Structure

Activity
Relationship

19/08/2024 1
Structure activity
relationship (SAR)

• SAR is the relationship between the chemical or 3D

structure of a molecule and its biological activity. or
• The analysis of the dependence of biological effects
of a chemical upon its molecular structure.
• Molecular structure and biological activity are
correlated by observing the results of systematic
structural modification on defined biological
endpoints.

19/08/2024 2
• Determination of the chemical groups responsible
for evoking a target biological effect in the
organism.

19/08/2024 3
 Biological
response

Crude drug Structure Receptor Ligand binding

4
19/08/2024 4
History- Brown and Fraser
in 1869
• They showed that many compounds containing
tertiary amine groups became muscle relaxants
when converted to quaternary ammonium
compounds.
• This hypothesis was later rejected.
• states “Molecules that block the effects of natural
neurotransmitters (antagonists) generally are larger
in size than the native compound.”
• Both agonists and antagonists share common
structural features.
• Composition and arrangement of chemical
functional groups, determines the type of
pharmacologic effect ,it possesses.
WHY SAR Exist?

• The interaction of the drug molecule with protein depends

on its chemical structure

NEED OF SAR STUDY

• A study of the structure–activity relationship is mainly

done by lead molecule.
• It is used to determine pharmacophore, to remove
unwanted side effects
• To develop a new drug that has increased activity.

19/08/2024 8
 Cont.…..

• To determine some different activity from an

existing drug

• Discovery of new drugs

• To know the changes in pharmacological properties

by performing minor changes in the drug molecule

19/08/2024 9
 SAR studies

Chemical compound

screening

Lead molecule

pruning

Pharmacophore

19/08/2024 10
 Screening
Screening is the systematic examination of a chemical
molecule to identify the lead molecule.

Methods of screening:

1. Identification by Random screening.

2. Identification by Non-Random screening.
3. Identification by drug metabolism
studies.

19/08/2024 11
 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

19/08/2024 12
 Identification by drug metabolism studies:

azo reductase

Prontosil Sulphanilamide

19/08/2024 13
 Pruning:

Pruning is the refinement of lead structure.

It is done to determine the pharmacophore.

Pharmacophore:

A pharmacophore is a spatial arrangement

of functional groups essential for biological
activity. It is a pattern that emerges from a
set of molecules with a common biological
activity.
19/08/2024 14
 Morphine Levorphanol

A
B D
B A C
E

D
C

Meperidine
Benzomorphan
D
D
B
A

A
19/08/2024 15
These SAR studies are done through Analog Approach.

ANALOG APPROACH:
1. Homologs.
2. Molecular fragmentation.
3. Addition of functional groups.
4. Isosteric Replacements.
5. Stereochemistry.
6. Ionisation.

19/08/2024 16
 MOLECULAR FRAGMENTATION:

cocaine tropococaine

19/08/2024 17
 ADDITION OF FUNCTIONAL GROUPS:

Tolazoline Naphazoline
(vasodilator) (vasoconstrictor)

19/08/2024 18
 ISOSTERIC REPLACEMENTS:

1.

5-Fluorouracil
Uracil

2.

Hypoxanthine 6-mercaptopurine

19/08/2024 19
 STEREOCHEMISTRY:
1.

Pentobarbitol Amobarbitol

2.

causes blindness
tuberculostatic
19/08/2024 Ethambutol 20
 IONISATION:
-
I
S+
HO S

HO
Dimethylsulfonium analog Permanently uncharged sulphide

19/08/2024 21
Molecular Modification to Improve the Therapeutic
Properties of Cocaine

local anesthetic, but retains the local

bad effect on the anesthetic property
central nervous system
19/08/2024 22
Anesthetics Obtained through Molecular Modification

19/08/2024 23
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

19/08/2024 24
 Molecular Modification of Morphine

Morphine and all the compounds prepared by molecular

modification of morphine have a structural feature in
common
19/08/2024 25
19/08/2024 26
 Librium

19/08/2024 27
Structural modification of Librium leads to the generation
of other tranquilizers

19/08/2024 28
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

19/08/2024 29
Antihistamines alleviate the action of histamine by
binding to the histamine receptor

19/08/2024 30
4-Methylhistamine is used as a lead compound to
develop antiulcer drugs

19/08/2024 31
In screening modified compounds, it is possible to find a
compound with completely different pharmacological
activity than the lead compound

e.g.
in 1942 by the chemist Marcel Janbon et al.

an antibiotic a drug with

hypoglycemic activity

19/08/2024 32
 STRUCTURE ACTIVITY
RELATIONSHIP

OF OPIOD

19/08/2024 33
• Mask or remove a functional group
• Test the analogue for activity
• Determines the importance of a
functional group for activity
 RO
Morphine
O
NMe
H
H
HO
Codeine
• R = methyl group
• Codeine It is methyl-
morphine, occurs naturally
in opium, and is partly
converted in the body to
morphine. It is less potent
than morphine (1/10th as
analgesic), also less
efficacious
RO HO

O
O
NMe
H
H NMe
H
HO H
Codeine RO

R=Me
Heterocodeine
5 x activity
 Heroin (Diamorphine,
Diacetylmorphine)
It is about 3 times more potent than morphine;
more lipid soluble, therefore enters the brain more rapidly,
here in brain acetyl group are hydrolysed to produce
morphine ,
but duration of action is similar.
It is considered to be more euphorient (especially on i.v.
injection) and highly addicting
 RO

O
NMe

HO
Morphine R=Ac
3-Acetylmorphine
Decreased activity
• Acetyl masks the polar phenol group
• Compound crosses the blood brain barrier more easily
•Acetyl group is hydrolysed in the brain to form morphine
 HO

NMe
H
H
HO

Dihydromorphine
Increased activity

The alkene group is not important to binding

SAR - Methyl group on nitrogen
SAR OF STEROIDS
Why SAR of
Corticosteroids?
Chemical modifications leads to generation of
derivatives with

• Greater separation of glucocorticoid &

mineralocorticoid activity

• Different potency & duration of action

Cyclopentano perhydro
phenanthrene nucleus
•All contain 21 carbon atoms.
•Steroid nucleus
•α,β substitution
All require 3 keto group and
4,5 unsaturation, carbonyl group in
C20
Glucocorticoid activity requires 11 β hydroxyl(OH) group , an α-
hydroxyl group linked to C17
 Additional unsaturation
of Ring A
Slow
increase in GC metabolism
activity

glucocorticoid/
mineralocorticoid
potency ratio

Enhance
antiinflammatory
Salt retaining activity
effect
decreases
•Increases glucocorticoid activity,
•Enhanced glucocorticoid/ mineralocorticoid
potency ratio.
•Metabolized more slowly than hydrocortisone
 Some structural changes

• Changing single bond between C1 & C2 into the double,

the anti-inflammatory effect enhances and salt & water
effects weakens;
• Cortisone→ prednisone
• Hydrocortisone → prednisolone

• Adding a -CH3 to C6, the anti-inflammatory effect enhances

more;
• Prednisolone→ 6-methyl-prednisolone
9α-chlorination
• 9α-chloro derivative of betamethasone
• Beclomethasone dipropionate
• Increase stabilization
• Increase lipophilicity
• Increase bronchial tissue absorption
• Increase duration of action
 9α-
chlorination
17 α hydroxyl group on ring D-
esterification of the hydroxyl group

Valerate at C17
Propionate at C17
and C21
Substitution group
at C21 with chlorine

IMPORTANT FOR
GC ACTIVITY-
optimal potency
 Changes that increase glucocorticoid
activity

• Additional double bond b/w 1 & 2 carbon

atoms

• Alpha methylation at 6th position

• Alpha fluorination at 9th position

• Substitution at 16th position

In a
nutshell
Advantages
• Increased potency
• Greater selectivity
• Controlled duration of action
• Low toxicity
• Increased stability
• Drug discovery