Patrick: An Introduction to Medicinal Chemistry 5e · © Oxford University Press, 2013 QUANTITATIVE...

© Oxford University Press, 2013

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSAR)

Patrick: An Introduction to Medicinal Chemistry 5e

Chapter 18


1. Introduction

• Aims• To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula• Requirements• Quantitative measurements for biological and physicochemical properties

• Physicochemical Properties• Hydrophobicity of the molecule• Hydrophobicity of substituents• Electronic properties of substituents• Steric properties of substituents

Most commonproperties studied


2. Hydrophobicity of the Molecule

Partition Coefficient P = [Drug in octanol][Drug in water]

High P High hydrophobicity


• Activity of drugs is often related to Pe.g. binding of drugs to serum albumin (straight line - limited range of log P)

• Binding increases as log P increases• Binding is greater for hydrophobic drugs

Log1C⎛ ⎝ ⎞

⎠ = 0.75 logP + 2.30


Log (1/C)

Log P

. .. .. .. ..

0.78 3.82


Example 2 General anaesthetic activity of ethers (parabolic curve - larger range of log P values)

Optimum value of log P for anaesthetic activity = log Po

Log1C⎛ ⎝ ⎞

⎠ = -0.22(logP)2 + 1.04 logP + 2.16


Log Po Log P

Log (1/C)


QSAR equations are only applicable to compounds in the same structural class (e.g. ethers)

• However, log Po is similar for anaesthetics of different structural classes (ca. 2.3)

• Structures with log P ca. 2.3 enter the CNS easily (e.g. potent barbiturates have a log P of approximately 2.0)

• Can alter log P value of drugs away from 2.0 to avoid CNS side effects


Notes:


3. Hydrophobicity of Substituents- the substituent hydrophobicity constant (π)

Notes:• A measure of a substituent’s hydrophobicity relative to hydrogen• Tabulated values exist for aliphatic and aromatic substituents• Measured experimentally by comparison of log P values with log P of parent structureExample:

• Positive values imply substituents are more hydrophobic than H• Negative values imply substituents are less hydrophobic than H

Benzene(Log P = 2.13) Chlorobenzene

(Log P = 2.84) Benzamide(Log P = 0.64)

Cl CONH2

πCl = 0.71 πCONH = -1.492


Notes:• The value of π is only valid for parent structures• It is possible to calculate log P using π values

• A QSAR equation may include both P and π. • P measures the importance of a molecule’s overall hydrophobicity (relevant to absorption, binding etc)•  π identifies specific regions of the molecule that might interact with hydrophobic regions in the binding site

3. Hydrophobicity of Substituents- the substituent hydrophobicity constant (π)

Example:

meta-Chlorobenzamide

Cl

CONH2

Log P(theory) = log P(benzene) + πCl + πCONH = 2.13 + 0.71 - 1.49 = 1.35

Log P(observed) = 1.51

2


4. Electronic Effects 4.1 Hammett Substituent Constant (σ)

Notes:• The constant (σ) is a measure of the e-withdrawing or e-donating influence of substituents• It can be measured experimentally and tabulated

(e.g. σ for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid)

X=H KH = Dissociation constant = [PhCO2-][PhCO2H]

+CO2H CO2 HX X


+

X = electron withdrawing group

XCO2CO2H

XH

X= electron-withdrawing group (e.g. NO2)

σX = log KXKH

= logKX - logKH

Charge is stabilised by XEquilibrium shifts to rightKX > KH

Positive value

4.1 Hammett Substituent Constant (σ)


X= electron-donating group (e.g. CH3)

σX = log KXKH

= logKX - logKH

Charge destabilisedEquilibrium shifts to leftKX < KH

Negative value


+

X = electron withdrawing group

XCO2CO2H

XH


NOTES:

σ value depends on inductive and resonance effectsσ value depends on whether the substituent is meta or paraortho values are invalid due to steric factors



DRUG

N

O

O

meta-Substitution

EXAMPLES: σp (NO2) = 0.78 σm (NO2) = 0.71

e-withdrawing (inductive effect only)

e-withdrawing (inductive + resonance effects)


NO O

DRUG DRUG

NOO

NO O

DRUG DRUG

NOO

para-Substitution


σm (OH) = 0.12 σp (OH) = -0.37

e-withdrawing (inductive effect only)

e-donating by resonance more important than e-withdrawing inductive effect


EXAMPLES:

DRUG

OH

meta-Substitution

DRUG

OH

DRUG DRUG

OH OH

DRUG

OH

para-Substitution


QSAR Equation:

Diethylphenylphosphates(Insecticides)

log1C⎛ ⎝ ⎞

⎠ = 2.282σ - 0.348

Conclusion: e-withdrawing substituents increase activity


XO P

O

OEt

OEt


4.2 Electronic Factors R & F

• R - Quantifies a substituent’s resonance effects

• F - Quantifies a substituent’s inductive effects


4.3 Aliphatic electronic substituents • Defined by σI• Purely inductive effects• Obtained experimentally by measuring the rates of hydrolyses of aliphatic esters• Hydrolysis rates measured under basic and acidic conditions

X= electron donating Rate σI = -ve

X= electron withdrawing Rate σI = +ve

Basic conditions: Rate affected by steric + electronic factors Gives σI after correction for steric effect

Acidic conditions: Rate affected by steric factors only (see Es)

+Hydrolysis

HOMeCH2 OMe

C

O

X CH2 OHC

O

X


5. Steric Factors Taft’s Steric Factor (Es)• Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditionsEs = log kx - log ko kx represents the rate of hydrolysis of a substituted ester

ko represents the rate of hydrolysis of the parent ester • Limited to substituents which interact sterically with the tetrahedral transition state for the reaction• Cannot be used for substituents which interact with the transition state by resonance or hydrogen bonding• May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor)


5. Steric Factors Molar Refractivity (MR) - a measure of a substituent’s volume

MR = (n2-1)

(n2-2) x

mol. wt.density

Correction factor for polarisation

(n=index of refraction)

Defines volume


5. Steric Factors Verloop Steric Parameter

- calculated by software (STERIMOL)- gives dimensions of a substituent

- can be used for any substituent

L

B3

B4

B4 B3

B2B1

C

O

O

H

H O C O

Example - Carboxylic acid


6. Hansch Equation

• A QSAR equation relating various physicochemical properties to the biological activity of a series of compounds

• Usually includes log P, electronic and steric factors

• Start with simple equations and elaborate as more structures are synthesised

• Typical equation for a wide range of log P is parabolic

Log 1C⎛ ⎝

⎞ ⎠ = -k (logP)2 + k2 logP + k3 σ + k4 Es + k51


6. Hansch Equation

Log 1C⎛ ⎝

⎞ ⎠ = 1.22 π - 1.59 σ + 7.89

Conclusions:• Activity increases if π is +ve (i.e. hydrophobic substituents)• Activity increases if σ is negative (i.e. e-donating substituents)

Example: Adrenergic blocking activity of β-halo-β-arylamines

CH CH2 NRR'

XY


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)

Log1C⎛ ⎝ ⎞

⎠ = -0.015 (logP)2 + 0.14 logP + 0.27 ΣπX + 0.40 ΣπY + 0.65 ΣσX+ 0.88 ΣσY + 2.34

6. Hansch Equation Example:Antimalarial activity of phenanthrene aminocarbinols

X

Y

(HO)HC

CH2NHR'R"


Substituents must be chosen to satisfy the following criteria;• A range of values for each physicochemical property studied• Values must not be correlated for different properties (i.e. they must be orthogonal in value) • At least 5 structures are required for each parameter studied

Correlated values. Are any differences in activity due to π or MR?

No correlation in valuesValid for analysing effectsof π and MR.

6. Hansch Equation

Substituent H Me Et n-Pr n-Buπ 0.00 0.56 1.02 1.50 2.13MR 0.10 0.56 1.03 1.55 1.96

Substituent H Me OMe NHCONH2 I CNπ 0.00 0.56 -0.02 -1.30 1.12 -0.57MR 0.10 0.56 0.79 1.37 1.39 0.63

Choosing suitable substituents


7. Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituentsExample:

-σ +π

+σ +π

-σ -π

+σ -π

.-0.25

0.75

0.50

1.0

-1.0

-0.75

-0.50

0.25

-0.4-0.8-1.2-1.6-2.0 2.01.61.20.80.4. . . ..

...

.. . ..

..

.

......

CF3SO2

CF3

Me

Cl Br I

OCF3

F

NMe2

OCH3OH

NH2

CH3CONH

CO2H

CH3CO

CN

NO2

CH3SO2

CONH2

Ett-Butyl

SF5SO2NH2

+π-π

+σ

-σ


• Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties

• Choose a substituent from each quadrant to ensure orthogonality

• Choose substituents with a range of values for each property

7. Craig Plot


8. Topliss Scheme Used to decide which substituents to use if optimising compounds one by one (where synthesis is complex and slow)Example: Aromatic substituents

L E M

ML EL E M

L E M

L E M

See CentralBranch

L E M

H4-Cl4-CH34-OMe 3,4-Cl2

4-But 3-CF3-4-Cl3-Cl 3-Cl 4-CF3

2,4-Cl24-NO2

C -3- F34-NO2

2-Cl3-NMe2 3-CH3 3-CF3

3,5-Cl24-NO2 3-NO24-NMe24-F3-Me-4-NMe2

4-NH2


RationaleReplace H with para-Cl (+π and +σ)

+π and/or +σadvantageous

Favourable πunfavourable σ

+π and/or +σdisadvantageous

Act. Littlechange

Act.

Add second Cl to increase π and σfurther

Replace with OMe(-π and -σ)

Replace with Me(+π and -σ)

Further changes suggested based on arguments of π, σ and steric strain

8. Topliss Scheme


8. Topliss Scheme Aliphatic substituents

L E M

L E L E MM

CH3

i-Pr

H; CH2OCH3 ; CH2SO2CH3 Et Cyclopentyl

END Cyclohexyl

CHCl2 ; CF3 ; CH2CF3 ; CH2SCH3

Ph ; CH2Ph

CH2Ph

CH2CH2Ph

Cyclobutyl; cyclopropyl

t-Bu


8. Topliss Scheme Example

M= More ActivityL= Less ActivityE = Equal Activity

HighPotency

*

-MLEM

H4-Cl3,4-Cl24-Br4-NO2

12345

Biological Activity

ROrder ofSynthesis

RSO2NH2


8. Topliss Scheme Example

**

Order ofSynthesis R Biological

Activity12345678

H4-Cl4-MeO3-Cl3-CF33-Br3-I3,5-Cl2

-LLMLMLM

*

HighPotency

M= More ActivityL= Less ActivityE = Equal Activity

R N N

N

CH2CH2CO2H

N


9. Bio-isosteres

• Choose substituents with similar physicochemical properties (e.g. CN, NO2 and COMe could be bio-isosteres)• Choose bio-isosteres based on most important physicochemical property (e.g. COMe & SOMe are similar in σp; SOMe and SO2Me are similar in π)

π -0.55 0.40 -1.58 -1.63 -1.82 -1.51σp 0.50 0.84 0.49 0.72 0.57 0.36σm 0.38 0.66 0.52 0.60 0.46 0.35MR 11.2 21.5 13.7 13.5 16.9 19.2

Substitu ent C

O

CH3C CH3

CNC CN

SCH3

O

S

O

CH3

O

S

O

NHCH3

O

C

O

NMe2


10. Free-Wilson Approach

• The biological activity of the parent structure is measured and compared with the activity of analogues bearing different substituents• An equation is derived relating biological activity to the presence or absence of particular substituents

Activity = k1X1 + k2X2 +.…knXn + Z

• Xn is an indicator variable which is given the value 0 or 1 depending on whether the substituent (n) is present or not• The contribution of each substituent (n) to activity is determined by the value of kn• Z is a constant representing the overall activity of the structures studied

Method


10. Free-Wilson Approach

• No need for physicochemical constants or tables• Useful for structures with unusual substituents• Useful for quantifying the biological effects of molecular features that cannot be quantified or tabulated by the Hansch method

Advantages

Disadvantages

• A large number of analogues need to be synthesised to represent each different substituent and each different position of a substituent• It is difficult to rationalise why specific substituents are good or bad for activity• The effects of different substituents may not be additive(e.g. intramolecular interactions)

Patrick: An Introduction to Medicinal Chemistry 5e · © Oxford University Press, 2013 QUANTITATIVE...

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Transcript of Patrick: An Introduction to Medicinal Chemistry 5e · © Oxford University Press, 2013 QUANTITATIVE...