Medicinal Chemistry :

History & evolution

M. Hatta Prabowo
 Introduction

Medicinal chemistry is best to be

defined as an interdisciplinary
research area incorporating
different branches of chemistry
and biology in the research for
better and new drugs (Drug
Discovery).
Medicinal
Computational
In other words, medicinal Chemistry Chemistry
chemistry is the science, which
deals with the discovery and
design of new and better
therapeutic chemicals and
development of these chemicals
into new medicines and drugs.
 Introduction
According to IUPAC:
Medicinal chemistry it
concerns the discovery,
the development,
identification and
interpretation of mode of
action of biological active
compounds at the
molecular level.
Generally Medicinal Chemists can:
▪ Make new compounds
▪ Determine their effect on biological
processes.
▪ Alter the structure of the compound for
optimum effect and minimum side
effects.
▪ Study uptake, distribution, metabolism
and excretion of drugs.
 Scope Medicinal Chemistry

Medicinal chemistry covers the three stages

It involves: 1. Discovery step: Involving choice of therapeutic target
(receptor, enzyme & target group, cellular or in vivo
• Synthesis model) & identification or discovery and production of
• Structure-Activity new active substances interacting with selected targets.
Relationships (SAR) Such compounds called Lead compound.
• Receptor interactions
• Absorption, 2. An optimization step: Which deals with improvement of
distribution, lead compound. The optimization process takes
metabolism, and primarily into account the increase in potency,
excretion (ADME) selectivity and toxicity

3. Development stage: Whose purpose is continuation of

improvement of pharmacokinetic properties.
 Objective Medicinal Chemistry
Drug discovery Drug design Drug development
(finding a lead)
▪ Identify structure-activity ▪ Patent the drug
▪ Choose a disease. relationships (SARs) ▪ Carry out preclinical trials (drug
▪ Choose a drug target ▪ Identify the metabolism, toxicology, formulation
▪ Identify a bioassay pharmacophore and stability test, pharmacology
▪ Find a lead compound ▪ Improve target studies, etc)
▪ Isolate and purify the lead interactions ▪ Design a manufacturing process
compound if necessary (pharmacodynamics) (chemical and process development)
▪ Determine the structure of ▪ Improve ▪ Carry out clinical trials
the lead compound if pharmacokinetic ▪ Register and market the drug
necessary. properties, ▪ Make money.

Finally Medicinal chemistry includes synthetic & computational aspects of the study of existing drugs and
agents in development in relation to their bioactivities i.e., understandings a SARs (Structure Activity
Relationships).
 What is a Drugs ?
Good (ideal) Drugs : Unfortunately , ideal drug are hard to come by

• Produce only the desire effect Penicillin → allergies

• No side effects Morphine → tolerance, respiratory depression, addiction
• Totally safe Barbiturates → overdose
• Easy to take

Social Drugs : Bad Drugs?

• Cafeine : stimulant, addictive,
overdose possible
• Nicotine : sedative, addictive
• Alcohol : euphoria, depression,
tolerance, liver toxicity.
Heroin → one of the best pain killers
Cocaine →effective anesthetic
Again, what’s the differences?
• Medicine can act as poisons
• Poison can act as medicines
 Drugs Classifications ?
These remedial agents could be classified according to their
origin: Alkaloid

1. Natural compounds: materials obtained from both plant and

animal, e.g. vitamins, hormones, amino acids, antibiotics,
alkaloids, glycosides…. etc.).

2. Synthesis compounds: either pure synthesis or synthesis

naturally occurring compounds (e.g. morphine, atropine, Morphine
steroids and cocaine) to reduce their cost.

3. Semi-synthesis compounds: Some compounds either can

not be purely synthesized or can not be isolated from
natural sources in low cost. Therefore, the natural
intermediate of such drugs could be used for the synthesis
of a desired product (e.g. semi synthetic penicillins). Penicillins
 Drugs Classifications ?
Since there is no certain relation between chemical structure and pharmacological activity therefore, it would
be unwise to arrange all drugs based on their structures or origin. Thus, it is better to arrange the drugs
according to their medicinal use.

Drugs can be classified Based on medicinal :

Paracetamol
1. Pharmacodynamic agents:
Drugs that act on the various physiological functions of the body
(e.g. general anaesthetic, hypnotic and sedatives, analgesic etc.).

2. Chemotherapeutic agents:
Those drugs which are used to fight pathogenic (e.g.
sulphonamides, antibiotics, antimalarial agents, antiviral, Artemisinin
anticancer etc.).
 Drugs can treat different types of diseases:

1. Infectious diseases: Born (transmitted) from person to person by outside agents, bacteria
(pneumonia, salmonella), viruses (common cold, AIDS), fungi (thrush, athletes' foot), parasites
(malaria)

2. Non-infectious diseases: disorders of the human body caused by genetic malfunction,

environmental factors, stress, old age etc. (e.g. diabetes, heart disease, cancer. Haemophilia,
asthma, mental illness, stomach ulcers, arthritis).

3. Non-diseases: alleviation of pain (analgesic), prevention of pregnancy (contraception) ,

anesthesia.
Diseases classification :
 History : Medicine in the antiquity
Chinese medicine: (3500 BC) Egyptian medicine (3000 BC)
Chinese herbs, some of the ingredients are still in use – Papyrus Ebers, 877 descriptions and recipes
today, e.g.
- Reserpine (blood high pressure; emotional and
mental control),
- Ephedrine (Asthma)
 Medicine in the antiquity
Greek medicine (from 700 BC) Roman medicine (from approx. 200 BC):
• illness is no punishment from God, medicine • invention of hospitals
is considered a science • large influence of Greek medicine
• diseases are due to natural causes • Materia Medica: pharmaceutical
• Hippocratic oath descriptions
 The Middle Ages (400 to 1500 AC)
Middle Eastern medicine preserved, systematized and developed the
The basic studies of medical knowledge of classical antiquity, including the major traditions of
chemistry and physics Hippocrates, Galen and Dioscorides.
shifted from the Greco-
Roman to the Arabian
alchemists between the 13th
and 16th centuries.

Paracelsus (1493–1541)
glorified antimony and its
salts in elixirs as cure-alls in
the belief that chemicals
could cure disease.

Folio from an Arabic manuscript The Byzantine embassy of John the Grammarian in 829 to Al-
of Dioscorides, De materia Ma'mun (depicted left) from Theophilos (depicted right)
medica, 1229
 The Middle Ages (400 to 1500 AC)

During the post-classical

era, Middle Eastern
medicine was the most
advanced in the world,
integrating concepts of
ancient Greek, Roman,
Mesopotamian and
Persian medicine as well
as the ancient Indian
tradition of Ayurveda, A B
A. Folio from the "Liber continens" by Al-Razi
while making numerous B"Liber continens", translated by Gerard of Cremona, second half of the 13th century
advances and innovations.

In the beginning of an illness, chose remedies which do not weaken the

[patient's] strength. […] Whenever a change of nutrition is sufficient, do not
use medication, and whenever single drugs are sufficient, do not use
composite drugs. — Al-Razi
 The Middle Ages (400 to 1500 AC)
Ibn Sina is credited with many varied
medical observations and discoveries,
such as recognizing the potential of
airborne transmission of disease,
providing insight into many psychiatric
conditions, recommending use of
forceps in deliveries complicated by fetal
distress, distinguishing central from
peripheral facial paralysis and describing
guinea worm infection and trigeminal
neuralgia.

He is credited for writing two books in

particular: al-Canon fi al Tibb (The Canon
of Medicine), and also The Book of
Healing. His other works cover subjects
including angelology, heart medicines,
and treatment of kidney diseases.
 The 19th Century: Age of Innovation and Chemistry

Friedrich Sertürner in 1803 : morphine isolation

Pharmacognosy, the science
that deals with medicinal
products of plant, animal, or
mineral origin in their crude
state, was replaced by
physiologic chemistry.
Pierre-Joseph Pelletier in 1816 : emetine isolation from ipecacuanha,
and in 1820 purification of caffeine, quinine, and colchicine.
William Withering in the 19th century, using digitalis for the treatment
of edema.

The emphasis was shifted from Albert Niemann in 1860 : cocaine isolation, and in 1864, he isolated the
finding new medicaments from active ingredient, physostigmine, from the Calabar bean.
the vast world of plants to
finding the active ingredients
that accounted for their
pharmacologic properties.
 The 20th Century and the Pharmaceutical Industry
Diseases of protozoal and spirochetal origin responded to synthetic chemotherapeutic agents.

Interest in synthetic chemicals that could inhibit the rapid reproduction of pathogenic bacteria and enable the
host organism to cope with invasive bacteria was dramatically increased when the red dyestuff 2,4-
diaminoazobenzene- 4′-sulfonamide (Prontosil) reported by Gerhard Domagk dramatically cured dangerous
systemic gram-positive bacterial infections in man and animals.
 The 20th Century and the Pharmaceutical Industry

The observation by Woods

and Fildes in 1940

- the bacteriostatic action of

sulfonamide-like drugs is
antagonized by p-
aminobenzoic acid is one
of the early examples in
which a balance of
stimulatory

- inhibitory properties
depends on the structural
analogies of chemicals.
 The 20th Century and the Pharmaceutical Industry
The discovery of penicillin by
Alexander Fleming in 1929 and
its subsequent examination by
Howard Florey and Ernst Chain in
1941:

- led to a water-soluble powder

of much higher antibacterial
potency and lower toxicity than
that of previously known
synthetic chemotherapeutic
agents.

With the discovery of a variety of

highly potent anti-infective
agents, a significant change was
introduced into medical practice.
 Serendipity Drug

Serendipity

▪ The word serendipity means “happy

accident”
▪ Making discoveries, by accident and
sagacity, of things which are not in
quest of
▪ The ability to see significance and find
values of things stumbled upon
▪ An aptitude for making discoveries by
accident
▪ In modern drug discovery,
serendipitous drugs include empirical
discoveries, it is not always unsought
 Serendipity Antibiotics
Penicillin – discovered by Alexander Fleming , Streptomycin –first antibiotic for tuberculosis
in 1928 ; was discovered when a , invented from a random curative trial of TB.
staphylococcus Petridis was left untreated.
 Serendipity Anticancer Drugs

Cisplatin – used as a chemotherapy

for bladder cancer , discovered while
studying E.coli bacteria

Mustin – discovered in 1940 , was Cisplatin

used on enemy in wars which is used
as an anti cancer therapy

Vinblastine – was first discovered

while studying a plant’s anti- diabetic Metotrexate
effect

Methotrexate – was discovered while

studying leukemia

Mustin

Vinblastine
 Serendipity CNS Drugs

Ephedrine – was used in

ancient china for
respiratory relief ,
rediscovered by Ma-
hung for asthma

Lidocaine – was Ephedrine was isolated from this

discovered while plant Ephedrine
studying genes and
enzymes chemical
relation Ephedra

Marinol – was
discovered while
studying the effects of
marijuana
Marinol
 Serendipity Cardiovascular Drugs

Warfarin –anticoagulant, was

discovered in 1920 , prevented
death of northern cattle ; later
used on humans .

Nitro Glycerin – Was used as an

explosive by Alfred Nobel , later
was synthesized to relax blood
vessels

Digoxin- was extracted from

Digitalis while studying toxic
product of foxgloves
 Serendipity Diabetics Drugs

Saccharine –
Discovered by
Fahiberg in 19th
century ; discovered
from the study of
Saccharine
sulfobenzoic acids

Insulin – was
discovered while
studying the structure
of the pancreas
Insulin
 Serendipity Neuro Drugs

Meprobamate – anxiolytic
drug , used for anxiety
disorders , was discovered
while looking for preservative
for penicillin . Discovered by
Frank Berger

Botulinum Toxin- used for

spasms treatment and
dystonia , discovered by
Justine Cerner

Ergotamine – isolated from

ergot fungus by Arthur Stoll ;
used for migraine
 Serendipity Sedative Drugs

Potassium bromide –
oldest widely used
sedative in medicine ,
was discovered as a
substitute for iodine

Viagra – was discovered

while studying a
cardiovascular drug ,
used as a powerful
sexual sedative
KBr
 Effect serendipity in Drug Discovery

Encourages to do more researches

Anti-serendipity factors
Many drugs were discovered, and
interfering with current drug
many are expected to come
discovery system
Starting of antibiotics
Irrelevant trend towards
rational drug design
New era against cancer treatment ;
35.2% anticancer drugs were
Time constriction of clinical
serendipitously discovered Changes
researchers
the focus of research to effective
results
The use of double-blind
placebo control design
Therapeutic field (specially CNS
drugs) is being benefited greatly
History of Drug Discovery and Development
Rational drug discovery and development
Pipeline drug discovery and development
Drug discovery and development
 Summary
Medicinal chemistry is a discipline involved in the development, synthesis, and analysis of drugs
and other bio-active agents. Medicinal chemistry draws from organic chemistry, biochemistry,
pharmacology, and medicine.

Required skills include:

▪ Synthetic organic chemistry skills

▪ Understanding of biology and how drugs work
▪ Analytical instrumentation expertise
▪ Demonstrated interpersonal skills and examples of teamwork
▪ Communication skills, including the ability to write reports, orally present findings, and ability
to communicate with nonscientists as well as different types of scientists