Medicinal

Chemistry-I
Dr. Firoj Ahmed
Professor
Department of Pharmaceutical
Chemistry
University of Dhaka

Introduction
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 structureactivity relationships (SARs).
In particular, Medicinal chemistry also involves
the discovery of new chemical entities for the
treatment of diseases and the systematic study of
the structure-activity relationships of the active
compounds.

Introduction
Such studies provide the basis for development of
better medicinal agents from lead compounds
found via random screening, systematic
screening and rational design.

The science that deals with the discovery or

design of new therapeutic chemicals and
the development of these chemicals into
useful medicine.
Therapeutic chemicals is also called lead compounds

Lead compounds
A lead compound is:
A compound from a series of related compounds
that has a desired biological activity.
This molecule can be characterized, and modified
to produce another molecule with a better profile.
A lead compound is a first foothold on the drug
discovery ladder
It takes much more effort to make a lead
compound into a drug candidate

Drug
Drug is any substance presented for treating, curing
or preventing disease in human beings or in animals.
It may also be used for making a medical diagnosis
or for restoring, correcting, or modifying physiological
functions.

Good vs. Bad Drugs

No medicine has only benefits or drawbacks
Morphine

Excellent analgesic

Addictive, tolerance

Respiratory depression

Barbiturates

Depressants, sedatives, anesthetics

Surgery

Overdoses fatal (Pearl Harbor)

Phenobarbit
al

Good vs. Bad Drugs

Depends on:
Dosage
Almost anything in excess will be toxic
Chronic exposure
Measure of safety of drug = therapeutic
index

Heroin

Diamorphine
One of the best painkillers (hero)
1898: on market
1903: withdrawn (addictive properties)
Today: still used

Therapeutic index
Measure of a drugs beneficial effects at low
dose vs. harmful effects at high dose
Comparison of dose levels which lead to toxic
effects to dose levels which lead to maximum
therapeutic effects
High therapeutic index = large margin of
safety
Marijuana = 1000
Alcohol = 10
Does not take chronic use into account

Classification of drugs
Four main groups (overlap)

1. By Biological Effect
Analgesics, anti-asthmatics, antipsychotics,
etc.
Large and varied assortment of drugs
Many mechanisms of action

2. By Chemical Structure
Penicillins, opiates
Common skeleton
Functions similar or different

Classification of drugs
3. By target system
1. Antihistamines
2. Affect a target system (synthesis, release,
receptor)
3. Variety of structures due to large number of
stages in system

4. By target site of action

4. Anticholinesterases (inhibit
acetylcholinesterase in CNS)
5. Target enzyme or receptor
6. Usually common mechanism

History of Medicinal Chemistry

Prehistoric period
Man has found, by trial and error, which berries, roots,
leaves and barks could be used for medicinal
purposes to alleviate symptoms of illness.
All ancient civilizations made discoveries in this field
Chinese herbal remedies are probably the most well
known
Natural products having a history as folk remedies were in
use.
For example, opium, belladonna, cinchona bark, etc.
Many drugs originally used as folk remedies, now a days,
have been abandoned.

History of Medicinal Chemistry

Early investigations of natural products
In the late eighteenth and early nineteenth centuries,
chemical experimentation led ultimately to its use in the
discovery of new drugs.
In 1853, Henry How conceived the idea that functional
groups in natural products might be modified by chemical
reagents.
He heated morphine with methyl iodide, hoping to convert
the alkaloid to codeine. He obtained, however, a new
substance of the quaternary salt of morphine.

History of Medicinal Chemistry

In 1898, the first commercially available semisynthetic
morphine derivative (codeine) was introduced as a cough
sedative in preference to codeine or other opiates.
Meanwhile, diacetylmorphine was introduced as a safer pain
reliever than morphine. It quickly became popular
throughout the world.
Four years passed before its addictive properties of heroin
were recognized. Laws were later passed by governments
to restrict its use.

History of Medicinal Chemistry

During the 1840s, the first use of synthetic organic
chemicals were introduced for anesthesia during a tooth
removal, such as nitrous oxide, ether, and chloroform.
In 1864, barbituric acid had been synthesized as a
useful hypnotic.
In 1875, salicylic acid was introduced as a possible cure
for typhoid fever as an effective antipyretic.
In 1899, Aspirin was marketed as an antipyretic without
the unpleasant side effects. This indicated that the
chemical structures from natural products were changed
into better drugs.
Medicinal Chemistry began.

History of Medicinal Chemistry

Willow bark and salicylic acid
400 BC: Hippocrates
Chew bark of willow tree for pain (childbirth and
eye infections
The Rev Edward Stone (1760s) searched along a
riverbank (i.e. a cold and wet place) for a plantbased cure for the fevers associated with influenza.
Found that the bark of the
willow was effective in
reducing fever.

Salix alba

Willow bark and salicylic acid

Native American Cherokees used willow bark for such
purposes for centuries.
* willow bark contains salicin
* metabolized in vivo to the active agent salicylic acid

* salicylic acid and more tolerable prodrug aspirin

made in late 19th century
O
O
* mechanism
of action not Odiscovered until the 1970s.
OH
glucose
O

salicin

OH

1. Hydrolysis
2. Oxidation
OH

Salisylic acid
- more effective
- no bitter taste
- gastric bleeding

OH

Ac2O
(1883: Bayer)

Ac
O

Acetylsalicylic acid (aspirin)

- less irritating
- ester hydrolyzes to active drug

History of Medicinal Chemistry

1920s~1930s: Anesthetics, Hypnotics, Analgesics were
used
extensively.
In
research
for
functional
pharmacophore, structure-function relationship was
investigated gradually.
After 1930s: The development of new drugs was speeded
greatly by the close combination of Medicinal Chemistry
and Experimental Pharmacology.
Theory of antimetabolite was formed by using metabolic
products as lead compounds.
Discovery of penicillin which is the first antibiotics is an
epoch-making achievement.
Afterward, tetracycline, streptomycin, chloramphenicol,
erythromycin were introduced one after another.

Quinine

Cocaine
O

South American coca bush

Anesthetic in dentistry

Addiction:

Plant used as a stimulant,

mystical/religious reasons

Isolated 1880s

Used for depression; other

drug addiction

Drug development based on

structure

Procaine

O
N
O

NH2

History of Medicinal Chemistry

In 1940s, the first drug used for treating cancer as a
biological alkylating agent was nitrogen mustard, which
began tumor chemical therapy.
In 1960s, oral steroidal contraceptive agents were
discovered. Corticosteroids have become an important
drugs.
After 1950s, aging disease, cerebrovascular and
cardiovascular diseases became first reason for human death.
New drugs design based on enzymes or receptors as drug
targets.
In 1964, first -Adrenergic blocking agent, Propranolol, was
marketed.
In 1979, Nifedipine, Calcium Channel Blocker was marketed.
In 1981, Captopril, Angiotensin Converting Enzyme (ACE)
Inhibitor was launched.

Early milestones in development of

medicinal chemistry

Causative agents of
TB, cholera, and
anthrax.
Nobel Prize-1905

principles of
vaccination,
microbial
fermentation and
pasteurization;
Germ theory of
diseases

Paul Ehrlich (1854-1915)

The so-called father of modern
chemotherapy.
Original proponent of the magic
bullet he aimed to use chemicals to
treat disease.
In 1910 the first fully synthetic drug
was made: Salvarsan which contained
arsenic!

Used for treating sleeping sickness

(trypanosomiasis) and syphilis (caused by
Treponema pallidum).
The Nobel Prize for Medicine 1908

Future of Medicinal Chemistry

New drugs will be discovered or

invented

by

investigating

human genomics and human

disease genomics.

Drug Discovery

Idea from Nature

Alkaloids from Papavar somniferam

Morphine
Analgesic
Addiction

Codeine
Antitussiv
e
Addiction

Thebaine
Devoid of
activity

Steps of Drug discovery

Choose a disease
Choose a drug target
Identify a bioassayA test used to determine
biological activity.
Find a lead compound (structure that has
some activity against the chosen target, but
not yet good enough to be the drug itself)
Synthesize analogs of the lead
Identify Structure-Activity-Relationships (SARs)
Identify the pharmacophore (the structural
features directly responsible for activity)

Steps of Drug discovery cont.--- Optimize structure to improve interactions

with target
Determine toxicity and efficacy in animal
models.
Determine pharmacodynamics and
pharmacokinetics of the drug.
Design a manufacturing process
Carry out clinical trials

Choosing a Disease
Pharmaceutical

companies

are

commercial

enterprises
Companies will tend to avoid products with a small
market
Companies will also avoid products that would be
consumed by individuals of lower economic status
Most research is carried out on diseases which
afflict

first

world

countries:

(e.g.

cancer,

cardiovascular diseases, depression, diabetes, flu,

migraine, obesity).

Identifying a Drug Target

Drug Target = specific macromolecule, or
biological system, which the drug will interact
with
Example:
Receptors
Enzymes
Ion-channels
Nucleic acids
Known targets: 480 receptors: 45%; enzymes:
28%

Receptor Used as Drug Target

Receptors: Histamin receptor; acetylcholine
receptor; adrenergic receptor; angiotensin
receptor;
dopamine
receptor;
serotonin
receptor; opioid receptor; etc.

Drugs
effecting
Agonist/Antagonist
Receptor
Drug

on

receptors

Receptor Used as Drug Target

Agonist is an endogenous substance or a drug that can
interact with a receptor and initiate a physiological or a
pharmacological
response
(contraction,
relaxation,
secretion, enzyme activation, etc.)
Antagonist is a drug or a compound that opposes the
receptor-associated responses normally induced by
another bioactive agent.
Partial agonist is an agonist which is unable to induce
maximal activation of a receptor population, regardless of
the amount of drug applied.

Enzyme Used as Drug Target

Enzyme: Angiotensin Converting Enzyme (ACE),
Cycloxygenase COX2 -Lactamase,
Acetylcholine Esterase etc.
Drugs effecting on enzyme: Enzyme Inhibitor

Ion Channal Used as Drug Target

Ion Channal: Calcium Ion Channal, Potassium Ion
Channal, Sodium Ion Channal, Chloride Ion Channal,
etc.
Drugs effecting on Ion Channal: Calcium Channal
Blocker, Potassium Channal Blocker, Sodium
Channal Blocker, etc.

Nucleic Acid Used as Drug Target

Nucleic Acid: RNA, DNA

Drugs: antiviral agent,
quinolone agent, etc.

Finding the Lead

Screening Natural Products
Plants, microbes, the marine world, and animals,
all provide a rich source of structurally
complex natural products.

Screening Natural Products

Screening Natural Products

Finding the Lead (cont.)

Screening synthetic banks
Pharmaceutical companies have prepared
thousands of compounds
These are stored (in the freezer), cataloged and
screened on new targets as these new
targets are identified

Finding the Lead (cont.)

Using Someone Elses Lead
Design structure which is similar to existing lead,
but different enough to avoid patent
restrictions.
Sometimes this can lead to dramatic
improvements in biological activity and
pharmacokinetic profile. (e.g. modern
penicillins are much better drugs than original
discovery).

Finding the Lead (cont.)

H2N

NH2

O side effects
Exploitation of
O

sulphanilamide
H N
2

sulphanilamide

glucose levels and diuretic

activity.

(anantibacterialwiththesideeffectof
loweringglucoselevelsinthebloodandalso
diureticactivity)

(anantibacterialwiththesideeffectof
loweringglucoselevelsinthebloodandalso
diureticactivity)
O
NH

NH

mide

NH2

(anantibacterialwiththesideeffectof
O agent with sideAntibacterial
loweringglucoselevelsinthebloodandalso
S NH2
diureticactivity)
sulphanilamide
effects
of lowering blood

H2N

lowerbloodglucoselevels.Usefulinthetreatment
ofTypeIIdiabetes.)

Cl

NH

S O
H2N
O

Chlorothiazide

NH

tolbutamide
beenoptimizedtoonly
els.Usefulinthetreatment
(acompoundwhichhasbeenoptimizedtoonly

O
H2N

Cl

Cl

NH

S
O

Chlorothiazide

(acompoundwhichhasbeenoptimizedtoonlydisp
N
activity.)
(acompoundwhichhasbeenoptimizedto
activity.)

Use structural similarity to a natural ligand

NH2

NH2

N(CH3)2

HO
H3C
N
H

N
H

ydroxytryptamine(5HT)
nin(anaturalneurotransmitter
5Hydroxytryptamine(5HT)
edincertainneuronsintheCNS)
Serotonin(anaturalneurotransmitter

synthesizedincertainneuronsintheCNS)

H
N

H3C

S
O

H
N

S
O

Sumatriptan(Imitrex)
Sumatriptan(Im
Usedtotreatmigrainheadaches
knowntobea5HTUsedtotreatmigrain
1agonist

knowntobea5HT

Serendipity: a chance occurrence

Must be accompanied by an experimentalist who
understands the big picture (and is not solely
focused on his/her immediate research goal),
who has an open mind toward unexpected
results, and who has the ability to use deductive
logic in the explanation of such results.
Example: Penicillin discovery
Example: development of Viagra

Finding a Lead (cont.)

Sildenafil (compound UK-92,480) was synthesized
by a group of pharmaceutical chemists working at
Pfizer's Sandwich, England.
It was initially studied for use in hypertension and
angina pectoris.
Phase I clinical trials suggested that the drug had
little effect on angina, but that it could induce
marked penile erections.
Pfizer therefore decided to market it for erectile
dysfunction, rather than for angina.
The drug was patented in 1996, approved for use
in erectile dysfunction by the FDA in 1998.

Finding a Lead (cont.)

It was the first pill approved to treat erectile
dysfunction in the United States.
It soon became a great success: annual sales of
Viagra in the period 19992001 exceeded $1
billion.

O
N

N
NH

S
O

Viagra
viagra

Structure-Activity-Relationships
(SARs)

Once a lead has been discovered, it is important to

understand precisely which structural features are
responsible for its biological activity (i.e. to identify
the pharmacophore)

Structure-Activity-Relationships
(SARs)

Pharmacophore
The pharmacophore is the precise section of the
molecule that is responsible for biological activity

Pharmacophore
This may enable one to prepare a more active
molecule
This may allow the elimination of excessive
functionality, thus reducing the toxicity and cost of
production of the active material
This can be done through synthetic modifications
Example: R-OH can be converted to R-OCH3 to see if
O-H is involved in an important interaction
Example: R-NH2 can be converted to R-NH-COR to
see if interaction with positive charge on
protonated amine is an important interaction

Improve Pharmacokinetic Properties

Improve pharmacokinetic properties.

pharmacokinetic = The study of absorption,
distribution, metabolism and excretion of a drug
(ADME).

Metabolism of Drugs
The body regards drugs as foreign substances, not
produced naturally.
Sometimes such substances are referred to as
xenobiotics
Body has goal of removing such xenobiotics from
system by excretion in the urine
The kidney is set up to allow polar substances to
escape in the urine, so the body tries to chemically
transform the drugs into more polar structures.

Computer-Assisted Drug Design

If one knows the precise molecular structure of the
target (enzyme or receptor), then one can use a
computer to design a perfectly-fitting ligand.
Drawbacks: Most commercially available programs do
not allow conformational movement in the target (as
the ligand is being designed and/or docked into the
active site). Thus, most programs are somewhat
inaccurate representations of reality.

Exploitation of Side-effects of existing

compounds
IPTD

Exploitation of Side-effects of existing

compounds

Structure - Activity Relationships

The benzene ring should contain one substituent, preferably
in the para position.
The substituents that seem to enhance hypoglycemic
activity are methyl, amino, acetyl, chloro, bromo,
methylthio, and trifluoromethyl groups.
Compounds with p-(-b-arylcarboxamidoethyl) substituents (the
second generation agents) are orders of magnitude better than
the first generation agents.
It is believed that this is because of a specific distance
between the nitrogen atom of the substituent and the
sulfonamide nitrogen atom.

Structure - Activity Relationships

The group attached to the terminal nitrogen should be
of certain size and should impart lipophilic properties
to the molecule.
The N-methyl are inactive, N-ethyl have low activity,
while N-propyl to N-hexyl are most active.
Activity is lost if N-substituent contains 12 or more
carbons.

Exploitation of Side-effects of existing

compounds

Astwood E.B. used it in 1943 as therapy of Graves'

disease for the first time. It remains in use.
Thiouracil inhibits thyroid activity by blocking the
enzyme thyroid peroxidase. Its use in recent times has
been replaced by advent of more potent and safer
antithyroid drugs.

PropylthiouracilPropylthiouracil does not

reverse hyperthyroidism as rapidly as
methimazole and it has more side effects.
Because of its potential for liver damage, it
is used only when methimazole or
carbimazole are not appropriate.
Methimazole is usually preferred over
propylthiouracil because it reverses
hyperthyroidism more quickly and has fewer side
effects. Methimazole can be taken once per day.

Carbimazole is a pro-drug as after absorption it is

converted to the active form, methimazole.
Methimazole prevents thyroid peroxidase enzyme from
coupling and iodinating the tyrosine residues on
thyroglobulin, hence reducing the production of the
thyroid hormones T3 and T4 (thyroxine).

Molecular Modification to Improve the

Therapeutic Properties of Cocaine

local anesthetic, but

bad effect on the
central nervous system

retains the local

anesthetic property

Anesthetics Obtained through Molecular

Modification

Replacing the ester linkage of procaine with an amide

linkage led to procainamide hydrochloride

Active as a cardiac depressant

Active as a local anesthetic
Used clinically as an antiarrhythmic

Molecular Modification of Morphine

Morphine and all the compounds prepared by

molecular modification of morphine have a
structural feature in common

Molecular Modification of Codeine

Dextromethorphan is the major ingredient in most

cough medicines

Random Screening
The lead compound for the development of most drugs
is found by screening thousands of compounds randomly

A random screen is a search for a pharmacologically

active lead compound without any information about
what structures might show activity

Many drugs exert their physiological effects by binding

to a specific cellular binding site called a receptor

Excess histamine in the body causes the symptoms

associated with the common cold and allergic responses

Antihistamines alleviate the action of histamine by

binding to the histamine receptor

Acetylcholine is a neurohormone that enhances

peristalsis, wakefulness, and memory

Cholinergic receptors are structurally similar to the

histamine receptors

The antihistamine diphenhydramine has been used to

treat insomnia and motion sickness

4-Methylhistamine is used as a lead compound to

develop antiulcer drugs

In screening modified compounds, it is possible to find a

compound with completely different pharmacological
activity than the lead compound

an antibiotic

a drug with
hypoglycemic activity

Molecular modification of promethazine leads to the

discovery of an antipsychotic drug

Drugs as Enzyme Inhibitors

Penicillin destroys bacteria by inhibiting the enzyme that
synthesizes bacterial cell walls

Bacteria develop resistance to penicillin by secreting

penicillinase which destroys pencillin

penicillinase

penicillinase

penicillinase

Chemists have developed drugs that inhibit penicillinase

Administering penicillin and the sulfone in combination

results in drug synergism

Bioisosteric replacements
Bioisosteric groups (bioisosteres) are substituents or
functional groups with related physical (or chemical)
properties that give rise to similar biological
properties in a compound.
The purpose of making an isosteric replacement is
to find enhanced biological (i.e. greater potency,
less toxicity etc.) and / or physical properties in a
compound, but without making significant changes
to the chemical structure. Isosteric replacements
may modulate molecular size, conformation, Hbonding, pKa, solubility and stability etc.

Bioisosteric replacements

Bioisosteres - examples
Making isosteric replacements were key steps in the
development of the H3-(histamine) receptor antagonist
cimetidine (7) from the initial starting point of
burimamide (1).

Burimamide is a very potent drug, but orally inactive due

to the fact that is very poorly absorbed

Analogues
Analogue design is an alternative to high-throughput
screening (and the other methods discussed) for
discovering a new lead, especially against a known
drug target.
Analogues can be compounds that either:
A. exhibit chemical and pharmacological
similarities, and these may be referred to as direct
analogues;
B. have chemical similarity, but which show
unexpected pharmacological profiles - structural
analogues;
C. exhibit pharmacological similarity but have distinct
chemical structures - functional analogues.

Direct and structural analogues

For direct analogues, a new lead must normally
promise improvements in properties over an existing
drug to be pursued. They are sometimes known as metoo compounds. For example ACE inhibitors:

For structural
analogues
compounds are of no
use unless they have
an
alternative biological
activity. For example:

Functional Analogues
How can functional analogues be designed (discovered
in a nonrandom fashion)? The central core of a drug
molecule, the scaffold, may be modified quite
drastically to produce a functional analogue if the
essential activity-determining groups of the drug are
retained.

Scaffold hopping (or scaffold morphing) is a

technique that use computational algorithms (i.e. a
computer programme) to identify scaffolds from a
virtual library of molecules or molecular fragments.

Identification of a pharmacophore
We have defined a lead compound as a compound
from a series of related compounds.... The question
is therefore posed what are the essential structural
elements for biological activity?

Prodrugs
A prodrug is drug which is given (taken) in an inactive form. Once
administered,the prodrug is metabolized by the body into the
biologically active compound. Prodrug strategies are used to
overcome a variety of problems by:
1. altering solubility
Making a compound either more or less soluble may assist in
achieving the
desired formulation
2. improving membrane permeability
Absorption into a cell means crossing a hydrophobic cell
membrane. If a drug is too polar drugs it may not pass the
membrane, but too non-polar and it may not come back out!
3. Slow release of the active agent
If a drug is eliminated from the body quickly then an effective
dosage cannot be sustained. Slow release of the active agent by
controlled release from a prodrug allows a more controlled dosage
of the active being released into the body.
4. Masking drug toxicity or side effects
Many anticancer agents are cytotoxic, but it is the cancerous cells
only which we want to kill. Masking toxicity can be achieved by

Prodrugs - examples
1. The antibiotic chloramphenicol is very bitter, but the
palmitate ester does not get absorbed by the tongue so
much when taken orally and so is more palatable. The
succinate ester on the other hand makes it more soluble
making IV formulation more effective. Once absorbed the
esters are quickly hydrolysed.

2. The ACE inhibitor enalaprilat is potent in vitro, but is

poorly absorbed and so not very effective in vivo. The ethyl
ester enalapril, is absorbed much better, hydrolyzed to the
carboxylic acid by esterase enzymes in the blood.

Drug-receptor Interaction
The ability of a drug to get bound to a receptor is termed as the affinity of the drug for the receptor.

The receptors are also dynamic in nature and have a special chemical
affinity and structural requirements for the drug. Thus, affinity
represents kinetic constants that relate to the drug and the receptor.
The drug elicits a pharmacological response after its interaction with
the receptor.
A given drug may act on more than one receptor differing both in
function and in binding characteristics (non-selective drugs).
There are also many factors effect changes in receptor concentration
and/or affinity.
A drug, which initiates a pharmacological action after combining with
the receptor, is termed agonist.
Drugs which binds to the receptors but are not capable of eliciting a
pharmacological response produce receptor blockage, these
compounds are termed antagonists.
84

Structural features of drugs and

their pharmacological activity
Stereochemistry: Space arrangement of the atoms or threedimensional structure of the molecule.
Stereochemistry plays a major role in the pharmacological
properties because:
(1) Any change in stereospecificity of the drug will affect its
pharmacological activity
(2) The isomeric pairs have different physical properties (partition
coefficient, pka, etc.) and thus differ in pharmacological
activity.
The following steric factors influence pharmacological activity:
Optical and geometric isomerism
Conformational isomerism
85
Isosterism and bioisosterism

Structural features of drugs and

their pharmacological activity
I-Optical and geometric isomerism and
pharmacological activity
Optical isomers are compounds that contain at least
one chiral carbon atom or are compounds that differ
only in their ability to rotate the pollarized light.
The (+) or dextrorotatory: isomer rotates light to the right
(clockwise). The (-) or levorotatory: isomer rotates light
to the left (counterclockwise).

86

I-Optical and geometric isomerism

and pharmacological activity
H3C

CH3
H
OH

CH3
H

CH3

OH
2-Hydroxybutane enantiomers (mirror images can not superimposed)

Enantiomers (optical isomers) can have large differences in

potency, receptor fit, biological activity, transport and
metabolism.
For example, levo-phenol has narcotic, analgesic, and
antitussive properties, whereas its mirror image, dextrophenol, has only antitussive activity.
87

I-Optical and geometric isomerism and pharmacological activity

Geometric isomerism (cis-trans isomerisms).

Occur as a result of restricted rotation about a chemical bond,

owing to double bonds or rigid ring system in the molecule.
They are not mirror images and have different physicochemical
properties and pharmacological activity. Because different
distances separate the functional groups of these isomers.
They generally do not fit to the same receptor equally well and if
these functional groups are pharmacophores the isomers will
differ in biologic activity.
For example, cis-diethylstilbestrol has only 7% of the oestrogenic
activity of trans- diethylstilbestrol
OH

HO

OH

Cis-die thylstilbestrol

HO
Trans -die thylstilbestrol
88

II- Conformational isomersim and

pharmacological activity
Conformational isomersim is the non-identical space arrangement
of atoms in a molecule, resulting from rotation about one or more
single bonds.
Almost every drug can exist in more than one conformation and thus
the drug might bind to more than one receptor but a specific
receptor site may bind only to one of many conformations of a
drug molecule.
For example, the trans conformation of acetylcholine binds to the
muscarinic receptor, where as the gauche conformation binds to
the nicotinic receptor.
N
H

(CH3) 3
H

H
OAc
Trans

N
H

(CH3) 3
H

OAc
H
Gauche

Conformations of acetylcholine

89

III- Isosterism, Bioisosterism and

pharmacological activity
Isosterism: Any two ions or molecules having an identical number
and arrangement of electrons
(e.g. CO and NO2;
-

CO2(O=C=O) and N2O ( N=N+=O

N= N+ O) ;

and N-3 and NCO- etc.).

Bioisosterism is the procedure of the synthesis of structural
analogues of a lead compound by substitution of an atom or a group
of atoms in the parent compound for another with similar electronic
and steric characteristics.
Bioisosetres are functional groups which have similar spatial and
electronic character, but they retain the activity of the parent.
Bioisosterism is important in medicinal chemistry because:
1-Maintain similar biological properties.
90

III- Isosterism and pharmacological

activity
Friedman defined bio-isosterism as- the
phenomenon by which compounds usually fit the
broadest definition of isosteres and possess the same
type of biological activity.
E.g. (Antihistamine; A; B and C)

CH3

CH2 CH3
CHO CH2 CH2

CHO CH2 CH2

CHO CH2 CH2 N

CH3

CH2 CH3

Compound A has twice the activity of C, and many times greater than B
91