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Physicochemical

Properties in Relation
to Biological Activity
Yan Zhang, Ph.D.
Department of Medicinal Chemistry
yzhang2@vcu.edu

A. Drug Distribution and Pharmacological


Response

Drug in formulation Drug in solution Drug in blood

Deggregation,
dissolution absorption across membrane

1. Absorption

„ pH values in each part of our


GI tract:

Stomach: 1-3
Small Intestine: ~7
large Intestine: 7-8

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2. Protein Binding

3. Membrane Structure

Phospholipid Molecule

„ The unique
chemical
structure of
phospholipid
molecule
decides the
character of the
membrane
architecture.

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Passive Diffusion

Active Transport

4. Distribution and Excretion

„ After the absorption,


some drug
molecules will act on
target site, some may
be metabolized.
Eventually all the
drug molecules
would be excreted
from our body.

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ADME

„ Absorption
„ Distribution
„ Metabolism
„ Excretion
„ (Toxicity)

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B. Properties that Influence Passage of Drugs


Across Membranes
1.Partition Coefficients
[Drug]octanol
P=
[Drug]water

The higher the P value is, the better


hydrophobic property the drug may
have, the easier they are going to be
absorbed. Log P is usually used.
Only unionized (non-charged)
compounds are lipid soluble
while ionized drugs normally do not
cross membrane as easy.

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2. Acid/Base Partition

„ Henderson-Hassalbach equation

[ base form ]
pH = pKa + log
[acid form ]
The pH value of
the solution A constant
in which drug is for any given
dissolved. molecule

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Example
„ In the stomach
2.5=4.5+logB/A
-2=logB/A
1/100=B/A
„ How about in the small intestine?
7.5=4.5+logB/A
COOH 3=logB/A
1000/1=B/A
Ibuprofen
Conclusion: in the stomach, ibuprofen will mainly be
in the acid form, which is less polar compared with
pKa = 4.5 its base form (charged mode), therefore, it is
easier to be absorbed. On the other hand, in the
small intestine, it is the opposite.

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Example 2
In the stomach
„
2.2=9.2+logB/A
-7=logB/A
NH2
1/10,000,000=B/A
Amphetamine „ In the small intestine
7.2=9.2+logB/A
-2=logB/A
pKa = 9.2 1/100=B/A
Conclusion: in the stomach, amphetamine will be
mainly in its acid form, which is charged. Since it is
very polar in the charged form, it will be very
difficult to be absorbed. Similarly, in the small
intestine, the dominated form is still the acid one,
which makes it still not easily absorbed.

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C. Properties and Biological Activity


1. Bonding Forces
Bond type Bond strength (kcal/mol) Example
Covalent 40-140 CH3-OH
H
Reinforced ionic 10
R N H O
H C R1
O

Ionic 5 R4N+ I-
R O R1
Hydrogen 1-7 H O C
R2

Ion-dipole 1-7 R4N+ ---- :NR3


Dipole-dipole 1-7 O C NR3

Van der Waals 0.5-1


hydrophobic 1
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Example
S1
S2

O
S3
H Me

HC N CH C N

C
O O2C
H
O O H
2 O
Zn

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Lock and Key Concept

Drugs Receptor types

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3D binding model

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2. Isosterism and Bioisoterism

Comparison of Physical Properties of N2O and CO2

Property N2O CO2


Viscosity at 20ºC 148 X 10-6 148 X 10-6
Density of liquid at 10 ºC 0.856 0.858
Refractive index of liquid, D line 16 ºC 1.193 1.190
Dielectric constant at 0 ºC 1.593 1.582
Solubility in alcohol at 15 ºC 3.250 3.130

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Isosterism: replacement or modification of


functional groups with other groups having
similar perperties

Grimm’s Hydride Displacement “Law”

C N O F Ne

CH NH OH FH

CH2 NH2 OH2

CH3 NH3

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Burger:

Bioisosteres are compounds or groups that


posses near equal molecular shapes and
volumes, approximately the same distribution of
electrons, and which exhibit similar physical
properties such as hydrophobicity.

Bioisosteric compounds affect the same


biochemically associated system as agonist or
antagonists and thereby produce biological
properties that are related to each other.

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Classical Bioisosteres (groups within the row
can replace each other)

Monovalent Divalent Ring equivalents

F, H -C=S, -C=O,
OH, NH -C=NH, -C=C-
S N O
F, OH, NH, or CH3 for H
SH, OH
Cl, Br, CF3

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Examples for Bioisosteres

O O R N
H F
HN HN NH
H2NO2S S
O N O N O O
H H
Uracil 5-F-uracil R=Cl, Br, CF3

While uracil is an anti-cancer For the thiazide diuretics, different


agent, substitution of one substitutions do not change the
proton with fluorine atom lead electronic and hydrophobic
to another antineoplastic properties of the molecule very much
agent 5-F-uracil. while the size of the substitutions
are significantly different.

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3. Geometric Isomeric Aspects of Biological


Activity:

A B A B

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Another example
OH OH HO OH

HO
HO
trans cis
Estradiol Diethylstilbestrol

„ The inter-atomic distances between the OH groups


in trans-diethylstilbestrol and in estradiol are similar,
accounting for the greater estrogenic activity of the
trans isomer.

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4. Conformational Aspects of Biological Activity:

„ While anti or staggered


NMe3 NMe3
conformation is more
H H H H
stable (lowest energy),
H3COC
H H O eclipsed one is not
O
COCH3
H H favorable for biological
activity of acetylcholine.
anti or staggered eclipsed

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5. Optical Isomerism and Biological Activity:


Stereochemistry & Chirality
„ Stereochemistry deals with the
arrangement of atoms and
groups in three dimensions.

„ Stereoisomers are possible


when there is a chirality in the
molecule.

„ Chirality is due to asymmetry

„ Chiral center, chiral axis and


chiral plane

„ Optically active
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Enantiomers

„ Chirality is the necessary and


sufficient condition for the
existence of enantiomers.

„ Enantiomers are non-


superimposable mirror images of
one another.

„ Share common structural


characteristics, as well as most of
the same physical and chemical
properties.

„ Show Optical activity

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„ Today we realize that most naturally occurring medicinal


agents exist in their optically active or single isomer form, such
as Quinine, Ephedrine and Pseudoephedrine
„ Almost half number of the drugs in use are chiral.
„ Normally only one enantiomer having the beneficial effect.
„ In the case of some drugs, the other enantiomer can even be
harmful
OH
O OH
H O O
H
H H O
N
H2N OH N
H H2N OH
O
H O H
H HO
OH
CH3
H3C
O
O

Left-handed Left-Handed
Right Right handed
Ibuprofen Aspartame
handed Aspartame not
powerful pain “Nutrasweet” 160
Ibuprofen at all sweet
killer times sweeter than
No activity slightly bitter
sugar
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Importance of Chirality
„ Pharmacological
Affinity to receptor: The
binding specificity of a chiral
receptor site for a chiral
molecule is usually only
favourable in one way

Potency: In enantiomeric
drugs, potency differences
may arise because the more
active enantiomer has a
greater capability of achieving
a pharmacophoric
conformation

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Pharmacokinetics

„ Absorption: Methotrexate, the L-enantiomer of the drug


are actively absorbed while the D- form absorbed in the
intestine by passive diffusion
„ Distribution: The S enantiomer of propranolol is
selectively bound in heart, whilst the R isomer is
selectively incorporated into the adipose tissue.
„ Metabolism: R enantiomer of warfarin has longer
elimination half life. S-warfarin is metabolized by CYP
2C9, R-warfarin is metabolized by CYP 1A2, 2C19 and
3A4
„ Excretion: Renal clearance of plasma Quinidine is four
times greater than quinine, its diastereoisomer

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Toxicological effect
Antagonistic effect
Teratogenicity
Mutagenicity/Carcinogenicity
O H
O H N
N O O
H
O O
H N N
O O

(S)-thalidomide (R)-thalidomide
(effective drug) (dangerous compound)

The body racemises


each enantiomer, so
even pure S is
dangerous as it
converts to R in the
body.
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