Secondary Metabolites

Plant Constituents
- Individual chemical from which plants are made
- Organic in nature and synthesized in plants by the activity of individual cells
- Plants and their products form the basis of medicine
Biosynthesis
- Process by which complex organic chemical constituents are formed, utilizing simple substance and
enzyme.
Active Constituents
- Chemical substance, which are solely responsible for the therapeutic activity of plants
- Secondary metabolite
o Secondary Plant Metabolite
Complex organic molecule biosynthesized from primary plant metabolite in plant cells
Unique to plant or group of plants, generally process therapeutic activity, neither essential
for plant life nor contain high energy bond
Usually stored in the vacuoles.
Inactive Constituents
- Chemical constituents present in plant that do not possess any definite therapeutic value
- Termed Primary plant metabolite
o Primary Plant Metabolite
Simple molecule or polymer of simple molecule synthesized by plant
Do not possess therapeutic as such but essential for the life of plants and contain high
energy bond
Natural Products
- Products from various natural sources, plants, microbes and animals
- Can be an entire organism, a part of an organism, an extract of an organism, exudates or pure compound
isolated from plants, animals or microorganism
- Refers to secondary metabolite, small molecules (MW < 1500 amu) produced by an organism but not strictly
necessary for the survival of the organism
ALKALOIDS
I.
Description
- Naturally occurring large group of pharmacologically active nitrogen containing secondary metabolite of
plants, microbial or animal origins
- Nitrogen atom is part of the ring
- Biosynthetically derived from amino acid
- Alkaloid is derived from the word alkaline meaning water soluble base
- Can be extracted from plants by the treatment with alcoholic solvent acidified with 1M HCl
- A number of natural alkaloid & their derivatives have been developed as drugs to treat various disease such
as morphine and reserpine
- Basic in nature & form water soluble salt with mineral acid
- One or more nitrogen atom that are present in an alkaloid, typically 1, 2, and 3 amine contribute to the
basicity of the alkaloid
- Most alkaloid are crystalline in form

II.

Classification
A. Based on Heterocyclic Ring
1. Atypical AKA non heterocyclic alkaloid; Nitrogen contained in the aliphatic chain
2. Typical AKA heterocyclic alkaloid; Nitrogen contained in the heterocyclic ring
B. Based on the Origin
1. True Alkaloid Basic in nature; derivative of amino acid having nitrogen in the heterocyclic ring;
occurs in plant as salt
2. Proto/Amino Alkaloid Simple biological amines; basic in nature; derivative of amino acid, do not
have nitrogen in the heterocyclic ring
3. Psuedo Alkaloid Weakly basic nitrogenous compound; do not derived from amino acid but have
a nitrogen in the heterocyclic ring
* True & Protoalkaloid (Amino Acid Derived)
a. Ornithine & Lysine Derivative Alkaloid
i.
Pyrolidine Alkaloid
ii.
Tropane Alkaloid
iii.
Pyrolizidine Alkaloid
iv.
Quinolizidine Alkaloid
v.
Indolizidine Alkaloid
vi.
Piperidine Alkaloid
b. Phenylalanine and Tyrosine Derivative Alkaloid
i.
Phenyl ethyl amine
ii.
Isoquinoline Alkaloid
iii.
Aporphine Alkaloid
iv.
Morphinan
c. Tryptophan Derivative Alkaloid
i.
Tryptamine and Carboline
ii.
Indoline
iii.
Ergoline
iv.
Monoterpenoid
d. HIstidine Derived Alkaloid
* Pseudo alkaloid (Non-amino Acid Derivative)
a. Alkaloid derivative from terpene metabolism
i.
Mono & Sesque terpene alkaloid
ii.
Diterpene Alkaloid
iii.
Steroidal Alkaloid
b. Purine Based
c. Miscellaneoud Alkaloid
C. Based on Generic Structure
1. Pyridine & Piperidine Possess a pyridine or modified pyridine heterocyclic ring
Piperine (C17H19NO3)
- Component of black pepper (Piper nigrum)
- Used in various traditional medicine preparation and also as an insecticide
- Has various effect on human drug metabolizing enzyme
Coniine (C8H17N2)
- (S)-2-propylpiperidine
- Poisonous alkaloid found in the hemlock poison and yellow pitcher plant (Satracinia flava)
- Neurotoxin, causes respiratory paralysis and is toxic to all classes of livestock and human

2.
-

3.
-

Nicotine (C10H14N2)
- Active component of tobacco (Nicotina tabaccum)
- Also found in other species of the family Solanaceae
- Hygroscopic oily liquid and miscible with water in its base as well as its salt form
- Possess 2 nitrogenous ring system one is pyridine but the other is pyrrolidine ring system
- Potent nerve poison and is included in many insecticide preparation
- At low concentration- stimulant; high doses- depressant
Pyrrole and Pyrrolidine Contains pyrrole and modified pyrrole
Pyrrolidine central structure of amino acid proline and hydroxyproline
Also found in many drug preparation which is an anti-cholinergic drug mainly used for the treatment
of drug induced Parkinsons akarthisia and acute dystonia
Hygrine (C8H15NO)
- Found mainly in coca leaves (Erythroxyium coca)
- Thick yellow oil, having pungent taste and odour
Cuscolygrine (C13H27N2O)
- Dimeric pyrrolidine alkaloid found in coca also in many species of Solanaceae
- It is an oil, but soluble in water
Tropane Possess a 8-methyl-8-azabicyclo [1, 2, 3] octane or tropane skeleton
Occurs mainly in plants from the families of Solanaceae & Erythroxylaceae
Atropine (C19H23NO3)
- First isolated from the deadly nightshade also found in many other plants of the
Solanaceae
- Racemic mixture of D-hyoscyamine and L-Hyoscuamine
- Most pharmaceutic property is due to its L-isomer and due to its binding to the muscarinic
acetylcholine receptor
- Main use ophthalmic drug
- Used as acycloplegic to paralyze accommodation temporarily and as mydriatic to dilate
pupil
- Injection of atropine are used in the treatment of bradycardia, asystole and pulseless
electrical activity in cardiac arrest
- Also used as antidote for poisoning by organophosphate insecticide and nerve gas
Cocaine (C17H21NO4)
- White crystalline tropane alkaloid found in coca plant
- Potent CNS stimulant and appetite suppressant
- Most common drug of abuse and addiction because of its euphoretic effect
- Used as topical anesthetic in eye, throat and nose surgery
- Excessive dosage produce hallucination, paranoid delusion, tachycardia, itching and
formication
- Overdose leads to tacharryhthmias and elevated blood pressure and can be fatal
4. Quinoline Alkaloid
Colorless, hygroscopic liquid with strong odour and slightly soluble in water, but readily miscible
with organic solvent
Toxic
Short term exposure to vapor causes irritation of the nose, eyes and throat, dizziness and nausea
May cause liver damage
Quinine (C20H24N2O2)
White crystalline quinoline alkaloid
Isolated from Cinchona bark (Cinchona succiruba)
Well known antimalarial drug
Extremely bitter

Also possess antipyretic, analgesic and anti-inflammatory properties

Drug of choicefor Falciparum malaria
Can also be used to treat nocturnal leg cramp and arthritis
Extremely basic and available in salt form
May cause paralysis if accidentally injected tothe nerve
Non-medicinal use: flavoring agent in tonic water and bitter lemon
Quinidine (C20H24N2O2)
Stereoisomer of quinine found in Cinchona bark
Chemically known as (2-ethenyl-4-azabicyclo[2.2.2] Oct-5- yl)-(6methyoxyquinolin-4-yl)- methanol or 6'methoxycins-9-ol
Class 1 anti-arrhythmic drug
IV injection is used in the treatment of P.falciparum malaria
5. Isoquinoline Alkaloid
Isomer of quinoline
Chemically known as benzo [c] pyridine or 2-benzamine
Isoquinoline backbone is biosynthesized from aromatic amino acid tyrosine
Hygroscopic liquid at room temperature
Has an unpleasant odor
Slightly soluble in water but well soluble in ethanol, acetone & other common organic
solvent
Weak base with pKa of 8.6
Used in the manufacture of dye, paint, insecticide and as solvent for extraction of resin
Papaverine ( C20H21NO4)
Isolated from poppy seed (Papaver somniferum)
Mainly used in the treatment of spasm and erectile dysfunction
Used as cerebral and coronary vasodilator
Used as smooth muscle relaxant in miscroscopy
Morphine (C17H17NO3)
Habit forming class A analgesic drug
Najor bioactive constituent of opium poppy seed
Acts directly on the CNS to relieve pain
Treatment of post surgical pain and chronic pain (cancer) and as adjunct
to general anesthesia and anti-tussive for severe cough
6. Phenylethylamine (Non-heterocyclic)
Neurotransmitter or neuromodu
Nitrogen is not part of the ring
Colorless liquid
Biosynthesized from phenylalamine through enzymatic decarboxylation
Used as neurotransmitter, stimulant, hallucinogen, bronchodilator and antidepressant
7. Indole/Benzopyrrole
Contains an indole
Classified into three categories a.) Tryptamine & its derivative, b.) Ergoline & its
derivatives c.) beta carboline & its derivatives

I.
-

Glycosides
Compounds that yields one or more sugar upon hydrolysis
Composed of 2 moieties: sugar portion (glycone) and non sugar (aglycone)
The sugar moiety of a glycoside can be joined to the aglycone in various ways, the most common being via
an Oxygen atom (O-glycoside); Carbon atom (C-Glycoside); Nitrogen atom (N-glycoside); or sulfur atom (SGlycoside)

Classification
Based on Sugar Component
o Glucoside Glucose
o Fructoside- Fructose
Based on Aglycone
o Anthraquinone
o Flavonoid
Based on Properties or Function
o Saponin- Soap like
o Cyanogenic- Liberates HCN upon hydrolysis
o Cardiac- effect on heart muscle
a. Cyanogenic Glycoside/ Cyanophore
- Liberates HCN upon hydrolysis
- Biosynthetically derived from L-amino acid eg. Amygdalin from L-Phenylalanine
- Cyanogenic Glycoside particularly amygdalin and prunasin are found in kernel of apricot, bitter
almonds, cherries, plums and peaches
- - glycosidic derivative of 2-hydroxynitriles (cyanohydriles)
- Fairly unstable and stabilized by glycosylation
- Intermediately polar, water soluble compound
- Used as flavoring agents
- All plants produce cyanide, however in most cases cyanide present are in small quantities
- 10mg of HCN per Kg of plant is the content needed before a plant is considered Cyanogenic

Excessive ingestion is fatal

Lethal level single dose 0.5 to 3.5mg/kg body weight
Lost after harvest due to plant hydrolysis

Amygdalin
b. Anthraquinone
- Form the largest group of naturally occurring quinine segment
- Occur in plants usually as hydroxylated, methylated or carboxylated derivative of antraquinone,
anthrone, anthral or diantrone
- Occur as O and/or C-glycoside or as their aglycone
- Aglycone of anthracene derivative
- Most common sugar are glucose and rhamnose
- Colored substance and are the active component of laxative and purgative
- They increase peristaltic movement
- Short term use causes constipation; while frequent or long term use causes intestinal tumor as side
effect
- Found extensively in various plant species eg. Family Liliaceae, Polygonaceae, Rubiaceae
- Biosynthesized in micro-organism eg. Penicillium and Aspergillus

Aglycone of Anthraquinone Glycoside

c. Saponin
- Possess a soap like behavior in water and produces foam
- Upon Hydrolysis, an aglycone is produced which sapogenin
- 2 types of sapogenin: Steroidal and Triterpenoidal
Steroidal saponin- used in commercial production of sex hormone (example:
progesterone derived from diosgenin)

Triterpenoid saponin- aglycone is tritrpene; most slygcone of triterpenoidal saponin are

pentacyclic compound derived from one of the 3 basic structural classes represented
amyrin, amyrin and lupeol

Usually sugar is attached at C-3 in saponin because in most sapogenin there is a hydroxyl group at
C-3
Used as fish poison causing paralysis of the gills
Exert a powerful hemolytic action on red blood cells and are and are highly toxic when into the
blood stream

d. Cardiac Glycoside
- Exert prominent effect on heart muscle eg. Digotoxin from Digitalis purpurea which is used for
Myocardial contraction and atrioventricular condition
- Aglycone of cardiac glycoside are steroid wide side chain containing unsaturated lactone ring
either 5 member - lactone (cardenolide) or 6 member - lactone (bufadienolide)
- Sugar mainly attached are : digitoxose, cymarose, digitalose, rhamnose and sarmentose
- Digitoxose , cymarose and sarmentose are 2-deoxysugar
- Found only in few plant families example Liliaceae, Apocynaceae
- The sugar part possibly is responsible for binding the glycoside to the heart muscle and the
glycone moiety has the desired effect on the heart muscle once bound

II.
-

Tannins
Heterogenous group of natural product widely distributed in the plant kingdom
Often present in unripe fruits but disappear during ripening
Provides plants with protection against microbial attack
Amorphous substance, which provides colloidal acidic aqueous solution with astringent taste
They form insoluble and indigestible compound with protein and this is the basis of their extensive use in
leathery industry and for the treatment of diarrhea, bleeding gum and skin injuries
2 Types of Tannins
Hydrolyzable- split into simpler molecule upon treatment with acid or enzyme.
Gallotannin-on hydrolysis, yield sugar and gallic acid
Ellagitannin- on hydrolysis, yields sugar, gallic acid and ellagic acid
Condensed complex polymer where the building block are usually catechin and
flavonoid, esterified with gallic acid

III.
-

Flavonoid
Derivative of 1,3 diphenylpropane
Large group of natural product, which are widespread in higher plants but also found in some lower plants
including algae
Yellow compound and contribute to yellow color of the flower and fruit, where they are usually present as
glycoside
Most glycoside and within any one class maybe characterized as monoglycosidic, diglycosidic
Both O- and C-glycoside are common in plant flavonoid
Most flavonoid are potent anti-oxidant compound
Several flavonoid possess anti-inflammatory, antihepatotoxic, antitumor and antimicrobial and antiviral
properties
Many traditional medicine and medicinal plant contain flavonoid as bioactive compound
Some flavonoid are both intermediates in biosynthesis and end product (example: chalcone, flavanone,
flavnon-3-ol, and flavan-3,4-diol

5. Volatile Oils
Definition:
- Complex mixtures of odorous and steam volatile compounds which are deposited by plants in the
subcuticular spaces of glandular hairs, in cell organelles (oil-bodies of Hepaticae), in idioblasts, in excretory
cavities and canals, or exceptionally in heartwoods (Cantoria, 1994).
Occurrence:
- Present in glandular hairs (Labiatae and Compositae)
- Individual oil cells or idioblasts (Piperaceae and Umbelliferae)
- Secreted by cell lining canals or ducts (Pinaceae and Umbelliferae)
- Secreted by cell lining cavities or glands (Myrtaceae and Rutaceae)
- Deposited in heartwoods (Santalaceae and Rosaceae)
Uses:
- Therapeutic actions (Eucalyptus Oils)
- Flavorant (Lemon Oil)
- Perfumery (Santal Oil)
- Starting material for synthesis of other compounds (Turpentine Oil)
- High phenol content; antiseptic property (Clove oil)
- Carminative (Peppermint Oil)
- Antispasmodic activity (Rosmarinus officinalis, Mentha piperita, Matricaria chamomilla, Foeniculum vulgare,
Carum carvi and Citrus aurantium) (Evans, 1989)
Biosynthesis of Volatile Oil Constituents
A. Composition of Volatile Oils
- mixtures of hydrocarbons (monoterpenes and sesquiterpenes), oxygenated derivatives of terpenes, and
nonterpene compounds. In some oils (e.g. Turpentine Oils), the hydrocarbons predominate and only limited
amounts of oxygenated constituents are present.
- Odor and taste are mainly determined by oxygenated constituents which are appreciably soluble in water but
more soluble in alcohol.
- Many volatile oils are terpenoids in origin. Cinnamon and clove oils are aromatic (benzene) derivatives. A few
compounds (thymol and carvacrol), although aromatic in structure are terpenoids in origin. Other classes of
compounds may be present with terpenes in volatile oils such as phenylpropanoids (ex. Cinnamic aldehyde) and
sulfur-containing compounds in the Cruciferae and in Allium. Quantitatively, however, the lower terpene are
characteristic if volatile oils.
B. Terpenoids in Volatile Oils
- this comprise the volatile steam-distillable fraction responsible for the characteristic aroma of many plants
(Harborne, 1984).
2 Classes of terpenes in volatile oils:
(1) Monoterpenes C10 isoprenoids
- b.p. 140 180OC

Subtypes:
(a) Acyclic geraniol, linalool and myrcene

Geraniol

Linalool

Myrcene

(b) Monocyclic -terpineol, limonene, terpinolene, menthol, menthone and carvone

-terpineol

limonene

menthone

terpinolene

menthol

carvone

(c) Bicyclic -pinene, thujone, camphor and fenchone

Alpha pinene

thujone

camphor

(2) Sesquiterpenes C15 isoprenoids

- b.p. > 200OC
Subtypes:
(a) Acyclic farnesol, nerolidol

Farnesol

nerolidol

fenchone

(b) Monocyclic -bisabolene, abscisic acid

Gamma-bisabolene

abscisic acid

(c) Bicyclic - cadinene, -selinene, caryophyllene, carotol

Alpha-cadinene

beta-selinene

caryophyllene

carotol

Methods of obtaining Volatile oils

- Obtained by distillation with the exception of the citrus oils (obtained by expression of the rind) and juniper
oil (obtained by destructive distillation of the heartwood) (Evans, 1989; Tyler et al., 1988).
- The volatile oil stills contain the raw material on perforated trays or on perforated baskets.
- The still contains water at the base which is heated by steam coils, and free steam under pressure may also
be passed in.
- Tough material such as barks, seeds and roots may be comminuted to facilitate extraction.
- The distillate which consists of a mixture of oil and water, is condensed and collected in a suitable receiver
(Florentine flask or large glass jar). The distillate separates into 2 layers, the oil being withdrawn through the
upper outlet and the water from the lower outlet or vice versa in the case of oils heavier than water (ex.
Clove oil). The oil-saturated aqueous layer may be returned to the still or may form an article of commerce
(Rose water and Orange Flower water). Solvent extraction of some volatile oils which cannot be obtained by
distillation may be done based on the Soxhlet principle.
Fractionation and Isolation of Constituents
- Most common are fractional distillation and chemical methods (Kubeczka, 1985).
- By formation of different decomposable and water-soluble derivatives, corresponding to the different
functional groups, a preparative separation of volatile oil into several fractions was achieved. Acids, phenols,
as well as relatively seldom-occurring bases, may be separated by formation of water-soluble salts. Esters
and lactones are hydrolyzed, and the resulting acids may be separated as alkaline salts. Carbonyl
compounds can be isolated after reaction with sodium hydrogen sulfite or Girard reagent; primary and
secondary alcohols can be isolated with phthalic esters. The final separation of the remaining mixture,
consisting of tertiary alcohols, ethers and hydrocarbons, as well as that of the individual fractions, must be
accomplished through physical methods such as fractional distillation, or on the basis of different solubilities.
However, it was recognized that natural terpene mixtures could not be sufficiently separated by fractional
distillation due to the similarity of their boiling points and as a consequence, the formation of crystalline
derivatives was introduced as a separation and purification method.