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Dr. Pran Kishore DebAssistant Professor
Pharmaceutical Medicinal Chemistry
Faculty of Pharmacy, Philadelphia University-Jordan
Email: [email protected]
Simple phenolic/aldehyde glycosides
This group of glycosides contains phenolic, alcoholic, or aldehyde,group as an aglycone part of glycosides.
All are derived from shikimic acid pathway.
ALCOHOL GLYCOSIDES
1. Salicin
It is O-hydroxy benzoylglucoside. It is found in different species ofWillow bark صفصاف like the following:
1. Salix purpurea Family: Salicaceae
2. Salix fragilis Family: Salicaceae
3. Populus species.
Usually it is hydrolyzed by the enzyme emulsin to D-glucose andsaligenin.
Act as an analgesic, antipyretic and anti-inflammatory agent inhuman body.
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S. purpureaالصفصاف االرجواني
S. fragilisالصفصاف الهش
2. Popul in:
It is benzoyl salicin and is a phenolic alcoholic glucoside.
It is found in the bark and leaves of Populus species and Family:Salicaceae.
H ydro l ys i s :
1 . By a l k a l i : it gives benzoic acid and salicin.
2 . By ac i d : it gives benzoic acid, saligenin (salicyl alcohol) and
glucose.
6P o p u l i n
Populus deltoides
3.Coniferin :
It is m-methoxy-p-hydroxy cinnamyl alcohol glycoside .
This is found in most coniferous plants الصنوبرية النباتات
Is used for preparation of vanillin.
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Phenol Glycosides
Arbutin Extracted from the dried leaf of Arctostaphylos uva-ursi
Family Ericaceae .الخلنجية
USES
1. The leaves of uva ursi are traditionally brewed into a tea and usefultreatment option for urinary tract infections (UTIs).
2. It inhibits tyrosinase and thus prevents the formation of melanin.Arbutin is therefore used as a skin-lightening agent.
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Its glycoside arbutin which is upon hydrolysis yieldshydroquinone and glucose.
USES:
Uva ursi has antibacterial properties because of its mainbioactive, arbutin.
Arbutin creates a metabolite called hydroquinone glucuronide.When this metabolite is eliminated through urine, it also preventsbacteria from adhering to tissue in the area. This is why uva ursimay be effective at alleviating UTIs.
Aldehyde glycosides
Glucovanillin
Fruits of Vanilla planifolia Andrews, known in Commerce asMexican or Bourbon vanilla.
Vanilla tahitensis J. W. Moore known in commerce as Tahiti vanilla
Family: Orchidaceae
Vanilla contains Glucovanillin (avenin) as o-glycoside which uponenzymatic hydrolysis gives vanillin (aldehyde aglycone) and glucose.
Vanillin is used as a flavoring agent specially in bakery.
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Green vanilla pods
Bitter in taste
(odourless)
Brown vanilla pods
Sweet in taste
(Vanilla odour)
At the same time, vanillin can be prepared synthetically from
isoeugenol or coniferin or guaicol as follows:
Commercial Preparation of Vanillin
CH2-CH=CH2
OH
OCH3
CH=CH-CH3
OH
OCH3
OH
OCH3
CH=CH-CH2OH
O-glc
OCH3
Eugenol
KOH
Iso-eugenol
OxidationVanillin
VanillinCHCl3+ NaOH
Reflux
Guaiacol
VanillinH2SO4/K2Cr2O7
Coniferin
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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 phytoalexins 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.
19Psoralens 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.
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O
O
CH3
OCH3
OCH3
O
Khellin
In Egypt, the plant "Khella" was used for renal colic. The incidence
of renal colic was due mostly to 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. 24
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.
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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.
30PicrotinPicrotoxin
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Terpenes and Terpenoids• Terpenes - Class of >20,000 natural organic compounds
containing carbon atoms in multiples of five (5)
• Terpenoids - Oxygen-containing terpenes (alcohols, ketones,aldehydes)
• The name ‘terpene’ is derived from the Greek word ‘terebinth’.Terebinth is a type of pine tree from which terpene-containingresins are obtained.
• Terpenes and terpenoids are the primary constituents of the essentialoils of many types of plants and flowers.
(kereviz)(zencefil)(rose oil) 32
• The basic molecular formulae of terpenes are multiples of
(C5H8)n where n is the number of linked isoprene (2-methyl-1,3-
butadiene) units. This is called the isoprene rule or the C5 rule.
• All terpenes are built up from units of isoprene- isoprene units linked in a
“head-to-tail” fashion
• “Head” - branched end of isoprene
• “Tail” - unbranched end of isoprene
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C
CH3
CH2
CH
CH2
Head Tail
Isoprene(2-methylbuta-1,3-diene)
=
One isoprene unit contains five carbon atoms
Myrcene – a linear terpeneMyrcene is a component of plants, including bay, ylang-ylang and
thyme.
Head Tail
C
CH3
CH2
CH
CH2
Head Tail
C
CH3
CH3
CH
CH2
C
CH2
CH2
CH
CH2
C
CH3
CH2
CH
CH2
Building of terpenes from isoprene
Isoprene units can be linked:
head to tail to form linear terpenes
in rings to form cyclic terpenes.
Menthol – a cyclic terpenoid This terpene has been
oxidised to a terpenoid
Limonene – a cyclic terpene
(a strong smell of oranges)
-carotene is the compound that causes carrots and apricots to be orange
• Monoterpenes consist of two isoprene (10C) units and have the
molecular formula C10H16. Examples: geraniol, limonene and terpineol.
• Sesquiterpenes consist of three isoprene (15C) units and have the
molecular formula C15H24. Examples: humulene, farnesenes, farnesol.
• Hemiterpenes consist of a single
isoprene unit. Isoprene itself is
considered the only hemiterpene.
• But oxygen-containing derivatives are
hemiterpenoids such as prenol (found in
citrus fruits, cranberry, grapes, raspberry,
blackberry, tomato) and isovaleric
acid (found in in essential oils).
• Sesterterpenes, consist of five isoprene units (25 carbons), Example:
geranylfarnesol.
• Triterpenes consist of six isoprene units with molecular formula C30H48.
The linear triterpene squalene, the major constituent of shark liver oil.
• Squalene has a natural and vital part in the synthesis of all plant and
animal sterols, including cholesterol, steroid hormones, and vitamin D
in the human body.
• Diterpenes are composed of four isoprene units (20C) and have the
molecular formula C20H32.
• Diterpenes also form the basis for biologically important compounds such
as retinol, retinal, and phytol. They are known to be antimicrobial and
antiinflammatory.
Retinol is one of the forms of vitamin A
• (Tetraterpene) contain eight isoprene units (40 carbons) and have the
molecular formula C40H64. Biologically important tetraterpenes include
the acyclic lycopene, the monocyclic gamma-carotene, and the
bicyclic alpha- and beta-carotenes.
• Polyterpenes consist of long chains of many isoprene units.
Natural rubber consists of polyisoprene in which the double bonds are cis.
• Lycopene's eleven conjugated double bonds give it its deep red color and
are responsible for its antioxidant activity.
• Lycopene is responsible for the red color in tomatoes and watermelon.
Biosynthesis of monoterpenes
40
Acyclic monoterpenes
Linalool
Found in aromatic plants like Rosmarinus officinalis.
Used in:
1. Perfume industry.
2. Cosmotics.
3. As preservative.
Medicinal uses:
1. A potent antimicrobial for G-negative and G-positive bacteria as
well against yeast.
2. Anti-spasmodic.
3. Sedative activity to counteract the convulsant activity (Rats
experiment).
4. Local anesthetic. 41
Linalool
42
Cyclopropane Monoterpenes
Pyrethric acid and Chrysanthemic acid
They are transformed into pyrethrin which is a compound used asinsecticide for certain types of insects like spiders, lice, as wellas potentially disease-carrying mosquitoes.
Found in the flowers of Chrysanthemum cinerariaefolium.
43Pyrethric acid Pyrethrin
Cyclopropane Monoterpenes
• Chrysanthemum cinerariaefolium
44
Menthanes Monoterpenes
Menthoglycol or para-menthane-3,8-diol, PMD
• It is an active ingredient used in insect repellents. It smells
similar to menthol and has a cooling feel.
• There are eight possible isomers of PMD, and the exact
composition is rarely specified and is commonly assumed to be a
complex mixture.
45
Menthol
It is found in Mentha piperita leaves which contain volatile oil as
the chief constituents.
The oil is distilled from young plants containing large quantities of
menthofuran with a lower grade than the one from old plant.
46
Uses
• Antibacterial.
• Antipruritic.
• Chilling sensation when applied on skin, thus can be used as a
remedy for itching.
• The volatile oil is largely consumed for making tooth pastes,
chocolate and sweets.
Thymus species
Thymus vulgaris
The bactericidal activity is strongest for thymol and carvacrol-
containing types.
Traditionally, thyme is used as antispasmodic and for cough.
Locally, it is used to treat minor wounds, analgesic for oral cavity.
Used for common cold.
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Thujone monoterpene
Thujone
It is found in Artemisia absinthium as α-thujone and β-thujone.
It is a poisonous monoterpene ketone.
They induce genotoxicity, neurotoxicity, reproductive toxicity andcarcinogenicity.
They are convulsant due to blockage of the GABA, (ϒ – aminobutyricacid) receptors.
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Sesquiterpenes
Plants containing sesquiterpenes
Matricaria recutita: (German chamomile) consists of the
flower heads.
Main constituent: volatile oil which contains bisabolol up to 50%.
Bisabolol has an anti-ulcer activity.
Also it contains chamazulene which has a blue color.
49Bisabolol
Feverfew
أقحوان زهرة الذهب
Tanacetum parthenium
This plant has a strong aromatic odor .
It contains parthenolide which is a prophylactic remedy for migraine.
50
Parthenolide
Artemisia annua
شيح حولي
• Is cultivated in China and other East Asian countries.
• Artimisinine is found in the leaves or flower tops.
• It is toxic to malaria parasites at nano-molar concentrations.
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Diterpenes
ريبوادياناستيفيا
Stevia rebaudiana
It is native to Brazil and cultivated in many parts of the world.
The leaves contain glycosides such as stevioside which is a natural
sweetener.
• It is 200 time more potent than sucrose and devoid of toxicity
52Stevioside
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Tannins
A tannin (or tannoid) is an astringent, polyphenolic biomolecule
that binds to and precipitates proteins and various other organic
compounds including amino acids and alkaloids.
The term tannin (from tanna, an Old High German word for oak or
fir tree) refers to the use of wood tannins from oak in tanning
animal hides into leather; hence the words "tan" and "tanning" for
the treatment of leather.
The consequence of tanning is the formation of bonds between the
collagen fibers in the hide, which imparts resistance to water,
heat, and abrasion.
This capability of tannins to combine with macromolecules explains
why they precipitate cellulose, pectins, and proteins.
54
Tannins The tannin compounds are widely distributed in many species of
plants, where they play a role as
Source of acids in fruits.
Source of energy by oxidation in plant growth regulation.
Antiseptic and astringent.
Prevent damage by insects.
Binds quickly to precipitate proteins and other organic compounds.
Finally destroyed or deposited.
Tannins general characters
Not crystallisable.
Precipitate solutions of proteins.
Antidote for alkaloids poisoning.
Astringent (tend to contract body tissues)
Antimicrobial, Anti-inflammatory.
Antiulcer, Antioxidant.
Anti-viral.55
Types of Tannins The tannin compounds are divided into two (2) classes
A. Hydrolysable tannins
B. Condensed tannins
A. Hydrolysable tannins:
These are ester of sugars and phenolic acid molecules like gallic acid(Gallotannins) or ellagic acid (Ellagitannins).
HTs are of low M.W (500-3000)
HTs are soluble in water and their solution produces blue color withferric chloride.
gallic acid
Hydrolysable tannin (Trigalloyl glucose)
gallic acid
ester
suger
ellagic acid
Types of Tannins
B. Condensed tannins:
These are Proanthocyanidins
Condensed tannins are formed through the polymerization of flavan-3-ol(catechin) and flavan–3,4-diols (leucoanthocyanidins).
The polymers may include 2 to 50 monomer units.
On treatment with acids or enzymes condensed tannins are converted intored insoluble compounds known as phlobaphenes.
Phlobaphenes give the characteristic red colour to many drugs such asred cinnamon bark.
On dry distillation, they yield catechol derivatives.
Condensed tannins are also soluble in water and
produces green colour with ferric chloride.
O
OH
OH
Flavan-3,4-diols(Leucoanthocyanidins)
O
OH
Flavan-3-ols(Catechins)
O
OH
OH
Flavan-3,4-diols(Leucoanthocyanidins)
O
OH
Flavan-3-ols(Catechins)
Condensed Tannins
Hydrolysable Tannins
Nutgall: Galls are vegetable growths formed on the young twigs
(branches) of the dyer’s oak = Aleppo Oak (Quercus infectoria)as a result of the deposition of the eggs by small insect (Adleriagallaetinctoriae).
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Uses:
• Astringent.
• For aphthous ulcer.
• Putrid sore throat
• Anti-heommorrhagic.
• Burns.
Nutgall Constituent: Tannic acid (C76H52O46)
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Acorn cups from Quercusspp., Fagaceae
Quercus infectoria
Tannic acid
Witch Hazel بندق الساحرة
Leaves of Hamamelis virginiana
Family: Hamamelidaceae
It contains hamamelitannin,
vegetable oil, gallic acid.
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Hamamelitannin
Witch Hazel USES
The leaves and bark may be used to produce an astringent.
Hamamelitannin reported to exert a protective action against
colon cancer [Ref: J. Nat. Prod., 2012, 75 (1), pp 26–33.; DOI:
10.1021/np200426k].
It is mainly used externally on sores, bruises, and swelling.
Witch hazel hydrosol is used in skin care. It is a strong anti-
oxidant and astringent.
It is often used as a natural remedy for psoriasis, eczema,
aftershave applications, ingrown nails, cracked or blistered skin,
for treating insect bites.
The extracts are also used as a treatment for varicose veins and
hemorrhoids.
Chestnut leaves
• Leaves of Castanea dentata
• Family: Fagaceae
• Constituent: Tannic acid
• Uses: astringent
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Green Tea leaves
• Thea sinensis, (Family: Theaceae)
• Main Constituents: Catechins
Effects:
1. Limits the growth of colorectal cancer.
2. Reduces mortality due to different causes and cardiac diseases.
3. Reduces cognitive impairment.
4. Reduces obesity.
64
(+)-Catechin (-)-Epicatechin (cis) (-)-Epigallocatechin
(-)-Epicatechin gallate (-)-Epigallocatechin gallate
Green tea contains:
• (+)-gallocatechin (GC), (-)-epicatechin (EC), (-)-epigallocatechin (EGC),
(-)-epicatechingallate (ECG), (-)-epigallocatechingallate (EGCG) which
shows numerous biological activities including antibacterial, anti-oxidant,
anti-tumor and cancer preventive activities.
Green tea Uses:
• (+) Catechin prevents cancer (liver, lung, breast and colon cancer) in
at least one of three ways:
First, they can prevent the formation of carcinogens,
Second, they tone up the body's natural detoxification defences,
Finally, they suppress cancer promotion.
• (+) Catechin has other promising qualities: antiviral agent,
regulating cholesterol and blood pressure, and reducing blood
clotting tendencies that may cause heart attacks or strokes.
• Catechins may stimulate the secretion of Bile salts and the faecal
excretion of cholesterol.
• Catechins also have anti-hyperglycemic action and normalizing
insulin release
Identification tests of tannins
With FeCl3:
• Hydrolysable tannins: BLUE color.
• Condensed tannins: GREEN color.
67
