Medicinal Chemistry

1. Medicinal Chemistry
Lecture 6

2. Electronic Effects
• The electronic distribution in a drug molecule
has a considerable influence on the distribution
and activity of the drug.
• Once the drug reaches its site of action, the
electronic distribution will control the type of
bonds it will form with the target, which in turn
affects its biological activity.
• Quantification of the electronic effects of groups
on the physicochemical properties was first
carried out by Hammet.

3. The Hammet Substitution Constant
• Primarily quantifies the electronic effects of substituents
on aromatic rings.
• A measure of electron withdrawing or donating abilities
of substituents
• Has been determined by measuring the dissociation of a
series of substituted benzoic acids compared to the
dissociation of the benzoic acid itself
• Hammet substitution constants are additive.

8. • Table of constants that quantify inductive effect (F) and
resonance effect (R) are available.
• Substituent effect could be mainly attributed to F rather
than R or vice versa.
• A certain substituent may has a more significant effect at
a particular position.
• There are limitations to electronic effects
• There are very few drugs whose activities are solely
influenced by a substituent electronic effects

9. • The insecticidal activity of diethyl phenyl phosphate can
be explained by electronic effects alone

10. • The above constants are only valid for substituents on
aromatic rings
• But there exists a system for substituents on aliphatic
molecules

12. Steric Parameters
• Used to show the relationship between the shape
and size of a drug, the dimension of its drug site
and drug activity
• Taft steric parameter (Es) and molar refractivity
(MR) are the most important size parameters

13. The Taft Steric Parameter (Es(
• Defined on the bases of the relative rate constants of the
acid hydrolyzed α-substituted methyl ethanoates
• These rates of hydrolysis are almost entirely dependent
on steric factors

14. • K is the rate constant of the appropriate hydrolysis
reaction
• E = 0 when X = CH3
• It is assumed that the value of Es obtained for a group
using hydrolysis data are applicable to other structures
containing that group
• Es values are obtained by experiments (disadvantage)
• Limited number of them.

16. Molar Refractivity (MR(
• A measure of both the volume of the compound and how
easily it can be polarized
• Additive parameter

17. • n is the refractive index, MW is the molecular mass, and
P is the density of the compound, MW/P is the volume,
and the refractive index term is a measure of the
polarizability of the compound

18. Other physicochemical parameters
• Include: dipole moments, hydrogen bonding,
conformation and inter atomic distances.
• These are difficult to quantify. Therefore they are
much less useful in comparison with the above
parameters.

19. Hansch Analysis
• Attempt to mathematically relate drug activity to
measurable chemical properties
• Based on Hansch proposal:
Drug action could be divided into two stages:
1.Transport of the drug to the site of action
2.Binding of the drug to the target site
• Both stages are dependent on the chemical and physical
properties of the drug and its target site
• These properties are described by the studied
parameters

20. • Hansch postulated that the biological activity of the drug
could be related to these parameters by simple
mathematical relationships based on the general format:

21. • C is the minimum concentration needed to cause a
specific biological response, K1, K2, K3, and K4 are
numerical constants obtained by feeding the values of
the parameters selected by the investigating team into a
suitable statistical package.
• These parameter values are either obtained from the
literature (e.g. Π, σ, and Es) or determined by
experiments (C, P, etc).

22. • Not all parameters will necessarily be significant
• Example:
The ardegenic blocking activity of β-halo-β-arylamine:

24. • Accuracy of Hansch equations will depend on:
1.The number of analogues used: the greater the number
the higher the opportunity of obtaining an accurate
Hansch equation
2.The accuracy of the biological data used in the derivation
of the equation
3.The choice of the parameter

25. Craig Plot
• Easier way to visualize the properties of different
substituents
• Plot where the y axis is the value of σ factor and the x
axis is the value of π factor.

27. • The plot shows that there is no overall relationship
between σ and π.
• It is possible to tell at a glance which substituents have a
positive σ and π parameters, which substituents have a
negative σ and π, and which substituents have one
positive and one negative σ and π parameters.
• It is easy to see which substituents have a similar π
values. In theory, such substituents which will be on the
same vertical line could be interchangeable on drugs
where the principle factor affecting biological activity is
hydrophobicity.

28. • Groups on the same horizontal line are isoelectronic and
should be exchangable as well (e.g. Cl, Br, I)
• The Craig plot is useful in planning which substituents to
use in QSAR studies. For example:
1. halide substituents (increased hydrophobicity and
electron withdrawing activity, positive σ and positive π)
2. OH (increased hydrophilicity and electron donating
properties, negative σ and negative π)
3. Alkyl groups (positive π and negative σ)
4. Acyl groups (negative π and positive σ)

29. • Once the Hansch equation is derived it will show
whether π or σ should be positive or negative in order to
obtain the desired biological activity.
• Further developments would then concentrate on
substituents from a certain quadrant. For example:
Positive π and σ values in Hansch equation means that
we should focus on the top right quadrant.

30. What is next?
• Receptors and receptor sites