1.

INTRODUCTION

Medicinal chemistry:

- One of the oldest branches of chemistry

- But youngest division of organic

At present, the development of a medicinal

compound focuses on: rational design of
synthetic compound:

a) target-selective po

b specific pharmacologically active.

However, medicinal chemistry also includes:

a) Tribal or herbal cures and medicines which

are as old as civilization itself.

b) Besides, the past two decades increased

growth and interest in combining

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 traditional/herbal medicines with modern
analysis and structure manipulation. This has
been claimed to produce effective, safe,
patient-choice, profitable and medically
important compounds.

c) At present about 25% of all current medicines

in the market are derived from plant sources.

2. Objective of the medicinal chemistry:

The students will:

- understand about specific drugs

- increase their awareness on drug discovery
and the history of medicinal chemistry
- realize the fact that historical role of medicinal
chemistry is rooted largely in herbal medicine

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- be able to interpret and understand
medicinally active agents, including their
structure, site of action and effect.
- Understand specific drug-receptor
interactions.

3. Development of a medicinal compound

The main pathways of discovery are|:

i) isolation or imitation of naturally occurring

substances (e.g., antibiotics),

ii) chance observation and random testing (e.g.,

cocaine, digitalis),

iii) research to compare the fundamental nature

of a biological process in health with its altered
function in disease and effect of a drug.

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The first two approaches relay upon herbal
knowledge. Thus, to understand the process,
there is a need link "herbal science" to medicinal
chemistry.

Example:

i) Coca leaves and cocaine provides a good

understanding about the link. The Coca plant has
numerous alkaloids present in its leaves. The
leaves produce overall stimulant effect:

- suppressed hunger
- elevated blood pressure, etc.
- These observations and effects were
predominantly learned from South American
civilizations (mainly farm workers and coal
miners).

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 - Western science looked at the plant,
reasoned and found out active ingredients:
Cocaine, Procaine, Lidocaine and
Novocaine were unveiled.

ii) There are many active ingredients still used in

therapy which were directly extracted from
medicinal plants. Examples of few active
compounds:
- Atropine was isolated from Belladonna/
Datura leaves. Hyoscine (C17H21NO4) was
isolated from Belladonna/Datura leaves.

H H

C C

C C

H H

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 CH2
CH2OH

O
CH3 CH O CO CH

CH2

Hyoscine

- From the bark of Cinchona ledgeriana

quinine (antimalerial drug) was isolated.
- From the root of Raulwolfia at least 17
alkaloids have been isolated. Of them
reserpine is very important. Reserpine has
effect on central nervous system. It is also
used as antihypertensive drug.

Main Aim of medicinal chemistry: I

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- to synthesise a new molecule or already
known molecule by using different chemical
substances.

a) Synthesis of an already known molecule:

- Many modern drugs have been developed by

imitating the naturally occurring chemicals
present in plants/animals.
- Identification and characterization of active
component allowed definition of mechanism
of action, leading to synthesis of improved
agents with greater selectivity, potency,
altered duration of action, etc.
- These chemicals and active ingredients are
complex and require good understanding of
chemistry.

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- Active ingredients designed based on natural
products is still thought to be as the good
basis for developing a drug molecule
- Several compounds isolated from the natural
sources are being produced by synthetic route.

Example:
i) Ephedrine can be synthesized from propionic
aldehyde, bromine, and phenylmagnesium
bromide.

ii) Camphor is obtained from Cinnamomum

camphora, a large evergreen tree found in Asia.
It can also be synthesis by using diethyl oxalate
and 3,3-dimethylpentanoic acid.

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b) Synthesis of a new molecule (analogues to
existing drugs)
Based on a molecule showing some
pharmacological effect, a new and potent
molecule can be synthesized.
e.g. Aspirin can be synthesized from salicylic
acid.

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c) Modification in existing molecule for
better potency, absorption and duration of
action:
Examples|:
i) Benzyl penicillin is short acting, it has
narrow range (can only be used against some
bacteria, typically given by a parenteral route
of administration, because it is unstable in the
hydrochloric acid of the stomach).
ii) Now many semi synthetic penicillins, like
Amoxycillin, Cloxacillin, with longer duration
of action and which can be orally used have
been produced. The latter compounds also
contain the main β-lactam structure present in
Benzylpenicillin.

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d) Design of compounds for a specific
biological function (“Rational design”)
- Synthesis of naturally occurring compounds
or structural analogues
Examples: Levodopa, H2 receptor
antagonists, omeprazole

- Cloning of genes to produce large

biologically active peptides
Examples: cytokines; antibodies
4. Approach for the synthesis of a medicinal
compound
 At first a suitable structure is estimated for
the synthesis. Such structure is expected to
give a pharmacological action.

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  Sometimes groups are changed or modified
in a parent compound showing some
activity.
 Alcohols and carboxylic acid derivatives are
the starting points for several reactions.
 Benzene, toluene and phenol are important
chemicals to produce simple aromatic
compounds.
 Cheap reagents such as water, hydrogen,
sodium hydroxide, sulphuric acid are
important auxiliary materials in chemical
industries.

(extra reading)

5. Relation between the eastern and western

medical substances

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 It is a truth that there is relation between
folk/herbal medicine (of east or west) and
western medicine (modern scientific medicine).
The centuries of tradition have become most
powerful tool in medicinal chemistry to develop
newer and better ways to combat disease.

Synthetic medicines showed "power" to wipe

out certain diseases. As cure after cure was
found, great excitement spread through medical
research. Younger scientists carried out reaches
to synthesize modern drugs. Thus, the scientific
method spawned a new era of medicine.

During this period of change, the notion of

specificity (one disease-one site of action-one
cure) evolved (e.g., smallpox, cholera,
tuberculosis, typhus, etc.). Herbal medicine did

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not fit well into this new theme. Public attitudes
also inclined towards the modern drugs. As a
result, the importance of traditional medicines
declined. A notion was established: there is pill
for every ill.

However, every ill cannot be cured by modern

drugs

 diabetes
 cancer
 heart disease
 viruses

These days, American Medical Association

(AMA) has advised that a part of treatment for
such disease is a well-planned, preventative
health care, conscious and learned dietary habits

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 in parallel with a program of regular aerobic
exercise.

Herbs are not drugs as defined by different

government. The purity, quantity, etc. cannot be
controlled or regulated easily. We are in lack of
an expert of traditional herbal medicine.

The following table shows many modern drugs

and substances derived from herbal source and
associated malady

Herbal Notes/
Malady or Illness
Medicine Comments
Hops Insomnia Found in beer
Reserpine (used
High Blood
Rauwolfia  clinically;
Pressure
dangerous)
Garlic High blood pressure Allicin
Effect probably
Alfalfa/Celery
Arthritis due to vitamins
Seed
present
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 Essential oils
prevent
Peppermint  Mental alertness congestion of
brain blood
supply 
Contains
Cayenne/ Fatigue/sore capsaicin
pepper  throat/viruses (potential anti-
viral)
Contains
Foxglove  "Slow" heart digitalis
(dangerous)
Binds bile acids
Apple pectin High Cholesterol to decrease
absorption
Exhibits
Dandelion
Diabetes  hypoglycemic
(garden flower)
effects
Contains papain
Papaya leaves  Digestion/Worms (proteolytic
enzyme)
Stimulant yet
Fatigue and
Ginseng  anti-stress
infertility (see topic)
(various types)

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Chincona bark  Malaria Has quinine
Overweight/
Coffee  caffeine
inebriated (drunk)
Anti-bacterial
Aloe Vera  Wounds 
present
Contains
Chamomile Menstrual cramps apigenin, a
flavenoid
Contains anti-
Turmeric Pain inflammatory
agents
contains
Valerian Root  Nervous Tension valmane
(sedative)

Although the pure molecules isolated from herbs

are the mainstay of modern medical treatment,
the crude herbs (plant parts) or their extracts are

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being used in herbal/alternative medicine. The
following examples clarify the reason of using
the crude plant materials.

 It can be shown that chewing the coca leaves

has different effects than purified material
(isolated compounds) when compared on an
equal concentration basis.

The difference may be due to

- The route of administration (oral vs. i.v. vs.

nasal) alters the effect.
- The combined effect of different components
may show different pharmacology
(antagonistic, synergistic or just
complementary effect).
- All components are not isolated by our
scientific knowledge and skills

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The scientific observation shows that, chewing
coca leaves cause 70% less addiction/heart
attacks/bp increases than their synthetic or
purified counterparts (Fact).

 Case 1: Ginseng has been used for thousands

of years as an anti-stress and mediator of well-
being. Over 2,000 scientific papers have now
addressed its utility and yet no "single
molecule" has been associated with its
calming effect.

Does this mean Ginseng is false drug? Or, our

western method is not equipped to isolate the
right ingredient. The active principle(s) may be
labile to isolation, may be a combination of
molecules, or may be macromolecular. Thus,

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whatever is present may not be isolated easily. It
may need further attempts.

Case 2: Yarsagumba(Cordycep sinensis) found

in the Mountain region of Nepal is widely
popular in Chinese medicine. Its aphrodiasis and
immunostimulant effects have promoted the use
in other countries also. Yet some chemicals
isolated from it have not shown such effects. It
may need further attempts.
Case 3: Another example could be the garlic
story.
- Aristotal, Hippocrates and Aristophanes
recommended garlic to kill tapeworm and
related intestinal parasites. Albert Schweiter
tecommended it against amoebic dysentry,
cholera and typhus. During last 30 years garlic

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 extract capsules are claimed to be effective for
lowering the the blood pressure.
- Medicinal chemists have isolated several
active compounds but none has shown the
effect against blood pressure. Many molecules
have been found in preventing the aggregation
of blood platelates. The most active is ‘ajoene.
Ajo is the spanish word for garlic.

- Allicin another compound found in garlic kill

bacteria, viruses, parasites, fungi, yeasts,
and molds, including many that cause
serious disease in humans. Garlic
Conclusion:

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i) Thus, before there were modern scientific
approaches to drug therapy, there was herbal
medicine. Relying largely upon trial and error
(often fatal error), cures or least preventative
therapeutic approaches were chosen from among
the rich plant pharmacy.

ii) Sometimes, however, the process by which

herbal medicines were administered has a great
impact upon the medicinal effect. Careful
attention must be paid to the holders of
traditional medicine knowledge when attempting
to bring such important discoveries to the
modern laboratory.
(iii) Modern science has unarguably improved
upon this approach leading to miraculous
chemical cures by using the knowledge, skills
and methods of medicinal chemistry.
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iv) However, continous efforts are needed to
characrerise and identify various ingredient
presnt in the crude drug material, and to identify
the expected biological effect.

C20H24N2O2
Quinine structure, t0.5= 8-14 hrs

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The word 'drug' is derived from the French word
"drogue" which means a dry herb. It was
developed in 14th century. It meant. The word
drug means different things to different people.

 For pharmacists,

- it is a substance described by an official

formulary or pharmacopoeia

- a drug is defined as any substance used for the

purpose of diagnosis, prevention, relief or cure
of a disease in man or animals.
- a substance used medicinally or in the
preparation of a medicine
- a non-food substance used to affect body
function or substance

 According to WHO "a drug is any substance

used in a pharmaceutical product that is

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 intended to modify or explore physiological
system or pathological state for the benefit
of the recipient”.

For chemists, it is a drug substance with definite

structure “showing activity in a biological
screen”.
For pharmacologist, it is an agent showing
action in biological system (even without
structural activity).

For marketting manager, making money.

For patient, difference between life and death.

Medical needs are unmet in the world.

The word ‘drug’ generally refers all medicines
designed to be prescribed by doctors, all raw
materials or pharmaceuticals used for the

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formulation of a medicines. In some countries
legally ‘a drug means a narcotic substance e.g.
heroin, cannabis, opium, cocaine etc.’
Legal definition of "drug" for drug
regulation/control
Drugs Act Nepal, 1978 defines "Drug" as any
substance intended to be used for or in the
diagnosis, cure, mitigation, treatment or
prevention of disease in human beings, animals
or birds or any substance intended to be used for
the destruction of vermin or insects which cause
disease in human being, animals or birds or any
article intended to affect the structure or any
organic function of the body of human beings,
animals or birds or such ingredients or
components intended to be used prepare such
drugs.
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b. What is Medicine:
What is Medicine
Medicine is drug or remedy for use in treating,
preventing, or alleviating the symptoms of
disease. It is an agent or such as a drug, used to
treat disease or injury. If a doctor prescribes
something, for the treatment of a patient that
substance or material is strictly understood as a
medicine e.g. evens a glass of water prescribed
by a doctor is regarded as a medicine. A
medicines should be in a suitable dosage form
e.g. tablet/pill, liquid, capsule, powder, injection,
ointment etc., so that it can be easily
administrated to a patient. Example, tablet of
aspirin is called medicine.

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c. Importance of drugs/medicine
Today as well in the past, drugs have been the
part and parcel of life. When a child is born
drugs are frequently applied. With their help the
human being lives on earth and in most cases,
he/she needs them to depart from this world.

In a sense of good, drugs have been used as

health promotive, disease curative and disease
preventive tools. For example, the widespread
use of iron and folic acid tablets in pregnant
mothers and vitamin A in young children has
been considered to be a health promotive
activity in some Asian Countries. In all
countries, the application of drugs for the
treatment of a vast majority of diseases and their

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symptoms has been a best strategy in the
medical practice. Similarly, for the prevention of
diseases due to possible exposure to the
causative factors in the future, different types of
vaccines have been developed and used
extensively throughout the world.

Today, in all societies, people value drugs and

all countries recognize them as a means of
safeguarding the health of their people.
Throughout the human history, drugs have held
a special fascination. Drugs are related with
sensational stories in exploration, commerce,
political intrigue, scientific discovery, arts and
development. They have directly influenced the
lives of millions.

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