INTRODUCTION TO MEDICINAL CHEMISTRY

1. Introduction to Medicinal Chemistry

2. • As defined by IUPAC, medicinal chemistry is a chemistry-based discipline, involving aspects of biological,
medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification
and preparation of biologically active compounds, the study of their metabolism, the interpretation of their
mode of action at the molecular level and the construction of structure-activity relationships (SAR), the
relationship between chemical structure and pharmacological activity for a series of compounds.
• Medicinal chemistry is central to modern drug discovery and development. For most of the 20th century, the
majority of drugs were discovered either by identifying the active ingredient in traditional natural remedies,
by rational drug design or by serendipity.
• Medicinal chemistry has advanced during the past several decades from not only synthesizing new
compounds but to understanding the molecular basis of a disease and its control, identifying biomolecular
targets implicated as disease-causing and ultimately inventing specific compounds that blocks the
biomolecules from progressing to an illness or stop the disease in its tracks.
Introduction

3. Medicinal chemists use structure-activity relationships to improve the hits into lead candidates
by optimizing their selectivity against the target and reducing their activity against nontargets, and
ADME to understand how the body causes drug clearance, what’s involved in drug distribution, and
the nature of the molecules that control those factors.
Medicinal chemistry covers the following stages:
• In the first stage new active substances or drugs are identified and prepared from natural sources,
organic chemical reactions or biotechnological processes. They are known as lead molecules.
• The second stage is optimization of lead structure to improve potency, selectivity and to reduce
toxicity.
• Third stage is development stage, which involves optimization of synthetic route for bulk production
and modification of pharmacokinetic and pharmaceutical properties of active substance to render it
clinically useful.

4. • Modern drug design, compared with the classical approach-let’s make a change on an
existing compound or synthesize a new structure and see what happens-continues to
evolve rapidly as an approach to solving a drug design problem.
• A good understanding of how the drug is transported into the body, distributed throughout
the body compartments, metabolically altered by the liver and other organs, and excreted
from the patient is required, along with the structural characteristics of the receptor.
• With the isolation and structural determination of specific receptors and the availability of
computer software that can estimate the three-dimensional shape of the receptor, it is
possible to design molecules that will show an optimum fit to the receptor.

5. History and Evolution of Medicinal Chemistry
Just as in all fields of science, the history of medicinal chemistry is comprised of the ideas, knowledge, and
available tools that have advanced contemporary knowledge. To place the development of medicinal chemical research into
its proper perspective, one needs to examine the evolution of the ideas and concepts that have led to our present knowledge.
Drugs of Antiquity
• The oldest records of the use of therapeutic plants and minerals are derived from the ancient civilization of the Chinese,
the Hindus, the Mayans of Central America and the Mediterranean peoples of antiquity.
• The Emperor Shen Nung (2735 BC) compiled what may be called a pharmacopoeia, including ch’ang shang, an
antimalarial alkaloid and ma huang, from which ephedrine was isolated.
• Chaulmoogra fruit was known to the indigenous American Indians, and the ipecacuanha root containing emetine was
used in Brazil for the treatment of amebiasis.
• The early explorers found that the South American Indians also chewed cocoa leaves and used mushrooms as
hallucinogens. In ancient Greek apothecary shops could be found herbs such as opium, squill, hyoscyamus and viper
toxin and such metallic drugs as copper and zinc ores, iron sulfate, and cadmium oxide.

6. The Middle Ages
• The basic studies of chemistry and physics shifted from the Greco-Roman to the Arabian alchemists between the
thirteenth and sixteenth centuries. Paracelsus (1493-1541) glorified antimony and its salts in elixirs as cure-alls in the
belief that chemicals could cure disease.
The Nineteenth Century Age of Innovation and Chemistry
• The nineteenth century saw a great expansion in the knowledge of chemistry, which greatly extended the herbal
pharmacopoeia that had previously been established.
• Building on the work of Lavoisier, chemists throughout Europe refined and extended the techniques of chemical
analysis.
• The synthesis of acetic acid by Kolbe in 1845 and of methane by Berthelot in 1856 set the stage for organic chemistry.
Pharmacognosy, the science that deals with medicinal products of plant, animal or mineral origin, in their crude state,
was replaced by physiological chemistry. The emphasis was shifted from finding new medicaments from the vast world
of plants to finding the active ingredients that accounted for their pharmacological properties.
• The isolation of morphine by Serturner in 1803, of emetine from ipecacuanha by Pelletier in 1816, and his purification
of caffeine, quinine and colchicine in 1820 all contributed to the increased use of pure substances as therapeutic agents.

7. • As a result of these discoveries and the progress made in organic chemistry, the pharmaceutical industry came
into being at the end of the nineteenth century.
The Twentieth 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 Domagk reported that the red dyestuff 2,4-
diaminoazobenzene-4’-sulfonamide (Prontosil) dramatically cured dangerous, systemic Gram-positive bacterial
infections in man and animals.
• Together with the discovery of penicillin by Fleming in 1929 and its subsequent examination by Florey and
Chain in 1941, this led to a water soluble powder of much higher antibacterial potency and lower toxicity than
those 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.