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A) -CF3 (1.07)
B) -Br (0.94)
C) -OCH3 (-0.02)
D) -CH2OH (-1.03)
E) They will all make the drug equally lipophilic
STERIC FACTORS
The bulk, size and shape of a drug will influence how easily it can
approach and interact with binding site.
A bulky substituents may act like a shield and hinder the ideal
interaction between a drug and its binding site.
Examples are:
Tafts steric factor (Es) (~1956), an experimental value
based on rate constants
Disadvantages
(n 2 - 1) mol. wt.
MR = x
(n 2 - 2) density
B4 B3
O B
3
B2
C
H O C O B1
O B
4
L
HANSCH EQUATION
1
Log C = - k1(logP)2 + k 2 logP + k 3 s + k 4 Es + k 5
Craig Plot
Craig plot shows values for 2 different physicochemical
properties for various substituents
. . + 1.0
.. . .
CF3SO 2
. ..
.75
NO2
.
CN SF5
CH3SO2 .50
. ..
SO 2NH2 CF3
.
CH3CO
CONH2
OCF3
.
.25
I
.
CO2H Cl Br
.
-.8 -.4 .4
.
-2.0 -1.6 -1.2 F
.8 1.2 1.6 2.0
-p
. .
CH3CONH +p
. OCH3
-.25 Me Et
t-Butyl
. .
OH
-.50
NMe 2
NH2
-.75
-1.0
-
Allows an easy identification of suitable substituents for
a QSAR analysis which includes both relevant properties
o
Log P Log P
Where
activity expressed as 1/C, C = concentration,
is the Hansch constant (measure of lipophilicty),
is constant related to the given molecule,
is the Hammett substituent constant which is a measure of
the electronic effect.
Es Tafts constant
Hansch Analysis
Look at size and sign for each
component of the equation.
Values of r <<0.9 indicate equation not
reliable
Accuracy depends on using enough
analogs, accuracy of data, & choice of
parameters.
Examples for Hansch equations
Y X
CH CH2 NRR'
1
Log C = 1.22 p - 1.59 s + 7.89
Conclusions:
Activity increases if p is + (i.e. hydrophobic substituents)
Activity increases if s is negative (i.e. e-donating substituents)
For the antibacterial activity of substituted phenols
OH
NH
(CH2)n (NH-C-NH2)2
log 1/C = -0.081 2 + 1.483 1.578
Example: Antimalarial activity of phenanthrene aminocarbinols
CH2NHR'R"
(HO)HC
1
Log C = - 0.015 (logP)2 + 0.14 logP + 0.27 SpX + 0.40 SpY + 0.65 SsX + 0.88 SsY + 2.34
Conclusions:
Activity increases slightly as log P (hydrophobicity) increases
(note that the constant is only 0.14)
Parabolic equation implies an optimum log Po value for activity
Activity increases for hydrophobic substituents (esp. ring Y)
Activity increases for e-withdrawing substituents (esp. ring Y)
Electronic effect
Lipophilicityt
Steric effect