• To design better drugs:

Molecular Mechanism.
Physicochemical Principles of Drug Action

Functional group contributions to the
physicochemical properties.

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Physicochemical Principles of Drug Action

• Drug action results from the interaction of
drug molecules with either normal or
abnormal physiological processes. • The influence of the organic functional groups
• Drugs normally interact with targets (which within a drug molecule on:
they are proteins, enzymes, cell lipids, or
Water solubility.
pieces of DNA or RNA).
Lipid solubility.
• The ability of a chemical compound to elicit a
Partition coefficient.
pharmacologic /therapeutic effect is related to
Acid-base properties.
the influence of its various physical and

Steric factors.
chemical (physicochemical) properties

Stereochemistry.
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 • Pharmacokinetic properties:

Absorption.
• Proper physicochemical parameters ensure
Distribution.
good drug action:
Metabolism.

Pharmacokinetic properties.
Excretion.

Pharmacodynamic properties. • Pharmacodynamic properties:

Drug-receptor interaction:
o Activity.
o Toxicity.
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Water solubility Versus Lipid solubility

• Majority of drugs’ molecules possess balanced

solubility (have some degree of solubility in
both aqueous and lipid media).
• Because there is a need for drugs’ molecules
to move through both aqueous (plasma,
extracellular fluid, cytoplasm, etc.) and lipid
media (biologic membranes) in the biological
system.
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Most Important Intermolecular Attractive
Van der Waals Attraction
forces Involved in Solubilization

• Weakest intermolecular force (0.5-1.0

• Van der Waals attraction. kcal/mole)
• Dipole-dipole attraction. • Electrostatic
• Ion-dipole bonding. • Occurs between nonpolar groups (e.g.
hydrocarbons) .
• Highly distance and temperature dependent.

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Dipole-Dipole Attraction

• Stronger (1.0 to 10 kcal/mole).

• Occurs electrostatically between electron
deficient and electron excessive/rich atoms
(dipoles).
• Hydrogen bonding is a specific example of this
bonding and serves as a prime contributor to
hydrophilicity.

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 Functional Groups Number of Potential H-bonds
R OH 3
H H
O O
H 2
R R`
O
H R NH2 3
H
R NH
N 2
H R`

R N R``
1
R`
O
H H O
R` 4
R O

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O O
Ion-Dipole Bonding
H
O O
H
O
H • Electrostatic between a cation/anion and a
O dipole.
H
less water solube more water solube • Relatively strong (1-5 kcal/mole).
• Low temperature and distance dependence.
• Why does an intramolecular hydrogen
bonding decrease water solubility? • Important attraction between drugs’ molecule
and H2O.
• Because one less interaction with solvent
occurs.
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 • Highly dissociable salts are more water soluble
than less dissociable ones.
• Because the cation and anion must be able to
separate and interact with water molecules.
• Highly dissociable salts are formed from:

strong acids with strong bases.

weak acids with strong bases.

strong acids with weak bases
• Less dissociable salts are formed from:

weak acids with weak bases.
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H3C CH3 H H3C CH3

S COO N S COO
N N Na

HN O O O HN O
O O

NH2

(Water solubility = 1g/250ml) (Water solubility = 1g/40ml)

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 • Why is the amino acid tyrosine less water
soluble than expected?

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COO

N
HO H H
H
• The ionizable functional groups can react with
one another to form a zwitterionic molecule.
• The two opposite charges are sufficiently close
to allow a strong ion-ion interaction to form.
• Thereby keeping each of these groups from
forming ion-dipole interaction with • Solubility of tyrosine in water, aqueous base,
surrounding water molecules. and aqueous acid.
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 Laboratory Estimation of Relative
Prediction of Relative Solubility
Solubility
• The relative solubility of a drug molecule is a
function of the presence of both lipophilic and
• The relative solubility of a drug molecule can
hydrophilic features within its structure, which
be determined in the laboratory.
serve to determine the extent of interaction of
the drug molecule with lipid and/or aqueous • The ratio of the solubility of the compound in
phases. an organic solvent to the solubility of the
same compound in an aqueous is called
• Therefore, the relative solubility of a drug
partition coefficient (P).
molecule is the sum of the contributions of
each group and substituent to overall
solubility.
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• Partition coefficient (P) is a measure of the • Determined in vitro.

solubility of a drug in aqueous and lipid • n-Octanol (lipid phase)
phases.
• Phosphate buffer of pH 7.4 (aqueous phase).
• Simulation.
• P is often expressed as a log value.
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 Mathematical Estimation of Relative Mathematical Estimation of Relative
Solubility Solubility
(i) the molecule is dissected into its various
• Solubility contributions (groups and groups, functionalities and substitutents,
substituents) are expressed as hydrophilic
(ii) appropriate hydrophilic/lipophilic fragment
(negative value) or lipophilic (positive value)
constants are assigned and summed, and
fragment constants.
(iii) compounds with log Pcalc values greater
Log Pcalc = Σπ than +0.5 are considered water insoluble
• Where; Log Pcalc = log of partition cofficient (lipophilic, solubility is less than 3.3% in
and Σπ = sum of hydrophilic-lipophilic water) and those with log Pcalc values less
constants. than +0.5 are considered water soluble
(hydrophilic).
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Hydrophilic-Lipophilic Fragment Constants

Hydrophilic-Lipophilic Fragment Constants (π)
(π) Fragment π Value
• Measures the hydrophobicity of a specific C (aliphatic) +0.5
region on the drug. C6H5- +2.0
Cl +0.5
• Log P is measured experimentally for a
O2NO +0.2
standard compound with and without a Intramolecular hydrogen bonding (IMHB) +0.65
substituent (X). S 0.0
• The following equation is used: O=C-O -0.7
O=C-N -0.7
πx = log Px — log PH
O(hydroxyl, phenol, ether) -1.0
• Positive π = X more hydrophobic than H. N (amine) -1.0
O2N (aliphatic) -0.85
• Negative π = X less hydrophobic than H. O2N (aromatic) -0.28
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 π Values For Various Substituents on Aromatic Rings

Substituent π Value

CH3 +0.52
t-Bu +1.68
OH -0.67
CONH2 -1.49
CF3 +1.16
Cl +0.71
Br +0.86
F +0.14

• Log P for benzene = 2.13.

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Impact of Partition Coefficient On Drug

Action

• The relative solubility of a drug molecule

greatly affects:

Routes of administration.

Absorption.

Distribution.

Elimination.
• Prediction: water insoluble.

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 CH3
CH3 O N CH3
H
OH
O N CH3
H
OH
• Higher or smaller values of (Log P):
HN CH3

Solubility in plasma (distribution).
Propranolol ( -blocker) O

Lipid barriers (brain and neuronal tissues). Practolol ( -blocker)

Trapping (first site of loss).
• Contrary to propranolol, practolol has no CNS
side effects.
• Drugs with Log P values close to 2 should be
able to enter the CNS efficiently.
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Overton-Meyer Hypothesis The Ferguson Principle

• Relation between physicochemical properties

and drugs action (theories).
• Based on the observation that neutral and • Extended theory (for all drugs).
lipid soluble substances have a depressant • The concentration (molarity or partial
effect on neurons. pressure) of a drug in plasma is directly
• It states that, for these compounds, the higher proportional to its activity.
the partition ratio P, the higher the
pharmacological effect.

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 The Ferguson Principle

Pt St
= X or = X
P0 S0 • High thermodynamic activity (X = 0.1 to 1)
Where:
means :
Pt is partial pressure required for a pharmacological effect, and the activity of the drug is based on its physical
P0 is the partial pressure of the pure substance.
properties only (e.g. gaseous anesthetics).
or
• Low thermodynamic activity (X < 0.1) means:
St is the molar concentration required for a pharmacological effect, and the activity of the drug is based on its
S0 is the molar solubility of the compound.
structure rather than its physical properties.
X = 1 to 0.1 means the drug has high thermodynamic activity.
X < 0.1 means the drug has low thermodynamic activity.

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Structurally Non-specific Drugs

• They have no specific site of action.
• The activity does not depend on chemical
• Depending upon the degree to which chemical structure.
structure affects biological action, drugs can
• The activity depends on physical properties.
be classified as:
• Minor modifications do not affect the activity.

Structurally non-specific (X = 0.1 to 1).
• Effective only in high concentrations.

Structurally specific (X < 0.1).
• Examples of these drugs are gaseous
anesthetics (diethyl ether, N2O, CHCl3), some
sedative and hypnotics and many antiseptics
and disinfectants.
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 Structurally Specific Drugs

• They act at specific sites, such as a receptor or

an enzyme.
• Biological action is related to the chemical
structure.
• Minor alterations in groups in parent structure
bring about appreciable difference in activity.
• Effective in a relatively low concentration.
• Stereoisomers differ greatly in activity.

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Acid-Base Properties

• Absorption:

Un-ionized form (lipid soluble).
• Distribution:

Ionized form (soluble in plasma).
• Excretion.
• Drug-Receptor interaction.
• Drug-Drug incompatibility.

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CH3COOH + H2O CH3COO + H3O CH3COOH + H2O CH3COO + H3O
acid base conjugate conjugate acid base conjugate conjugate
base acid base acid

• Bronsted-Lowery theory. • Ionized forms are water-soluble.

• Proton donor (acid). • Unionized forms are lipid soluble.
• Proton acceptor (base).
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Acidic Functional Groups Basic Functional Groups

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 Neutral Functional Groups Electronic Effects of Substituents

• The electronic effects of various substituents

O R C N
R OH R R1 will clearly have an effect on a drug’s
alkyl alcohol ether nitrile ionization or polarity.
H • This in turn may have an effect on how easily a
O O O N drug can pass through cell membranes or how
R OR1 R NH2 R R1 strongly it can bind to a receptor.
ester amide ketone & • It is therefore useful to have some measure of
diarylamine
aldehyde
the electronic effect a substituent can have on
a molecule.
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The Hammett Substitution Constant (σx)

• Is a measure of the electron withdrawing or

electron donating ability of a substituent on
the molecule.
• For the effect of substituent on an aromatic
ring, the Hammett constant (σx) is used.
• This constant has been determined by
measuring the ionization of a series of
substituted benzoic acids compared to the
ionization of benzoic acid itself.
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 The Hammett Substitution Constant (σx) The Hammett Substitution Constant (σx)

• The Hammett constant takes into account

• The value of σx for an electron withdrawing both resonance (R) and inductive effects (F).
substituent (e.g. Cl, CN, CF3, NO2) is positive.
• Therefore, the value of σ for a particular
• The value of σx for an electron donating substituent will depend on whether the
substituent (e.g. Me, Et, t-Bu) is ngative. substituent is meta or para.
• The Hammett substituent constant for H is • This is indicated by the subscript m or p after
zero. the σ symbol.

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The Hammett Substitution Constant (σx) meta Nitro group – electronic influence on R is inductive.

• The nitro group has two values for σ.

For para position, σp is 0.78.

For meta position, σm is 0.71. para Nitro group – electronic influence on R is due
• The hydroxyl group has two values for σ. to inductive and resonance effects.

For para position, σp is −0.37. O
N
O O
N
O O
N
O O
N
O

For meta position, σm is 0.12.

R R R R
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 meta Hydroxyl group – electronic influence on R is
inductive.
OH

para Hyroxyl group – electronic influence on R

dominated by resonance effects.

• Ciprofloxacin, a fluoroquinolone antibiotic.

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• Once in GIT, it behaves as an acid or a base.

• Factors:

pH (variable).

pKa (constant).
• Ciprofloxacin, a fluoroquinolone antibiotic
• Both acidic and basic properties (amphoteric).

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 • Drugs pass through membranes in an un-
ionized form.
• Drugs act as ions (if ionization is a possibility).
• Ideal pKa (6-8; weak acid or weak base).
• Assumption passive diffusion.

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O
Predicting the Degree of Ionization: Acids O
HN
[Cunionized]
pK a = pH + log
HN [Cionized]
O
amobarbital
pK a = 8
[Cunionized]
8 = 7.4 + log
[Cionized]
O [Cunionized]
HN 0.6 = log
O [Cionized]
N
O [Cunionized] 3.98
10 0.6 = =
[Cionized] 1
3.98 x 100
O % unionized = = 79.9%
• Henderson-Hassalbach equation. HN 4.98
O
Associate Prof. Magdi A. Mohamed, Faculty N Associate Prof. Magdi A. Mohamed, Faculty
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 Aspirin

• An orally administered drug (pKa = 3.5).

• Acidic stomach.

Partial absorption (un-ionized form).
• Basic intestinal tract. • pKa = 3.5.

Ionized form. • Oral route.

Microvilli. • Absorbed in

Huge surface area. stomach.

Absorption.
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Predicting the Degree of Ionization: Bases

BH + H2O B + H3O
conjugate (basic pH)
acid

absorbed
• Amines (pKa 9-10).
• BH+ is not absorbed (stomach).
• Alkaline intestinal tract (pH ≈ 8).
• Equilibrium.
• Henderson-Hassalbach equation.
• B and BH+ are absorbed.
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 Acid-Base Chemistry/ Compatibility
H PO
H3C 2 4
O
H H H N H
O H
N S
CH3
H CH3
N
O OH
COO K
O
Penicillin V Potassium
• K+/H+ ATPase inhibitor.
H3CO
Codeine Phosphate
• Used for treatment of peptic ulcer.
• pKa ≈ 4 (not protonated in the stomach).
• What is the chemical consequence of mixing
aqueous solutions of of these two drugs in the • Can be absorbed into the parietal cells.
same IV bag? • Is protonated inside the parietal cells (pH < 1).
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O O

O
O
N N
O N
H S ATPase S ATPase
S N N N NH S
N N
H
omeprazole

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 Steric Properties
• For a drug to interact with an enzyme or a
receptor, it has to approach, then bind to a
binding site.
• The bulk size, and shape of the drug may have
an influence on this process.

For example, a bulky substituent may act like a shield
and hinder the ideal interaction between drug and
receptor.

Alternatively, a bulky substituent may help orientate
a drug properly for maximum receptor binding and
increase activity.
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Quantitative Structure-Activity
Measuring Steric Properties
Relationship (QSAR)
• Attempts to identify and quantitate
• Quantifying steric properties is more difficult physicochemical properties of a drug in
than quantifying hydrophobic (P and π) or relation to its biological activity or binding.
electronic properties (σ).
• Study hydrophobic, electronic, and steric
• Several methods have been tried, e.g.: properties (either whole molecule or pieces).

Taft’s steric factor (Es).
• Medicinal chemist draws up an equation that

Molar refractivity (MR).
quantifies the relationship & allows one to

Verloop steric parameter.
predict (to some extent) the biological activity.

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 Hansch Equations Example-1

• Relate biological activity to the most

commonly used physicochemical properties:
(P and/or π, σ, and a steric factor)
• Not all these parameters will necessarily be
significant. • The adrenergic blocking activity was related to
π and σ and did not include a steric factor.
• The substituents should be hydrophobic (+π)
and electron donating (−σ).
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Example-2 Substituent π σm σp Es

-CN -0.57 0.56 0.66 -0.5

-Cl 0.71 0.37 0.23 -0.9

-OH -0.67 0.12 -0.37 -0.5

-NH2 -1.23 -0.16 -0.66 -0.6

• The QSAR equation indicates that inhibitory
activity was related to π, σ and steric factor. -phenyl 1.96 -0.06 -0.01 -3.8

-C3H7 1.55 -0.07 -0.13 -1.6

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 Stereochemistry & Drug Action
• Stereoisomers:

Similar MF.

Same connectivity of atoms.

Different three-dimensional structures.
• Two types:
• Calculate the IC50 values when X is:
Configurational isomers:

-NH2. o Enantiomers.

-phenyl. o Diastereoisomers.

-CN.
Conformational isomers.
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Enantiomers
• Physicochemical properties:

Type of functional groups. • Not superposable mirror-image isomers.

Spatial arrangement of functional groups. • The presence of a chiral center.
• Human body is an asymmetric environment. • Identical physicochemical properties.

Proteins. • Differences:

Macromolecules.
Optical activity.
• Better biological activity.
Reaction with chiral molecules.

Proper three-dimensional orientation.
Do they have different biological activities?

Very strong Drug-Receptor interaction.
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 Three-point fit Hypothesis

• Selective reactivity of one enantiomer with its

receptor.
• Three-dimensional drug-receptor interaction.
• Easson and Stedman Hypothesis.

• (+)-Asparagine has a sweet taste.

• (–)-Asparagine has a bland taste.
• First reported by Piutti (1886).
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• The Easson-Stedman Hypothesis states that

the most potent enantiomer must be involved
in a minimum of three intermolecular
interactions with the receptor surface and
that the least potent enantiomer only
interacts with two sites.

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 Hypothetical enantiomers

D A

A C D C

B B
• The vasopressor response of N-
A' C' A' C' methyldopamine is the same as that of (S)-(+)-
B' B'
adrenaline and less than that of (R)-(–)-
adrenaline.
Hypothetical receptor
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• Two-point fit:

N-Methyldopamine and (S)-(+)-adrenaline.
• Differences in biological activity also can result
• Three-point fit:
from differences in the ability of each

(R)-(–)-adrenaline. enantiomer to reach the receptor site.
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 Diastereoisomers

• Nonmirror-image isomers.

More than one chiral center.

Double bonds.

Ring systems.
• Different physicochemical properties.
• Different biological activity.

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Hypothetical geometric isomers

Geometric Isomers

Hypothetic receptor
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 Conformational Isomers

• Single bond rotation.

• Conformations (rotamers).
• Interconvertable (bond rotation).

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• Which conformation is favored? • NMR, X-ray, and molecular orbital
calculations.
• Gauche conformer is favored.
• Intramolecular electrostatic interactions.
• Quaternary nitrogen and oxygen of the
carbonyl.
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• Which conformation can properly

bind to cholinergic receptors?

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• The (+)-trans-enantiomer was observed to be

equally as or more potent, than acetylcholine
at muscarinic receptors; it was much more
potent than the (-)-trans-enantiomer. • Acetycholine would most probably interact
• The racemic cis-compound had almost no with muscarinic receptors in its less favored
activity in the same muscarinic receptor test anticlinal conformation (the angle between
system, and all compounds were very weak the ester oxygen and the quaternary nitrogen
nicotinic agonists. is 137°).
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