1. An Introduction to Drugs,
Their Action and Discovery
The basic concepts in Medicinal
Chemistry
1.1 Introduction
• Primary objective－ design and discovery of new
compounds that are suitable for use as drugs
• A team of workers－ chemistry, biology,
biochemistry, pharmacology, mathematics,
medicine and computing, amongst others
• Requires of drug discovery or design－ synthesis
of the drug, a method of administration, the
development of tests and procedures to establish
how it operates in the body, and a safety
assessment
• Drug discovery may also require fundamental
research into the biological and chemical
nature of the diseased state.
• Medicinal chemists need to have an outline
knowledge of the above mentioned aspects.
1.2 What are drugs and why do we need new
ones?
• Definition of drug －chemical substances that
are used to prevent or cure diseases in humans,
animals and plants
• Activity － pharmaceutical/pharmacological
effect on the subject, e.g. analgesic or βblocker
• Potency － the quantitative nature of the effect
• The word “Drug” usually defined as agent used
for the psychotic effect by the media or general
public.
• Even the drugs abused have their activity.
• Drugs act by interfering with biological processes,
so no drug is completely safe.
• That is, suitable quantity to cure or excess to be
poisonous! E.g. aspirin, paracetamol can be toxic
if excesses.
• Side effect – unwanted effect usually; however,
they are not always non-beneficial
• For example, the drowsiness side effect of
anti-histamine may help sleep.
• Drug resistance or tolerance (tachyphylaxis)
occurs when a drug is no longer effective in
controlling a medical condition.
• Reasons – induced oxidases in the liver that
are able to metabolize the drug; a special
enzyme induced to metabolize the drug; down
regulated drug receptors
Therapeutic index
• Chemotherapeutic index = Minimum curative
dose /Maximum tolerated dose
• By Ehrlich in search of a safer antiprotozoal
agent in 19th century -- more effective drugs
showed a greater selectivity for the target
microorganism than its host
• Therapeutic index = LD50/ED50
1.3 Drug discovery and design: a
historical outline
• Origin of drugs – natural products from plants,
animals, and/or minerals since ancient time
• Drugs ↔ Poison = pharmakon in Greece, and the
criteria can be ‘quantity’ usually
• Information about usages and toxicity of drugs
were limited by communication until the
invention of printing press in 15th century→
Herbals and Pharmacopeia↑ → drug misuse or
abuse ↑ →→ the ineffective and/or more toxic
preparations removed by the practitioners
Evolution and revolution
• Early 19th – plant extracts and pure isolates
from medicinal plants appearedSome of these
drugs were very toxic
• Late 19th, to find less toxic medicines than
those based on natural sources → synthetic
substances as drugs
• Early 20th synthetics dominated the main
origin of therapeutic drug origins
• Leads – the known pharmacologically active
chemicals used in drug design and
development
• Analogues – the-lead related compounds
Therapeutic index
• Paul Ehrlich and Sacachiro Hata who produced
arsphenamine in 1910 – in the search of more
effective anti-microbiotic agents: Atoxyl,
Arsphenamine (Salvarsan)
Therapeutic index 
Therapeutic index 
Minimum curative dose
Maximum tolerated dose
ED50
LD50
• The term structure–activity relationship (SAR)
is now used to describe Ehrlich’s approach to
drug discovery, which consisted of
synthesizing and testing a series of structurally
related compounds (see Chapter 3).
ONa
As O
OH
H2N
Atoxyl
H2N
NH2
HClx2
HO
As As
Arsphenamine (Salvarsan)
OH
QSAR – quantitative structure–activity
relationship
• 1960s that Hansch and Fujita devised a method
that successfully incorporated quantitative
measurements into structure–activity
relationship determinations
• The most successful uses of QSAR has been in
the development in the 1970s of the antiulcer
agents cimetidine and ranitidine.
• Both SAR and QSAR are important parts of
the foundations of medicinal chemistry.
Concept of Drug Receptor
• In 1905 John Langley proposed that so-called
receptive substances in the body could accept
either a stimulating compound, which would
cause a biological response, or a non-stimulating
compound, which would prevent a biological
response.
• Receptor sites (Chap. 8) usually take the form of
pockets, grooves or other cavities in the surface of
certain proteins and glycoproteins in the living
organism.
• Ligand – The binding of a chemical agent,
referred to as a ligand, to a receptor sets in
motion a series of biochemical events that
result in a biological or physiological effect.
• Stereoelectronic structure: Both as regards
molecular shape and electron distribution, is
complementary with the stereoelectronic
structure of the receptor responsible for the
desired biological action.
• The drug conformation adopted when binds to
the receptor is known as active conformation.
• The section of the structure of a ligand that binds
to a receptor is known as its pharmacophore.
• E.g., the “quaternary nitrogens” that are believed
to form the pharmacophore of the neuromuscular
blocking agent tubocrarine are separated in the
molecule by a distance of 115.3 nm.
H3CO
+ CH3
HO
O
H2C
H
H3C +
N (S)
H
N
H CH3
CH2
(R)
O
OH
OCH3
(+)-Tubocurarine chloride
2Cl-
• Esters and N-substituted amides, for example,
have structures with similar shapes and
electron distributions but N-substituted amides
hydrolyze more slowly than esters.
• However, changing a group or introducing a
group may change the nature of the activity of
O
O
the compound.
R'
R'
O
N
R
H
Amide
R
Ester
O
N
O
N
O
N
H
NH2
Procaine
(anaesthetic)
NH2
Procainamide
(antiarrhythmic)
Membranes
• Drugs normally have to cross non-polar lipid
membrane barriers (see sections 7.2 and 7.3) in
order to reach their site of action. As the polar
nature of the drug increases it usually becomes
more difficult for the compound to cross these
barriers.
HN
N
O
O
N
O
N
Physostigmine
O
Neostigmine
N+
Modern Techniques
• Computerized molecular modeling (1970s) –
allows the researcher to predict the threedimensional shapes of molecules and target,
calculate the binding energy, and reduced the
need to synthesize every analogue of a lead
compound
• Combinatorial chemistry (1990s) – originated
in the field of peptide chemistry but has now
been expanded to cover other areas.
• simultaneous production of large numbers of
compounds, known as libraries, for biological
testing.
• Used for structure–activity studies and to
discover new lead compounds.
• The procedures may be automated.
1.4 Leads and analogues: some
desirable properties
• Bioavailability – Lipinski’s rules to predict a
molecule to be likely orally bioavailable
1. a molecular mass less than 500;
2. a calculated value of log P* less than 5;
3. less than ten hydrogen bond acceptor groups (e.g.
-O- and -N-, etc.);
4. less than five hydrogen bond donor groups (e.g.
NH and OH, etc.).
⃰ P = partition coefficient of octanol/water
Solubility
• Any compounds that are potential drug
candidates have to be soluble to some extent in
both lipid and water.
• Ideal leads and/or analogues have a balance
between their water solubility and their
lipophilicity.
Structure
• The nature of the structures of leads and
analogues will determine their ability to bind
to receptors and other target sites.
• Binding forces between a drug and a receptor –
electrostatic bonds, such as hydrogen bonds
and van der Waals’ forces, ion pair, and
Cl
covalent bond
N
HOOC
NH2
Cl
Melphalan
DNA Alkylating agent
• A major consideration in the selection of leads
and analogues is their stereochemistry.
• It is necessary to pharmacologically evaluate
individual enantiomers as well as any
racemates.
Cl
OH
N
(Z)
(E)
H
N
chloroquine
R=S form
N
HO
HO
7
(potency)
100
(potency)
diethylstilbestrol
OH
Stablility
• Stability after administration and shelf-life
• Three strategies are commonly used for
improving a drug’s in situ stability:
1. modifying its structure; prepare a more stable
analogue with the same pharmacological
activity
2. administering the drug as a more stable
prodrug
3. using a suitable dosage form
Create a more stable analogue
OH
Hydrolysis
N
N
O
O
Pilocarpine
(active)
N
pH=7.4
OH
N
N
N
O
Pilocarpic acid
(inactive)
N
O
O
Carbamate analogue
Forming a complex
• Cyclodextrins are bottomless flower-potshaped cylindrical oligosaccharides consisting
of about 6–8 glucose units. The exterior of the
‘flower-pot’ is hydrophilic in character whilst
the interior has a hydrophobic nature.
• water solubility, bioavailability and
pharmacological action ↑
• ↓ side effects
Prodrug formation
H
N O
P
O N
Cl
Cl
Cyclophosphamide
H
HN O
P
HO N
Cl
Cl
Phosphoramidate mustard
Shelf-life
• Shelf-life is the time taken for a drug’s
pharmacological activity to decline to an
unacceptable level.
• 10 % decomposition is often taken as an
acceptable limit provided that the
decomposition products are not toxic.
• deterioration – microbial degradation and
adverse chemical interactions and reactions
• Adverse chemical interactions between the
components of a dosage form can also be
avoided by the use of suitable excipients.
• Decomposition by chemical reaction – heat,
light, atmospheric oxidation, hydrolysis by
atmospheric moisture and racemization