Medicinal Chemistry/ CHEM

458/658
Chapter 3- SAR and QSAR

Bela Torok
Department of Chemistry
University of Massachusetts Boston
Boston, MA

1
 Introduction
• Structure-Activity Relationship (SAR)
- similar structures –similar effects
- more potency or improved side effects

• Quantitative Structure-Activity Relationship (QSAR)

- similar structures –similar effects but uses parameters to
describe the potency
- parameters – anything (related to drug action) that can be
represented by a numerical values

2
 Structure-Activity Relationship (SAR)

• Usually go through minor changes on the lead structure

- the and shape of the carbon skeleton
- the nature and degree of substitution
- stereochemistry

3
 Structure-Activity Relationship (SAR)

• Changing size and shape

- number of methylene groups in chains and rings

- increasing or decreasing the degree of unsaturation

- introducing or removing a ring system

4
 Structure-Activity Relationship (SAR)

• Changing the number of methylene groups

- increases lipophilicity (increased activity)

- decreases water solubility (decreased activity)
- aliphatic compounds – micelle formation – no selective binding

antipsychotic antidepressant

5
 Structure-Activity Relationship (SAR)
• Changing the degree of unsaturation

- increasing – rigidity
- E-Z isomers might complicate the picture
- more sensitivity
- increased toxicity

1 : 30 antipsychotic antidepressant

6
 Structure-Activity Relationship (SAR)
• Introduction or removal of a ring system
- addition – size increase, shape changes (effect mostly
unpredictable
- increasing size – better fills the hydrophobic pocket

- small ring to substitute C=C double bonds - stability

antidepressant

7
 Structure-Activity Relationship (SAR)
• Introduction of an aromatic ring
- increases rigidity, shape changes resistance toward metabolism
might improve

8
 Structure-Activity Relationship (SAR)
• Modifying the ring system of drugs of natural origin
- fine tuning of effect and side effects

more potent less potent

(highly addictive)

equally potent
less potent (less addictive)
(less addictive)
9
 Structure-Activity Relationship (SAR)
• Introduction of new substituents
methyl groups increases lipophilicity
Compound Structure P Analogue Structure P

benzene 135 toluene 490

acetamide CH3 CONH 2 83 propionamide CH3 CH 2 CONH 2 360

urea NH2 CONH 2 15 N-methylurea CH 3NHCONH 2 44

steric hindrance – might block activity

0
1 3.7 10
 Structure-Activity Relationship (SAR)
• Introduction of methyl group
- methyl group on aromatic rings – increased rate of metabolism

- demethylation – easy on heteroatoms, especially on N+, S+

- reduce the rate of metabolism

- reduce unwanted side effects

11
 Structure-Activity Relationship (SAR)
• Introduction of halogens

Mostly F and Cl - C-X bond stability - reactivity

O
H3C
O
CF3 is also very popular CF3
O
HO

O F
O
CH3
N
H
location

12
 Structure-Activity Relationship (SAR)
• Introduction of hydroxyl groups

Mostly to increase hydrophilic character

Phenolic OH is special

13
 Structure-Activity Relationship (SAR)
• Introduction of basic groups

Mostly to increase binding via H-bonding/acid base

interactions

14
 Structure-Activity Relationship (SAR)
• Introduction of COOH and SO3H groups

Mostly to increase binding via H-bonding/acid base

interactions – in vivo salt formation
introduction to small leads – usually changes the activity

SO3H – no significant effect except faster excretion

Other S groups are rare - metabolism

15
 Structure-Activity Relationship (SAR)

• Changes the existing substituents of a lead

isosteres - bioisosteres

16
 Structure-Activity Relationship (SAR)

• Changes the existing substituents of a lead

isosteres - bioisosteres

17
 Structure-Activity Relationship (SAR)

• Case Study: SAR investigation to discover potent geminal

bisphosphonates

first generation

second generation

18
 Structure-Activity Relationship (SAR)
• Case Study: SAR investigation to discover potent geminal
bisphosphonates

19
 Structure-Activity Relationship (SAR)
• Case Study: SAR investigation to discover potent geminal
bisphosphonates

20
 Structure-Activity Relationship (SAR)
• Case Study:
SAR investigation
to discover potent geminal
bisphosphonates

21
 Structure-Activity Relationship (SAR)

• Case Study: SAR investigation to discover potent geminal

bisphosphonates

22
 Quantitative Structure-Activity Relationship
(QSAR)
• QSAR – mathematical relationship (equations)
biological effect vs. physicochemical parameters

- lipophilicity
- electron distribution
- shape
- size
- partition coefficients
- Hammett or Tafts constants

Biological activity = F {parameters (s)}

23
Quantitative Structure-Activity Relationship
(QSAR)
• Regression Analysis

24
Quantitative Structure-Activity Relationship
(QSAR)
• Lipophilic parameters
Partition coefficient

log (1/C) = k1 log P +k2

(1) Toxicity of alcohols to red spiders:

log (1/C) = 0.69 log P + 0.16 r = 0.979, n = 14, s = 0.087

(2) The binding of misc. neutral molecules to bovine serum:

log (1/C) = 0.75 log P +2.30 r = 0.96, n = 42, s = 0.159

(3) The binding of misc. neutral molecules to haemoglobin:

log (1/C) = 0.71 log P +1.51 r = 0.95, n = 17, s = 0.16

(4) Inhibition of phenols on the conversion of P-450 to P-420 cytochromes:

log (1/C) = 0.57 log P +036 r = 0.979, n = 13, s = 0.132

25
Quantitative Structure-Activity Relationship
(QSAR)
• Lipophilic parameters
Partition coefficient – often parabolic

log (1/C) = -k1 (log P)2 + k2log P + k3

26
Quantitative Structure-Activity Relationship
(QSAR)
• Lipophilic parameters
hypnosis (mice) with barbiturates

log (1/C) = - 0.44 (log P)2 + 1.58 log P + 1.93 (r=0.969)

Hansch – logP ~ 2 hypnotic (CNS drug)

27
Quantitative Structure-Activity Relationship
(QSAR)
• Lipophilic parameters

lipophilic substituent constants (π) (or hydrophobic)

contribution of substituents to P

π = logPX – logPH

π = logP(C6H5Cl) – logP(C6H6) = 2.84 – 2.13 = 0.71

π = π (substituent 1) + π (substituent 2) …..+ π (substituent n)

28
Quantitative Structure-Activity Relationship
(QSAR)
• Lipophilic parameters

lipophilic substituent constants (π)

Substituent X Aliphatic systems R-X X O2 N X HO X

-H 0.00 0.00 0.00 0.00

- CH 3 0.50 0.56 0.52 0.49
-F - 0.17 0.14 0.31
- Cl 0.39 0.71 0.54 0.93
- OH - 1.16 - 0.67 0.11 - 0.87
- NH 2 - 1.23 - 0.46 - 1.63
- NO 2 - 0.28 - 0.39 0.50
- OCH3 0.47 - 0.02 0.18 - 0.12

log (1/C) vs π high r and low s – important contributor

29
Quantitative Structure-Activity Relationship
(QSAR)
• Lipophilic parameters
distribution coefficients (D)

ionization
[ HAorganic ]
D=
[ H+aqueous ] + [ A-aqueous ]

for acids log (P/D-1) = pH -pK a

for bases log (P/D-1) = pK a - pH

30
Quantitative Structure-Activity Relationship
(QSAR)
• Electronic parameters

The Hammett constant (σ)

σx = log K x
K
σ x = log K x - log K

σ x = pK - pK x 31
Quantitative Structure-Activity Relationship
(QSAR)
• Electronic parameters

The Hammett constant (σ)

log (1/C) = 2.282 σ - 0.348

32
Quantitative Structure-Activity Relationship
(QSAR)
• Steric parameters

The Taft steric parameter (Es)

k (XCH2COOCH3)
Es = log = k (XCH2COOCH3) - k (CH3COOCH3)
k (CH3COOCH3)

log BR = 0.440Es - 2.204 (n=30; s=0.37; r= 0.886)

33
Quantitative Structure-Activity Relationship
(QSAR)
• Steric parameters

Molar refractivity (MR)

(n2 - 1) M
MR =
(n2 +2) ρ

additive – functional groups

34
Quantitative Structure-Activity Relationship
(QSAR)
• Hansch analysis

drug activity vs. measurable chemical properties

multiparameter approach

two stages: - transport to the site of action

- binding to the target site

log 1/C = k 1 (partition parameter)+k 2(electronic parameter)+k 3 (steric parameter)+k 4

log 1/C = k 1 P - k 2P2 +k 3σ +k 4 Es+ k 5

Quantitative Structure-Activity Relationship
(QSAR)
• Hansch analysis

Accuracy :

- Greater number of analogs – n=5x (x= number of parameters)

- biological data
- the choice of parameters

Use:
- Asses the factors controlling the activity
- predict optimum activity (ideal parameter values)

Sources of parameters
- CRC, CAS, Merck Index, etc.
Quantitative Structure-Activity Relationship
(QSAR)
• Craig plots

Use with Hansch analysis:

log 1/C = 2.67π – 2.56σ + 3.92