Bpharm Year 3
PHM 3160 : General
Pharmacognosy
Flavonoids
Martha Chulu Mussa
[Link], [Link] PHARM, PhD Candidate(Pharmacognosy)
School of Health Sciences
Levy Mwanawasa Medical University
Flavonoids
2
Flavane-derivatives
Chemically, they are 2-phenylchroman derivatives.
Flavonoids are virtually universal plant pigments.
They are responsible for the color of flowers, fruits
and sometimes leaves.
They ensure tissue protection against the
damaging effects of UV radiation.
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Classification
They fall into many classes depending on the degree of oxidation
of the central pyran ring:
1- Flavanones (4-Oxo-flavane) such as naringenin.
2- Flavones (4-Oxo-flav-2-ene) such as apigenin.
3- Flavonols (3-Hydroxy-4-Oxo-flav-2-ene) such as quercetin.
4- Flavanols (3-Hydroxyflavane, Catechine) such as (+)-catechine.
5- Flavandiols (3,4-Hydroxyflavane) Leukoanthocyanidine).
6- Flavylium-salts (Anthocyanidine) such as cyanidine.
4
OH OH OH
O HO O
HO HO O
2
OH
OH O
OH O OH O
Flavanone Flavone Falvonol
OH OH
OH
HO O HO O
HO O
X OH
OH OH
OH OH O OH OH
Flavanol Flavylium-salt Flavandiol
(Catechine) (Anthocyanidine)
(Proanthocyanidine)
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Distribution
Flavonoids are common in the plant kingdom, Bryophytes
(mosses and hepaticas), and in Pteridophytes.
No flavonoids have been found in algae.
More than 3000 of these compounds are now known, with
nearly 500 aglycones.
They are abundant in the Polygonaceae, Rutaceae,
Rosaceae, Leguminosae, Umbelliferae, Lamiaceae and
Compositae.
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Chemical structure
Many authors apply the term flavonoids to flavon-, flavanon-,
and flavonol-derivatives.
They occur in free state and as glycosides, most are O-glycosides.
But a considerable number of flavonoid C-glycosides are known.
In all the classes of flavonoids mentioned so far, biosynthesis
frequently places at least 3 phenolic OH-groups in the 5-, 7-, and
4´-positions of the aglycone.
OH
HO O
2
OH O
Flavanone
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Flavones and Flavonols
The essential difference between flavones and flavonols is the
presence of OH-group at C-3 in the flavonols.
Flavones and flavonols) represent about 80 % of the flavonoids.
Ring A is substituted by two phenolic OH-groups at C-5 and C-7.
These OH-groups are either free or etherified.
R R
Flavons Flavonols
3´ 3´
OH OH
4´ 4´
B B
HO O HO O
7 2 7 2
A C A C
3 3
5 5
OH
OH O OH O
Apigenin: R = H Quercetin: R = OH
Luteolin: R = OH Kaemferol: R = H
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Flavanones and Dihydroflavonols
These molecules are characterized by the absence of a 2,3-double
bond and by the presence of at least one asymmetric center.
Two isomeric forms of each flavanone structure are possible, thus
the B ring can be in the (2S)- or in (2R)-configuration.
R1 R1
Flavanons 3´ Dihydroflavonols 3´
R2 R2
4´ 4´
B H B
HO O H HO O
7 2 7 2
A C H A C H
3 3
5 H 5 OH
OH O OH O
R1 R2 R1 R2
Hesperitin: OH OCH 3 Taxifolin: OH OH
Naringenin: H OH Pinobanksin: H H
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Biflavonoids
They are flavonoids, which bond to one another, particularly
through their very reactive C-6 or C-8.
The interflavanic linkage can be of:
Carbon-carbon-type (3´,8, e.g. in amentoflavone, or 6,8, e.g. in
agathisflavone, or 8,8, e.g. in cupressiflavone).
Carbon-oxygen-carbon-type (6-O-4´, e.g. in hinokiflavone).
Biflavonoids are characteristic of the Gymnosperms.
OR2
4´
OR4
R1O O 3´
4´
7 2
R3O O R1=R2=R3=R4= H, Amentoflavone
3
7 2
R2=Me, R1=R3=R4= H, Bilobetin
5 3 R1=R2=Me, R3=R4= H, Ginkgetin
OH O 5 R2=R4=Me, R1=R3= H, Isoginkgetin
OH O
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Flavonoid glycosides
The sugar moiety may be a mono-, di-, or trisaccharide, linear or
branched.
Monosaccharides include D-glucose, D-glalctose or D-allose, L-
rhamnose, or D-glucuronic or D-galacturonic acid.
The glycosidic bond may be established through any of the phenolic
OH-group on the aglycone (O-glycosides).
C-glycosides are not rare, more than 300 are known.
The bond is established between the asymmetric carbon on the
sugar and the C-6 or C-8 of the aglycone.
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Types of C-glycosides
Mono-C-glycosylflavonoids
Di-C-glycosylflavonoids
C-glycosyl-O-glycosylflavonoids
Acyl-C-glycosyl-flavonoids
R4
OH
R3 R1 R2 R3 R4
R2O O Vitexin H H Glu H
Isovitexin Glu H H H
Schaftoside Glu H Ara H
R1
Vicenin 2 Glu H Glu H
OH O
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PROPERTIES OF FLAVONOIDS
Physical Properties
1. Crystalline solids, sharp MP
2. Solubility: in H2O & alcohol (Flavonoid glycoside) Non glycosidic flavonoid: Aglycon
part-sol. in organic solvents
3. Color: Flavonones, Flavanol, Isoflavones- Colorless Flavonols, Flavones: Yellow, Chalchones,
aurones: Y, Orange Anthocyanidine acid med.: Red In basic: Blue
4. Flavanols: optically active
Chemical properties
1. 15 C skeleton, 2 benzene linked by heterocyclic pyran ring
2. Being phenolic, dissolves in alkalies → Yellow sol. +HCl → colorless
3. Glycosidic linkage located at 3 or 7 C
4. Flavanones, Flaonoes are unstable compound , on oxidation → Chalcones, leucocyanidines
5. Flavonoid + FeCl3→ green/ purple/ red brown color
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Extraction and investigation methods of
flavonoids
Ethanol and methanol are mainly used for flavonoid extraction. Spirituous extracts are
evaporated to water residue, then diluted with water and treated by chloroform for
lipids and lipoids (chlorophylls, carotenoids, waxes, etc.) separation.
Purified water residue is treated by diethyl ether, ethyl acetate, propanol, butanol in
series, getting fractions of aglycones, mono-, di-, triglycosides
Quantitative analysis
There are plenty of methods for flavonoid assay: gravimetry, titration, fluorimetry,
polarography, photocolorimetry, but the most widespread method is spectrometry. It
is based on reactions with metal ions, azo coupling, boric acid with further
determination of the optical density in UV and visible regions of the spectrum at a
proper wavelength.
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Identification and Characterization
with 5% AlCl3 in methanol (yellow-green fluorescent spots in UV
light)
with 1 % solution of diphenylboric acid-2-aminoethyl ester
(Naturstoff Reagenz A) (red-brown color is formed).
with FeCl3, anisaldehyde-reagent phenols.
Pacheco´s test for dihydroflavonols (with sodium acetate/acetic
anhydrid/HCl) (Red color).
Pew´s test for dihydroflavonols (with Zinc/HCl)
a deep purple-red with dihydroflavonols and brownish color
Flavanones and other flavonoids.
Shinoda test for flavanones and dihydroflavonols (with Mg/HCl)
Deep-red or magenta color is produced.
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Pharmacological and biological properties
They decrease capillary permeability and fragility
They are enzyme inhibitors such as lipooxygenase,
cyclooxygenase, histidine decarboxylase, hyaluronidase,
cAMP phosphodiesterase.
Many flavonoids are antioxidants, because they react with
free radicals.
Therefore, they show anti-inflammatory, antiallergic,
hepatoprotective and antispasmodic.
They can decrease blood cholestrol, be diuretic,
antibacterial and antiviral.
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Therapeutic uses
Treatment of the symptoms of venous and
lymphatic vessel insufficiency (tiredness or
fullness in the legs, cramps, pains and other
dysfunctions, edemas)
Treatment of circulatory disturbances.
Treatment of capillary fragility disorders of the
skin (ecchymosis, petechiae) and of mucosas
(gingival hemorrhage, epistaxis).
Treatment of dysfunctions linked to the acute
attack of piles.
Metrorrhagias linked to intra-uterine
contraceptive devices.
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Chief flavonoids on the Market
1- Rutin
It is a flavonol glycoside. Chemically, it is quercetin-3-O-(6-O-
rhamnoside) glucoside.
It occurs as yellow crystals, soluble in boiling water and alcohol.
Rutin alone or in combination with other substances is used as
described previously, particulaly to treat hemorrhages linked to
diabetes and hypertension, and to treat the functional symptoms
of the acute attack of piles. OH
3´
OH
4´
HO O
7 2
5 O
Glu Rham
OH O
Rutin
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Sources of rutin
Ruta graveolens (Fam. Rutaceae)
Buckwheat-species: Herb of Fagopyrum esculentum (Fam.
Polygonaceae) (up 5%) and of Fagopyrum tataricum (up to 3%).
Japanese pagoda tree (Sophora japonica, Fam. Fabaceae).
The flower buds of which contain 15-23 % Rutin.
Ruta graveolens Fagopyrum Sp.
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2- Citroflavonoids (especially Hesperidin)
They are extracted from Pericarps and pulbs of Rham OH
Citrus-trees as Ca and Mg derivatives. Glu
3´
OCH 3
4´
Hesperidin is hesperitin-7-O-(6-O-rhamnoside) O O
glucoside, it occurs up to 8 % in the pericarp. 7 2
Uses: 5
OH O
in the treatment of the leg symptoms of Hesperidin
chronic, functional and organic venous
insufficiency,
and as adjuvant or prophylactic with vitamin C
for the treatment of common cold and
infections.
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3- Diosmin
Rham OH
It is a flavone glycoside found in Glu OCH3
Buchu leaves (Barosma sp.) O O
7
It occurs in pale yellow needles or
powder.
5
OH O
Acid hydrolysis of diosmin yields Diosmin
diosmetin (aglycone) besides one
molecule of rhamnose and glucose.
Uses:
diuretic and diaphoretic effect
also in the treatment of venous
disorders.
Barosma betulina
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Flavonoid containing drugs
1- Whitethorn herb
The drug consists of the herb and sometimes of
the fruits of Crataegus monogyna, C. laevigata
and of C. pentagyna (Fam. Rosaceae)
The drug contains:
2 % flavonoids (0.7 % as hyperoside), other chief
constituents are vitexin, rutoside, apigenin- and
luteolin-derivatives.
Up to 1 % oilgomeric procyanidines (4,8- or 4,6
dimeric, trimeric to hexameric flavan-3-ols).
It is used in the treatment of cardiac insufficiency
(grad I-II to NYHA), in treatment of brady C. monogyna
arrhythmia and to improve the circulation of the
coronary artery.
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2- Maidenhair tree
Leaves of Ginkgo biloba (Fam. Ginkgoaceae)
found in China and Japan, but also cultivated
in Europe.
The drug contains:
1- 0.4-2 % biflavonoids (amentoflavone,
bilobetin, and ginkgtin)
2- 0.5-2 % flavonol glycosides. (quercetin and
kaempferol-derivatives)
3- 4-12 % flavan-3-ols and proanthocyanidins
4- 0.02-0.2 % ginkgolides (comlexes of
diterpenlactones)
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Uses:
In the treatment of the symptoms of senile
cerebral insufficiency (vertigo, tinnitus and
hearing loss, lack of concentration).
In the treatment of the intermittent
claudication and of Raynaud´s disease.
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Ramzi A. Mothana, PhD PHG322, Flavonoids, Feb 2013 25
3- Passion flower
The drug consists of the herb of Passiflora incarnata (Fam.
Passifloraceae), found in south and North America (USA and Mexico).
The drug contains:
up to 2.5 % flavonoids (C-glycosylflavonoids) such as Vitexin,
isovetexin, schaftoside and vicenin-2.
Uses:
as sedative to treat the symptoms of nervousness in adults and
children and particularly minor sleeplessness.
also used to treat abnormities of the cardiac rhythm in the adult.
R4
OH
R3 R1 R2 R3 R4
R2 O O Vitexin H H Glu H
Isovitexin Glu H H H
Schaftoside Glu H Ara H
R1
Vicenin 2 Glu H Glu H
OH O
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P. incarnata
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4- Birch leaf
The drug consists of the leaves of Betula
pendula or Betula pubenscens (Fam.
Betulaceae), which is found in Europe
and in China.
The drug contains:
3 % flavonoids, paticularly
Hyperoside and quercitrin
used as diuretic (in the bacteriuria),
particularly in the urinary tract
infections such as pyelonephritis,
ureteritis, cystitis and urethritis.
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5- Lime tree flowers or Linden flowers
The drug consists of the flowers of Tilia
cordata or Tilia platyphyllos (Fam.
Tiliaceae), which is found in Europe and
in Asia (China).
The drug contains 1% flavonoids, specially
glycosides of quercetine such as rutin,
hyperoside and quercitrine and glycosides
of kaemferol such as tiliroside.
The drug is used as expectorant for the
treatment of cough and as diaphoretic
(common cold and fever).
Tilia cordata
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5- Lime tree flowers or Linden flowers
The drug consists of the flowers of Tilia
cordata or Tilia platyphyllos (Fam.
Tiliaceae), which is found in Europe and
in Asia (China).
The drug contains 1% flavonoids, specially
glycosides of quercetine such as rutin,
hyperoside and quercitrine and glycosides
of kaemferol such as tiliroside.
The drug is used as expectorant for the
treatment of cough and as diaphoretic
(common cold and fever).
Tilia cordata
Ramzi A. Mothana, PhD PHG322, Flavonoids, Feb 2013 30
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Motherwort Herb – Leonuri herba, EP
Motherwort – Leonurus cardiaca L., Leonurus quinquelobatus
Mint family- Lamiaceae
Syn.: Throw-wort, Lion’s Ear, Lion’s Tail.
Chemical constituents: complex flavonoids, alkaloids ,irydoides, tannins, terpenoids.
Major flavonoids – hyperoside, kaemferol-3-Dglucoside rutin, quercetin, isoquercetin,
tannins and a small amount of essential oil.
Pharmacological activity: infusion and tincture as
sedative and hypotensive agent in cardiovascular
neurosis, the initial stages of hypertension,
cardiosclerosis, increased nervous excitability.
Dosage forms:: infusion
Water pepper Herb – Polygoni hydropiperis Herba ,
Water pepper – Polygonum hydropiper L.,
Family Polygonacea– Polygonaceae.
Syn.: Smartweed, Biting persicaria, Bity tongue, Pepper plant
Chemical constituents: rutin, quercetin, hiperosed, cemppherol, tannins, vitamins
K and C. Raw materials containing substances such as colored phagopirin causing
phagopiryzm (sensitivity to light).
Pharmacological activity ::hemostatic,
•
Dosage forms: liquid extract
Black chokeberry fruit – Aroniae melanocarpae Fructus recentes
Black chokeberry – Aronia melanocarpa (Michx) Elliot
Rosaceae
• Constituents. Cyanidin and it’s
glycosides, phenolic acids,
flavonoids- rutin, quercetin,
gesperidin; pectines; ascorbic acid;
big amount of iodine (5-6
mcg/100g), Folic acid, riboflavin,
tocopherol, carotinoids; lipids, wax,
paraffin.
• Uses. Fresh fruits and juice are
used for prevention of vitamin P
insufficiency, they are useful for
those with hypertension. Lipophilic
substances are the part of Aromelin
which has restorative action
Pagoda tree buds – Sophorae japonicae Alabastrae
Pagoda tree fruit – Sophorae japonicae Fructus
Pagoda tree – Sophora japonica
Syn.: Chinese Scholar, Japanese pagoda tree.
Fabaceae
• Constituents. Up to 20% of
rutin.
Uses. As the main constituent
is rutin the plant is used in the
treatment of circulatory
diseases (Ascorutin, Vikalin,
Rutes). Tincture has
antiseptic properties
Lemon peel – Citri Exocarpium
Lemon - Citrus limon
Rutaceae
Constituents: flavonoids, especially
neohesperidosides and rutinosides of
hesperetin and naringenin (rutin, eriocitrin,
neohesperidin, hesperidin) along with many
other flavonoids (44 flavone glycoside were
detected); essential oil (+ limonene as the
principle component, citral – determine the
odour); carotenoids, citric acid and many
other plant acids, coumarin derivatives,
pectins.
Uses. It’s used chiefly as an aromatic and stomachic. The efficacy of
lemon flavonoids in treating varicose veins is related to their ability to reduce
capillary fragility, increase integrity of the venous wall and increase the
muscular tone of the vein.
The raw material and its extracts are used to treat diseases of the blood vessels
and lymph system, including haemorrhoids, chronic venous insufficiency, leg
ulcers, nosebleeds.
Tea leaf – Theae folia
Tea – Thea sinensis (syn. Camellia sinensis) (L.)
Theaceae
Constituents: abundant flavonoids, including the
apigenin derivatives isoschaftoside and vicetin-3,
catechols, leucoanthicyanidins, theaflavins,
condensed tannins (10-20 %), 4-gallocatechol,
phenolic carboxilic acids (gallic, chlorogenic);
methylxanthines (caffeine, theobromine,
theophylline, adenine, xanthine); the flavour and
aroma substances, some of which arise during the
fermentation stage (hex-3-en-1-ol, benzyl
alcohol, linalool in black tea and geraniol in grean
tea); triterpenoid saponins.
Uses. Owing to its caffeine content, tea serves as a stimulant, and bacause of its
tannin content it can be used an anthidiarrhoeic. Polyphenols have P-vitamin
and the antioxidant activity. Strong tea is given in poisonings caused by central
nervous system inhibitors, alcohol, heavy metals.