cases, to use sublimation.
 CHROMATOGRAPHICAL ANALYSIS
chromatographic methods are used for identification of coumarins in
plant material.
Coumarins have a characteristic UV spectrum, which is heavily
influenced by the nature and the position of substituents, and by
alkalinization. When examined under UV light, TLC spots from coumarin-
containing drugs have colors, which are enhanced in the presence of
ammonia, and range from blue to yellow and purple. Umbelliferone
derivatives have intensive brightly blue fluorescence in UV in neutral
alcohol, alkaline and concentrated sulfuric acid media.
Often in TLC as a mobile phase is used hexane, ether or chloroform in
combination with more polar solvent that allow separating coumarins in the
mixture. Standard system for separation of aglycones is an organic phase of
mixture of toluol and ether (1:1), saturated with 10% solution of 10% acetic
acid, and for glycosides is used mixture of ethylacetate: acetic acid: water
(100:11:11:26)
Coumarins
 QUANTITATIVE DETERMINATION
UV light and highest absorption depends from its concentration.
For a quantitative estimation of coumarins within a drug, it is possible to use :
➢ H i g h p er f o r ma nce li q ui d chr o ma t o g ra phy.
✓ spectrofluorometric technique (after elution of the TLC spots), or, more simply,
HPLC.
✓ gravimetric method of total contents of coumarins;
✓ neutralization (adverse titration) to estimate total content or
individual substances;
✓ polarography;
✓ fluorometry;
✓ colorimetry,
✓ spectrophotometry after TLC separation or paper chromatography, where
optical density is measured

Coumarins
BIOLOGICAL ACTIVITY
Coumarins are characterized with photosensitizing (Psoraleae
fructus, Ammeos majoris fructus, Ficusi carici folium), spasmolytic
(Pastinacae fructus), P- vitaminic (Hippocastani semina) action.
As individual substance coumarins possess anticoagulant
(dicoumarol), antimicrobic (umbelliferone), estrogenic (coumestrols of
Trifolium spp, Fabaceae), antitumour (ostol) action.
Aesculin is said to be a venous tonic and a vascular protective agent.
Some furanocoumarins are photosensitizers, therefore they are indicated for
the therapy of psoriasis and vitiligo.
Visnadin, a pyranocoumarin isolated from khella, has been extracted
and marketed for its coronary vasodilator effect and promoted as having a
favorable action on senile cerebral insufficiency.
Coumarins
• Chromones are natural biological active substances whith the
general formula C6-C3, at the base of which there is the system
9,10-benzo-γ-pyrone.

9,10-benzo-y-pyrone(chromone)
Chromones -
 CLASSIFICATION OF CHROMONES
1. Simple chromones include hydroxy-,alkyl- and hydroxy- 9,10-benzo-y-
pyrone derivatives, and their glycosides substituted:
with radical linked to the γ -pyrone ring;
with radical linked to the benzene ring;
with radical linked to the benzene and γ -pyrone rings.

3-methylchromone 5,7-dihydroxychromone
Chromones -
 CLASSIFICATION OF CHROMONES
2 Benzochromones
3 . Furano– and dihydrofuranochromones, and their
glycosides (khellin, visnagine).

Khellin

4. Pyranochromones
5. Oxepynochromones
 PHYSICOCHEMICAL PROPERTIES
Physical and chemical Properties
1. Specific odor.
2. Form with alkali solution 0-hydroxy- -diketones without re generation of y-pyrone
ring (unlike coumarine).
3. Fluorescence in the UV light (blue, yellow, greenish yellow, yellowish brown or
brown).
4. Don't give Azocoupling test, 2% solution of aluminium chloride, with magnesium
and concentrated hydrochloric acid (unlike flavonoids).
5. Form colored compounds with concentrate acid (citric colour), and concentrated
alkali (purple colour).
In UV spectrum chromones fluorescense like coumarins, but they do not produce colored
compounds with dinitrosulphonilic acid. Coumarins do not develop characteristic color with 2%
methanolic solution of zirconium chloride, with aluminum chloride, magnesium and concentrated
hydrochloric acid in comparison.
Chromones form with alkali o-hydroxy-ß-diketons with irreversible opening of γ-pyrone
ring, but coumarins after acidification transfer into primary compounds.

Chromones -
 EXTRACTION
For extraction of chromones as extragents are mostly used chloroform,
acetone, methanol or ethanol.
Column chromatography and fractional crystallization from
various solvents are widely employed for purification of chromone yielding
extracts.
QUANTITATIVE DETERMINATION

Methods of quantitative determination of chromones are worked out

for each MPM individually. Optical methods, combined with
chromatographic separation, are used mostly.

Chromones -
 BIOLOGICAL ACTIVITY
Furochromones are spasmolytic and coronarolytic agents.

➢ 5-acetonyl-7-hydroxy-2-methylchromones are antibacterial, amides

of 2-chromonecarbonilic acid – anticoagulant, tetrazole-derivatives
act as antiallergics and analgetics, pyranochromone-
derivatives are bacteriostatics.
➢ Khellin, a furochromone found in the fruit of Ammi visnaga, has
been used for urethral spasm and renal colic and is a potent
coronary vasodilator and bronchodilator in the treatment of
coronary insufficiency, angina pectoris, and bronchial asthma.
It is an antiasthmatic and antiallergic agent that acts locally on
the lung to which it is applied by inhalation, and possessing
antispasmodic, anticoagulant, coronary vasodilatory and other effects.
Chromones -
PHARMACOLOGICAL ACTION

1. Spasmolytic
2.Antibacterial
3.Anticoagulant
4.Analgetic,
5.Antiallergic
 Medicinal plant materials,
containing coumarins and chromones
 Fructus Ammi majoris
(Greater ammi fruits),
Ammi majus (Greater ammi ),
Apiaceae
Constituents: methoxilied psoralen
derivatives-bergaptene, xanthotoxin
Action & use: photosensitizing agent in vitiligo
treatment and for symptomatic control of psoriasis
Medicines
from leaves is used in photochemotherapy to
treat a number of skin disorders, including
mycosis fungoides, psoriasis and vitiligo
 Ficusi caricae folia (Figs leaf),
Ficusi caricae fructus (Figs fruit)
Ficus carica Linn (Figs), Moraceae
Constituents: phurocoumarins (psoralen,
angelicine, bergaptene); polysaccharides;
mucilages; fat; proteins; pectins; organic
acids; vitamins in fruits,
leaves contain tannins; volatile oils.
Action & use
➢ laxative and food, photosensitizing due to bergaptene and psoralen
Medicines from leaves are used in photochcmotherapy to treat a number
of skin disorders, including mycosis fungoides, pso riasis and vitiligo. Fig
fruit preparations are used as a laxative.
Psoraleae Fructus
Psoralea drupacea,
Fabaceae
Constituents:coumarins:
phurocoumarins psoralen, umbelliferone
Action & use: psoralens are
photosensitizing agents in vitiligo
treatment
Pastinacae sativae Fructus
Parsnip fruit
Pastinaca sativa (Parsnip),
Apiaceae
Constituents: coumarins:
imperatorine, bergaptene,
xanthotoxin; volatile oils
Action & use:
photosensitizing and
spasmolytic. The fruits are
used in kidney and
gastrointestinal complaints
and for digestion problems
Angelicae rhizomata et radices
(Angelica root and rhizome)
Angelica archangelica L. (Archangelica officinalis
Hoffm.), (Angelica), Apiaceae
Constituents: coumarins: simple, furanoid and
hydroxyisopropylfuranoid, linear and angular (osthol,
bergapten, xanthotoxin, angelicin, archangelicin),
imperatorin, angelic acid; essential oil; organic and
fatty acids; flavonoids
Action & use: aromatic bitter; decoction is spasmolytic,
anti-iflammatory and sedative, tincture is used in
neuralgias and radiculitis.
Fruits are used orally to treat the symptoms of
gastrointestinal disturbances (bloating, eructations,
flatulence)
Hippocastani Semina (Horse Chestnut seeds),
Hippocastani Folia (Horse Chestnut Leaf )
Aesculus hippocastanum L
(Common Horse Chestnut),
Hippocastanaceae
Constituents: coumarins:aesculin and fraxine;
starch (40-50%); lipids (6-8%), flavonol glycosides,
cyclitols, and saponins (aescine)
Action & use: aescin is antiedema agent treats
the symptoms of venous and lymphatic vessel
insufficiency
 Meliloti Herba (Melilot herb)
Melilotus officinalis (L.) Pall. (Sweet Clower,Melilot)
Fabaceae
Constituents: coumarins: melilotoside;
saponins with a pentacyclic
triterpenoid aglycone, flavonoids, and
about 15 phenolic acids
Action & use: venous and lymphatic
vessels disorders, including itching,
fullness in the legs, nocturnal cramps,
edema, post-thrombotic syndrome,
lymphatic congestion, and
hemorrhoids; topically for contusions,
sprains, or superficial bleeding
• USES. THE DRUG IS USED INTERNALLY FOR PROBLEMS ARISING FROM
CHRONIC VENOUS INSUFFICIENCY, SUCH AS PAIN AND HEAVINESS IN LEGS,
NIGHT CRAMPS IN LEGS, ITCHING AND SWELLING; FOR THE SUPPORTIVE
TREAT MENT OF THROMBOPHLEBITIS, POSTTHROMBOTIC SYNDROMES,
HEMORRHOIDS AND LYMPHATIC CONGESTION. EXTERNALLY, THE DRUG IS
USED FOR CONTUSIONS, SPRAINS AND SUPERFICIAL EFFUSIONS OFHLOOD.
APPROVED BY COMMISSION E: BLUNT INJURIES, HEMORRHOIDS, VENOUS
CONDITIONS.
Dauci carotae fructus
Wild carrot f r u i t s
Daucus carota L. Wild carrot
Apiaceae
Constituents. coumarins: umbelliferon, esculetin,
scopoletin; furanocoumarin 8-methoxypsoralen and 5-
methoxypsoralen; flavonoids: flavones, flavonols and
various glycosides, carotinoids;volatile oil
Uses. Wild carrot is stated to possess diuretic, antilithic, and car-
minative properties. traditionally, it has been used for urinary
calculus, lithuria, cystitis, gout, and specifically for urinary gravel
or calculus
Anethi graveolentis
(Dill fruit) Fructus
Anethum graveolens L.
(Dill)
, Apiaceae
Constituents: phuranochromones (visnagine
and khellin), pyranocoumarins (visnadine);
flavonoids; volatile and fixed oils
Action & use: coronary spasmolytic; diuretic
and aromatic, carminative and stimulant in
gastro-intestinal diseases
Visnagae daucoides fructus
(Ammi visnagae fructus )
(Bjshop,s w'eed fruit )
Visnaga daucoides(Ammi visnaga Lam.),
(Khella) (Bishop's Weed ),
Apiaceae
Constituents: furanochromones (2-4%), including
khellin,visnagin , angular pyrano- coumarins (visnadin);
lipids (up to 18%), furanoacetophenones, flavonoids, essential
oil
Action & use: khellin is a spasmolytic agent; visnadin is a
coronary vasodilator and a positive inotropic, bradycardic, and
spasmolytic agent
1. Coumarins are natural compounds with
their structure based on a benzo-alpha-
pyrone skeleton. What reaction is allowed
to detect this group of compounds?

A. Lactone test
B. Cyanide test

C. Iron (III) chloride reaction

D. Wilson’s reaction

E. Trim-Hill reagent
One of the features of coumarin as a lactone is its specific action with an
alkali. They are slowly hydrolyzed under the action of a dilute alkali and form
a yellow solution of salts of coumaric acid. The coumarin is regenerated at the
origin state with acidification of the alkaline solutions or at their saturation by
СО2.
 2.A medicinal plant contains hydroxycoumarins and
is used in production of venotonic agents. Name the
herbal raw material harvested from this plant:

A. Semina Hippocastani
B. Herba Meliloti
C. Fructus Ammi majoris
D. Fructus Pastinacae sativae
E. Fructus Dauci carotae
3.Ammifurinum contains furocumarines. These
biologically active substances are derived from:

A. Fruits of large ammi

B. Fruits of psoralea
C. Fruits of common parsnip
D. Fruits of toothpick ammi
E. Rhizomes and roots of angelica
Fruits from large Ammi (Ammi majus) contain fucocoumarins
(xanthotoxin, imperatorine, bergaptene). Ammifurinum is a medicine
based on furocumarine fruits of large ammi.