Medicinal ChemistryLecture 6

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.

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.

• 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

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

• The above constants are only valid for substituents on aromatic rings

• But there exists a system for substituents on aliphatic molecules

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

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

• 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.

Molar Refractivity (MR)• A measure of both the volume of the compound

and how easily it can be polarized

• Additive parameter

• 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

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.

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 action2.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

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

• 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).

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

• 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

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.

• 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.

• 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)

• 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.

What is next?

•Receptors and receptor sites