Lecture 4

Quantitative Structure–Activity
Relationship (QSAR) Studies

INTRODUCTION

The relationship between chemical structure and

biological activity has always been at the center
of drug research. All of the electronic properties
of a drug are determined by the atomic composition,
shape and size of the drug molecule, in other words,
by its chemical structure.
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1. Hansch Approach

• The substituent hydrophobicity constant, based on partition

coefficients-analogous to Hammet constants:

 x  logPx  logPH
• Where x is the substituent in question and P is the n-
octanol-water partition coefficient. Positif π value indicated
increased liphophilicity of the substituent. Since these
values are additive, P values measured on standard
molecules permit prediction of the hydrophobicity of novel
molecules.

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 H
R C N S
CH3
O
CH3
N
O COOH

H2
benzyl penisiline C

H
ampicilline C

NH2

amoxiciline H
HO C

NH2

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π values
P1 = CH3 – (CH2 ) – OH
P2 = CH3-OH
------------------------------
P2 – P1 = π for -CH2-
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 Quantifying Drug Molecule Electronic Properties:
The Hammet Correlations

There have been many attempts to quantify the

electronic properties of drug molecules. Hammet
correlations were among the first to be used and
represent the classical way of quantifying electronic
properties. The Hammet correlations (Hammet,
1970) express quantitatively the relationship
between chemical reactivity and the electron-
donating or electron-accepting nature of a
substituent.

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The Hammet constituent constant (σ)
was originally defined for the purpose of
quantifying the effect of a substituent on
the dissociation constant of benzoic acid.

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 2. The Hammet Correlations

O O
O O
C C
C C
O O
O O

N N
O O O O H O H
O

Fig. Resonance and field effects of the electron acceptor nitro group and the
electron donor hydroxyl group on the stability (and pKa) of the benzoate ion.
Electron acceptors stabilize the anion while electron donors have the opposite
effect, increasing the electron density in the vicinity of the carboxylate ion and
creating on unfavorable ion-dipole interaction.
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 KX
log 
KH
Where Kx is the dissociation
constant of benzoic acid carrying
substituent X; KH is the dissociation
constant of unsubstituted benzoic
acid. 8
Electron attracting substituent

O
such as C , NO2 , NR3
OH

have a positive σ value.

while electron donating substituent ( -OH, -OCH3,

NH2, -CH3) have a negative σ.
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  
 
CF3
COOH Cl Br

0,4 0,8 1,2 1,6

OH
NH2 CH3

 
 
Two-dimensional Craig plot of sigma(σ)substituent constants versus pi
(π) for aromatic substituents. 10
3. Taft steric parameter (Es)

This parameter was defined as the logarithm of the relative rate of the
acid-catalyzed hydrolysis of a carboxymethyl-substituted compound,
using the rate of hydrolysis of methyl acetate as standard:

Esx = log KXCOOCH3 – log KCH3COOCH3

Where X is the molecule in question. With some correction suggested

by other authors, Es has proven to be useful in quite a few structure-
activity correlations.

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The linear correlation (A) show the dose of substituted penicillins curing 50% of
mice infected by Staphyloccoccus aureus, versus the sum of π values of the
substituents

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The parabolic curve (B) is the bactericidal concentration of alifatic
fatty acids versus the partition coffecients
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