This document discusses structure-activity relationships in drug design and formulation. It introduces Hammett and Hansch plots, which relate reaction rates and biological activity to electronic and physicochemical properties. Modification of lead compounds is explored through changing functional groups, stereochemistry and lipophilicity. Morphine is used as a case study to illustrate how properties like log P, binding groups and stereochemistry impact opioid activity. The conclusion emphasizes the role of medicinal chemistry in understanding disease and developing safer, more effective pharmaceuticals.

1. HAMMETT AND
HANSCH PLOT
IN DRUG
FORMULATION
Presented by Naraino Majie Nabiilah
and Joorawon Svenia
Date: 10th November 2014

2. Table of Content
• Introduction
• Modification of lead compound
• Drug design
– a) Lipophilicity
– b) Electronic effects (Hammett plot)
– c) Steric effects
– d) Hansch analysis
• Morphine as example
• Conclusion
• References

3. Hammett
Louis Plack Hammett (April 1894- February 1987)
was an American physical chemist. He is known
for the Hammett equation which relates the
reaction rates and equilibrium constant for some
classes of organic reactions including substituted
aromatic compounds. He was awarded for his
numerous discoveries in 1961, 1967 and 1975.
Hansch
Corwin Herman Hansch (October 1918- May
2011) was a Professor of Chemistry in USA and
became known for his concept of QSAR, the
quantitative correlation of the physicochemical
properties of molecules with their biological
activities. He is known as the father of computer-assisted
molecule design.

4. INTRODUCTION

5. INTRODUCTION
• SAR is an advance designed to find the relationships
between chemical structure and biological activity of
studied compounds.
• Therefore it is the concept of linking chemical structure to
a chemical property or biological activity including
toxicity.
• The theory of SARs is to produce new drugs with similar
structure and effects as the original one but with having
more potency and improved side-effects.
• Moreover, SARs are essential for toxicological studies on a
compound.
• SARs have been used since long ago to design chemicals
with the commercially wanted properties and thus they are
important while designing drugs as the chemicals with
desired pharmacological and therapeutic activities are
known.

6. INTRODUCTION
• There are various factors that should be considered
while developing the mechanism of SARs, these are:
– the size and shape of the carbon skeleton,
– the nature and degree of substitution and
– the stereochemistry.
• During modifications on a drug analogue, effects on
water solubility, transport through membranes, receptor
binding, metabolism and other pharmacokinetics
properties should be considered.
• Computer assisted molecular modelling helps to solve
this problem by providing accurate targeting.

7. MODIFICATION
OF LEAD

8. MODIFICATION OF LEAD
• Varying size and shape
– Changing the number of methylene groups in chains and
rings
• This increases lipophilicity which results in an increased in activity
• Water solubility is reduced as well as activity
• No selective binding due to micelle formation in aliphatic
compounds
– Increasing or decreasing the degree of unsaturation
• A change in the degree of unsaturation causes an increase in
rigidity, complication of E-Z isomers, more sensitivity and
increased toxicity.
– Introducing or removing a ring system
• This results to an increase in size, shape changes and stability of
structure with the substitution of C=C double bonds.

9. MODIFICATION OF LEAD
• Introduction of new substituents
–New substituents may occupy the same position as
the previous compound but each will have its own
characteristics, pharmacokinetic and
pharmacodynamics properties to the analogue.
• Methyl group
• Halogen group
• Hydroxy group
• Amino group
• Carboxylic group
• Sulphonic group

10. MODIFICATION OF LEAD
• Bioisosterism
– Substituents or groups with chemical and physical
properties.
– Can attenuate toxicity, modify activity of a lead and
– Alter the pharmacokinetics profile of the lead.
– There are two types of bioisosterism:
• Classical isosteres- have same number of atoms and fit
the steric and electronic rules and have similar biological
activity
• Non- Classical isosteres- do not have same number of
atoms and do not fit the steric and electronic rules but
have similar biological activity

11. DRUG DESIGN

12. DRUG DESIGN
• SAR general equation is:
Biological activity = function {parameter(s)}
The following should be considered for drug design
a) Lipophilicity
Partition coefficient (P) and lipophilicity substituent constant
(π) are the two parameters that represent lipophilicity.
i) Partition coefficients (P)
P is used to measure the movement of drug through membranes. The
accuracy of the correlation of drug activity with P depends on the solvent
system used. The equation below shows the relationship between P and drug
activity:
log (1/C) = k1 log P + k2
k1 and k2 are constants and the equation indicates a linear relationship
between the activity of the drug and its partition coefficient.

13. DRUG DESIGN
ii) Lipophilic substituent constants (π)
The lipophilic substituent constant (π) can be calculated to
determine the contribution that different substituents make to
the hydrophobicity of the compound.
π = log PRH – logPRX
PRH : Partition coefficient of the unsubstituted molecule
PRX : Partition coefficient of the molecule carrying substituent
X
+ π value indicates accumulation of compound in organic layer (
Higher lipophilicity of the substituent)
- π value indicates accumulation of compound in aqueous layer (Higher
hydrophilicity of the substituent)

14. DRUG DESIGN
b) Electronic effects
• The activity of a drug is also affected by the distribution of
electrons in the molecule.
• Drugs in unionised form are carried easier through the
membranes compared to drugs in ionised form.
• The Hammett constant is used to quantify the electronic effects.
i) Hammett constant (σ)
σX = log (KBX/KB)
The distribution of electrons in a molecule depends on the nature
of the electron withdrawing or donating group present in that
drug. The Hammett constant calculates the equilibrium and rate
of chemical reactions.

15. c) Steric effects
DRUG DESIGN
(i) Taft steric parameter (Es)
Show the relationship between shape and size of a drug, the dimensions
of its target site and the drug’s activity
(ii) Molar refractivity (MR)
A measure of both the volume of a compound and how easily it is
polarized.
(iii) Other parameters
Van der Waals’ radii
Charton’s steric constants
Verloop steric parameters

16. DRUG DESIGN
d) Hansch analysis
• It tries to relate drug activity to measurable chemical
properties. According to Hansch, drug action is divided into 2
stages:
– Transport of drug to its site of action
– Binding of drug to target site
• Each stage depends on chemical and physical properties of
drug and target site.
• Hansch suggested that biological activity of drug is related to
parameters by the mathematical equation:

17. DRUG DESIGN
• The accuracy of the above equation depends on:
– The number of analogues (n) used; greater n 
more accurate
– The accuracy of biological data used in the
derivation of equation
– Choice of parameter
• Accuracy also depends on values of standard deviation
and regression constant.
• Hansch analysis is used to indicate the importance of a
parameter on a mechanism by which a drug acts.

18. CRAIG PLOTS
• Helps in determining suitable susbtituents to
quickly decide which analogs to synthesize.
• Plots of one parameter against another.
–For example, p vs. s
• Once the Hansch equation has been derived, it
will show whether p or s should be negative or
positive in order to get good biological
activity.

19. MORPHINE

20. MORPHINE
• Morphine, C17H19NO3, is the most abundant of opium’s 24
alkaloids, accounting for 9 to 14% of opium-extract by mass.
• Named after the Roman god of dreams, Morpheus, who also
became the god of slumber, the drug morphine numbs pain,
alters mood and induces sleep.
• Less popular and less mentioned effects include nausea,
vomiting and decreased gastrointestinal motility.
• The three dimensional structure of morphine is fascinating.
• It consists of five rings, three of which are approximately in
the same plane.
• The other two rings, including the nitrogen one, are each at
right angles to the other trio.

21. 1923
MORPHINE
Structure

22. MORPHINE
1923
Structure

23. MORPHINE
1923
Structure

24. Structure

25. Structure

26. Structure

27. Structure

28. T-Shaped molecule
Structure
Log P: 0.89

29. Potential Binding Groups
Functional groups
Carbon skeleton

30. Phenol
Ether
Alcohol
Amine
O
NMe
HO
HO
Potential Binding Groups

31. Phenol
Ether
Alcohol
Aromatic
ring
Alkene
Amine
O
NMe
HO
HO
Potential Binding Groups

32. Structure Activity Relationships
• Mask or remove a functional group
• Test the analogue for activity
• Determines the importance or other wise of a
functional group for activity

33. STRUCTURE ACTIVITY
RELATIONSHIPS
O
NMe
HO
HO

34. O
NMe
HO
STRUCTURE ACTIVITY
RELATIONSHIPS

35. O
NMe
HO
HO
STRUCTURE ACTIVITY
RELATIONSHIPS

36. O
NMe
STRUCTURE ACTIVITY HO
RELATIONSHIPS

37. O
NMe
HO
HO
STRUCTURE ACTIVITY
RELATIONSHIPS

38. SAR - The phenol moiety
R=H Morphine
R=Me Codeine
NMe
Codeine 20% active (injected peripherally)
0.1% active (injected into brain)
O
RO
HO
H
H
Log P: 1.19

39. SAR - The phenol moiety
Notes
Codeine is metabolised in the liver to morphine.
The activity observed is due to morphine.
Codeine is used for mild pain and coughs
Weaker analgesic but weaker side effects.
Conclusion
Masking phenol is bad for activity

40. SAR - The phenol moiety
R=Ac 3-Acetylmorphine
Decreased activity
NMe
O
RO
HO
H
H
•Acetyl masks the polar phenol group
•Compound crosses the blood brain barrier more easily
•Acetyl group is hydrolysed in the brain to form morphine

41. SAR - The 6-alcohol
R=Me Heterocodeine
5 x activity
NMe
O
HO
RO
H
H

42. SAR - The 6-alcohol
Morphine Hydromorphone
NMe
HO
HO
•Activity increases due to reduced polarity
•Compounds cross the blood brain barrier more easily
•6-OH is not important for binding
HO
O
HO
NMe
O
O
NMe
O
Log P: 0.89 Log P: 0.90
Log P: 2.50
Desomorphine

43. SAR - The 6-alcohol
R=Ac 6-Acetylmorphine
Increased activity (4x)
NMe
O
HO
RO
H
H
Log P: 1.55
•Acetyl masks a polar alcohol group making it easier to cross BBB
•Phenol group is free and molecule can bind immediately
•Dependence is very high
•6-Acetylmorphine is banned in many countries

44. SAR - The 6-alcohol and phenol
R=Ac Heroin
Increased activity (2x)
NMe
O
RO
RO
H
H
Log P: 1.58
•Increased lipid solubility
•Heroin crosses the blood brain barrier more quickly
•Acetyl groups are hydrolysed in the brain to generate morphine
•Fast onset and intense euphoric effects

45. SAR - Double bond at 7,8
Dihydromorphine
Increased activity
NMe
O
HO
HO
H
H
Log P: 1.26
The alkene group is not important to binding

46. SAR - Nitrogen
No activity
CHMe
O
HO
HO
H
H
Nitrogen is essential to binding

47. SAR - Methyl group on nitrogen
NR= NH Normorphine
Reduced activity (25%)
+
NR= NMe
-
O
N-Oxide
No activity
NR= N+Me2
No activity
Log P: -1.56
NR
O
HO
HO
H
H
Quaternary
salt
•Normorphine is more polar and crosses the BBB slowly
•Ionized molecules cannot cross the BBB and are inactive
•Ionized structures are active if injected directly into brain
•R affects whether the analogue is an agonist or an antagonist

48. SAR - Stereochemistry
Mirror image of morphine
No activity
H NR
10% activity
Changing the stereochemistry is detrimental to activity
NR
O
HO
HO
H
O
HO
HO
H
H

49. SAR - Important binding interactions
HBD or HBA
van derWaals
NMe
Ionic
(N is protonated)
O
HO
HO
H
H

50. CONCLUSION

51. CONCLUSION
• Medicinal chemistry has and will continue to play an important
role in today's society as it deals with development, synthesis
and design of pharmaceutical drugs.
• These results are then used to give us a better understanding of
diseases as well as giving us ways of preventing and curing
them.
• Although medicinal chemistry is about creating new drugs, the
properties and quantitative structure activity relationships
(QSAR) of existing drugs is important to see if a combination
of these biological properties can be mixed with a new hit to
produce the latest drug that will help fight against various
diseases.

52. CONCLUSION
• As the majority of medicinal chemistry is based around the
discovery of new drugs and development many companies
spend a considerable amount of money and maintaining and
improving their database of information to ensure that each
test is run as efficient as possible.
• Of course, thousands of compounds related to the morphine
structure have been prepared and many without activity, and
no compound has been found to halt the terrible addictive
morphine properties.
• Used correctly, the morphine family is an important class of
analgesics, and their study represents an important
contribution to the understanding of medicinal activity.

53. REFERENCES
• ANON, 2014. Assessment of chemicals. Introduction to (Quantitative)
structure activity relationships [online]. Available from:
http://www.oecd.org/chemicalsafety/risk-assessment/
introductiontoquantitativestructureactivityrelationships.htm
• MCKINNEY, J.D. et al, 2000. Toxicological sciences. The practice of
structure activity relationships (SAR) in toxicology [online], 56(1), 8-17.
Available from: http://toxsci.oxfordjournals.org/content/56/1/8.full
• PARIKH, 2009. Medicinal Chemistry. The SAR & QSAR approaches to
drug design [online]. Available from:
http://faculty.mville.edu/parikhs/courses/chm2004/lecture%20notes/CHM
%202004%20Lectures%20-%20Chapter%204.pdf
• TOROK, B. Medicinal chemistry. SAR and QSAR [online]. Available
from:
http://alpha.chem.umb.edu/chemistry/ch458/files/Lecture_Slides/Lecture_
Chapter_3.pdf [Accessed on 8 November 2014].
• MANIBUSAN, M. et al, 2012. Technical working group on pesticides.
(Quantitative) structure activity relationship [(Q)SAR] guidance
document [online]. Available from:
http://www.epa.gov/oppfead1/international/naftatwg/guidance/qsar-guidance.
pdf

54. REFERENCES
• ANON, 2014. Wikipedia. Louis Plack Hammett [online]. Available
from: http://en.wikipedia.org/wiki/Louis_Plack_Hammett
• ANON, 2014. Wikipedia. Corwin Hansch [online]. Available from:
http://en.wikipedia.org/wiki/Corwin_Hansch
• Medicinal Chemistry- Chapter 3, QSAR of Morphine. Available at:
http://carbon.indstate.edu/rfitch/CHEM%20452/Chapter_3.pdf
• Anon, Morphine Chemistry, Online. Available at:
http://www.emsb.qc.ca/laurenhill/science/morphine.html
• Anon, 2012, A Look at the Morphinan Structure Activity
Relationships of Six Popular Opiates, Online. Available at:
http://opiophilia.blogspot.com/2012/12/opiate-structure-activity-relationship.
html
• Florencio Zaragoza Dörwald : Lead Optimization for Medicinal
Chemists: Pharmacokinetic Properties of Functional Groups and
Organic Compounds