QSAR by hansch analysis

1. Drug Design Tutorial # 3
Quantitative Structure Activity
Relationships (QSAR) by Hansch Analysis
Tanta university
Faculty of pharmacy
Dept. of Pharm. Chem.
Pharmacy Seniors
2017/2018
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2. CONTENTS
 Introduction
 Hydrophobicity of Molecule
 Hydrophobicity of Substituents
 Electronic Effect
 Steric Effect
 Hansch Equation
 Craig Plot
 Examples
 References
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3. QSAR
 It is said to be a mathematical relationship in the form of an equation
between the biological activity and measurable physiochemical
parameters.
 QSAR approach attempts to identify and quantify the physicochemical
properties of a drug and to see whether any of these properties has an
effect on the drug’s biological activity by using a mathematical equation
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4.  PHYSICOCHEMICAL PROPERTIES
• Hydrophobicity of the molecule
• Hydrophobicity of substituents
• Electronic properties of substituents
• Steric properties of substituents
Activity is expressed as log(1/C).
C is the minimum concentration required to cause a defined
biological response.
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5. QSAR
 A range of compounds is synthesized in order to vary one
physicochemical property and to test it affects the bioactivity.
 A graph is then drawn to plot the biological activity on the y axis versus
the physicochemical feature on the x axis.
 It is necessary to draw the best possible line through the data points on
the graph.
 This done by procedure known as
 linear regression analysis by the least square method
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6. QSAR
 If we draw a line through a set of data points will be scattered on either side of the line.
 The best line will be the one closest to the data points.
 To measure how close the data points are , vertical lines are drawn from each point.
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7. 1 - HYDROPHOBICITY of the molecule
 Hydrophobic character of a drug is crucial to how easily it crosses the cell
membrane and may also important in receptor interactions.
 Hydrophobicity of a drug is measured experimentally by testing the drugs
relative distribution in octanol water mixture.
 This relative distribution is known as partition coefficient.
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8. Linear relationship between Log p and Log 1/C
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9. Non –linear relationship between Log P and Log 1/C 9

10. THE SUBSTITUENT HYDROPHOBICITY
CONSTANT (π)
 Partition coefficient can be calculated by knowing the contribution that various
substituents, is known as substituent hydrophobicity constant(π)
 A measure of a substituent’s hydrophobicity relative to hydrogen
 Partition coefficient is measured experimently for a standard compound such as
benzene with or without a substituent (X).
 The hydrophobicity constant (π x) for sustituent X.
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11.  A possitive p value shows that the substituent is more hydrophobic than
hydrogen
 A negative value indicates that the substituent is less hydrophobic.
 The p value is charecteristic for sustituent.
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12. 12Multiple substituents on a compound: additive treatment

13. 2 - Electronic properties of substituents
 The electronic effect of various sustituents will clearly have an effect on drug
ionisation and polarity.
 Have an effect on how easily a drug can pass through the cell membrane or how
strongly it can interact with a binding site.
 Hammet substituent constant(σ) this is a measure of electron with-drawing or
electron-donating ability of a substituents on an aromatic ring.
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14. 14

15. 15
donating

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17.  σ value depends on inductive and resonance effects
 σ value depends on whether the substituent is meta or para
 ortho values are invalid due to steric factors
 Hammet substituent constant (σ) can only be used for aromatic
substituents
N.B.
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18. Electronic properties of substituents(cont.)

19. 3 - 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.
 Bulky substituent may help to orient a drug properly for maximum
binding and increase activity
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20. Taft’s Steric Factor (Es)
• Measured by comparing the rates of hydrolysis of substituted aliphatic esters
against a standard ester under acidic conditions
Es = log kx - log ko
kx represents the rate of hydrolysis of a substituted ester
ko represents the rate of hydrolysis of the parent ester
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21. Steric effect
Taft steric parameter (Es)
XCH2
O
O CH3
XCH2
O
O
(-) + CH3OH+ H2O
k
Es = log k XCH2COOMe - log k CH3COOMe = log
kx__
kH
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22. Steric effect
Taft steric parameter (Es)
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23. 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
Log1/C = k1 – k22 + k3 +k4Es + k5
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24. HANSCH EQUATION
 1/C : Activity , where C is the concentration of a drug required to elicit a
given response
 Π : octanol/water partition coefficient, a measure of the hydrophobic
bonding power of the drug.
 σ : Hammett substituent constant, which is a measure of the electronic
effect on the rate of reaction.
 Es : Taft steric parameter
Log 1/C = k1 – k22 + k3 +k4Es + k5
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25. HANSCH EQUATION
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26. Craig Plot
Craig plot shows values for 2
different physicochemical
properties for various
substituents
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27. A comprehensive table
compiling some
physicochemical parameters
used in QSAR investigations is
cited below
Substituent  m p Es
-H 0.00 0.00 0.00 0.0
-CH3
0.56 -0.07 -0.17 -1.2
-CH2CH3
1.02 -0.07 -0.15 -1.3
-CH2CH2CH3
1.55 -0.07 -0.13 -1.6
-CH(CH3)2
1.53 -0.07 -0.15 -1.7
-OCH3
-0.02 0.12 -0.27 -0.5
-Phenyl 1.96 0.06 -0.01 -3.8
-NH2
-1.23 -0.16 -0.66 -0.6
-F 0.14 0.34 0.06 [0.4
-Cl 0.71 0.37 0.23 -0.9
-Br 0.86 0.39 0.23 -1.1
-I 1.12 0.35 0.18 -1.4
-CF3
0.88 0.43 0.54 -2.4
-OH -0.67 0.12 -0.37 -0.5
-COCH3
-0.55 0.38 0.50 -1.5
-COOCH3’ 0.01 0.50 0.56 -1.8
-NHCOCH3
-0.97 0.21 0.00 -2.8
-NO2
-0.8 0.71 0.78 -2.5
-CN -0.57 0.56 0.66 -0.5
-N+(CH3)3
-0.25 0.78 0.50 -2.3
-COOH -0.16 0.36 0.45 -1.4
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28. Ex.1
 log l/C = 0.684 log  - 0.921 + 0.268
I) X = CH3
II) X = -CH(CH3)2
III) X = NH2
IV) X = -OH
•1. Antibacterial activity of a group of substituted phenols.
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29. Ex. 2
 log l/C = - 0.081 2+ 1.483  - 1.578
2. Antibacterial activity of a group of substituted diguanidines antibacterial activity:
I) n= 1
II) n = 2
III) n = 3
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30. Ex. 3
 log K = - 0.152 - 1.681 + 4.053 Es + 7.2 12
I) R = CH3
II) R = N+(CH3)3
III) R = OCH3
IV) R = OH
3. Acetylcholinesterase inhibitory activity of phosphonate esters:
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32. Question? 32

33. Answer
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34. REFERENCES
 1. An introduction to medicinal chemistry by Graham L Patric 3rd edition
pagee no:271-298
 2. Foye : Principles of medicinal chemistry
 3. Burgers medicinal chemistry
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