Download Medicinal Chemistry N.19 Biological Activity and

Biological Activity and
Homologous Series
2nd Lecture
Dana Ameen
Biological Activity and
Homologous Series
The absolute and relative solubility of drug in
aqueous and lipid phase of body are physical
properties of importance in providing and
maintaining effective concentration of drug at the
site of action.
It have been shown that a regular changes in
biological activity is often near within
homologous series which provide a good example
to understand correlation of solubility and
partition coefficient with the drug action.
• For non ionized or slightly ionized molecule in
which change in structure (such as change in the
carbon chain) and graduation in intensity of
biological activity have been observed from a
number of pharmacologically unrelated groups or
compounds (e.g. resorcinol, estrogen and p-
amino benzoic derivative).
R2
OH
HO
R3
R
(Z)
R4
Alkyl resorcinol
Antibacterial
R1
Estrogen
Derivatives
R
NR'
COOH
Esters of PABA
• In these homologous series the lower show a low
order of biological activity, but with increasing
logarithm of carbon chain, the biological activity
increases and further increase in carbon chain
length lead to sudden decrease (or sharp cutoff)
in their biological activity.
• While in vitro with increasing logarithm of carbon
chain, the biological activity increases, i.e. there
will be no sharp cutoff in killing staph or bacilli.
Pharmacological
Activity
Partition Coefficient and
General Anesthesia
Most of the substance commonly used as general
anesthetics, do not react chemically with any body
constituents, indeed the inert gas xenon can produce
anesthesia.
Theories attempting to explain the action of
anesthetics have therefore, emphasized physical
rather than chemical properties.
Overton-Meyer theory emphasized the close
correlation of lipid solubility of a substance with its
anesthetic potency.
Quantitative Structure Activity
Relationship QSAR
• QSAR studies is try to show that the gradual chemical
modification in the molecular structure of a drug will
produce important difference in its action.
• Therefore, it is established that the physiological action Φ
of a molecule is some function of its chemical
constitutions C, this can be expressed as: Φ = f (C)
Hansch Theory
• Hansch
theory
relationship
takes
between
care
drug
of
quantitative
distribution
and
biological activity, depending on the base that the
biological activity is result of transition and
distribution of the drug in different compartments
(aqueous and lipid phase).
•(σ) means that the group has electron attracting character
(electron acceptor) it has great contribution to dissolve in
polar solvent.
(π) means electron donor (releasing) so has lipid solubility
contribution.
Lipid
Soluble
Water
Soluble
Group
σ
π
CH3
-0.17
+ 0.51
H
0
0
CH3CONH2
+ 0.1
- 0.79
σ
π
CF3
+ 0.55
+ 0.88
CH3
- 0.17
+ 0.58
SCF3
+ 0.51
+ 1.58
SCH3
- 0.5
+ 0.62
OCF3
+ 0.35
+ 1.21
OCH3
- 0.27
- 0.02
Group
CF3 > CH3
SCF3 > SCH3
OCF3 > OCH3
• Benzene boronic acid is a carrier for boron which if localized in
tumor tissue, it could be useful in the treatment of cancer.
• Radiation with neutrons would lead to neutron capture by boron and
release local high concentrations of high energy (alpha radiation)
capable of destroying the tumor.
• Penetration into the brain is highly depended on lipid solubility,
while localization of boronic acids in tumor tissue is dependent on
electron releasing substituent.
• Since compounds are not significantly ionized at
physiological pH, it is suggested that an electron
releasing group which would facilitate cleavage to
boric acid, might release this polar molecule inside
the tumor, where it would be trapped by lipophilic
barriers.
• Alternatively electron release might enhance
binding of the boronic acid with an electron
deficient component of the tumor tissue.
Drug-Receptor Interaction
And
Forces Involved in
Bond Type
Covalent
Reinforced ionic
Ionic
Hydrogen
Ion-dipole
Dipole-dipole
Bond Strenght kcal/mol
40-140
10
5
Example
H3C OH
H
R N H
H+
O
_
+
R4N
-
1-7
1-7
O
+
R4N
A
O
I
O
:NH
3
1-7
OC
van der Waals'
0.5-1
Hydrophobic
1
C
:NH
C
See text
3
Drug-Receptor Interaction:
Forces Involved
• A biological response is produced by
the interaction with the biological
receptor site.
• This interaction would be expected to
take place by using the same bonding
forces as are involved when simple
molecules interact.
Drug-Receptor Bonds
1. Covalent Bond
Very strong.
Not reversible
under
biologic
conditions

unusual
therapeutic drugs.
Phenoxybenzamine at a adrenergic receptors.
The rest of pharmacology is concerned with
weak, reversible, electrostatic attractions:
in
Most drugs do not possess functional groups of a type that would
readily lead to formation of strong and essentially irreversible
covalent bonds between drug and biological receptors.
In most cases, it is desirable to have the drug leave the receptor site
when the concentration decreases in the extracellular fluids.
Therefore, most useful drugs are held to their receptors by ionic or
weaker bonds.
When relatively long-lasting or irreversible effects are desired:
1. Antibacterial, antiprotozoal and antiviral agents.
2. Anticancer; alkylating agents (nitrogen mustards).
Baker's concept
• Covalent bond formation between drug and receptor
of active site will direct the irreversible inhibition.
1. Appropriate structural features for reversible and highly
selective association with an enzyme.
2. Carry reactive groups capable of forming covalent bonds,
the substrate may be irreversibly bound to the drug-
receptor complex by covalent bond formation with
reactive groups adjacent to the active site.
• The diuretic drug ethacrynic acid is an α,βunsaturated ketone, thought to act by covalent
bond formation with sulfhydryl groups of ion
transport systems in the renal tubules.
Cl
O
Cl
CH3
CH2COOH
O
H
H
N
CH3
CH2
H
CH
CH2CH3
Ethcrynic acid
Selegeline
• Selegiline is also covalently binds to the
receptor, inhibition of MAO B.
More example
• Reaction of arsenicals and mercurials with
cysteine sulfhydryl groups.
• Acylation of bacterial cell wall constituents by
penicillin.
• Phosphorylation of the serine hydroxyl moiety at
the active site of cholinesterase by organic
phosphate.
CH3
O
O
CH3
N
N
N
(Z)
CH3
O
O
H3C N
N
(Z)
N
H
N
H
O
CH3
N
H
(R)
N
N
O
O
O S O
CH3
O S O
N
N
N
N
CH3
Sildenafil
CH3
Vardenafil
(R)
CH3
O
Tadalafil
N
H
2. Ionic bond
 Weak, electrostatic attraction between positive and
negative forces.
 Easily made and destroyed.
 Ionization at physiological pH would normally occur
with the carboxyl, sulfonamido, and aliphatic amino
groups, as well as the quaternary ammonium group at
any pH.
3. Dipole-dipole interaction
 A stronger form of dispersion forces
formed by the instantaneous dipole
formed as a result of electrons being
biased towards a particular atom in a
molecule (an electronegative atom).
 Example: Hydrogen bonds
• Differences in electronegativity between carbon
and other atoms, such as oxygen and nitrogen,
lead to an asymmetric distribution of electrons
(dipoles) that are also capable of forming weak
bonds with regions of high or low electron
density, such as ions or other dipoles.
• Carbonyl, ester, amide, ether, nitrile, and
related groups that contain such dipolar
functions.
Hydrogen bond
• Drugs possess groups such as carbonyl,
hydroxyl, amino, and imino are acceptors or
donors in the formation of hydrogen bonds.
• As they would be solvated by water (as would the
corresponding groups on a biological receptor),
therefore, relatively little net change in free
energy would be expected in exchanging a
hydrogen bond with a water molecule for one
between drug and receptor.
• But hydrogen bond would contribute to the
stability of the interaction.
• Where multiple hydrogen bonds may be formed,
the total effect may be sizable.
• The stability of the protein α helix and by the
stabilizing influence of hydrogen bonds between
specific base pairs in the double-helical structure
of DNA.
4. Hydrophobic Interactions
The tendency of hydrocarbons (or of lipophilic
hydrocarbon-like groups in solutes) to form
intermolecular
aggregates
or
intramolecular
interactions in an aqueous medium”.
-usually quite weak.
-Important in the interactions of highly lipid-soluble
drugs with the lipids of cell membranes and perhaps
in the interaction of drugs with the internal walls of
receptor “pockets”.
• The isopropyl moiety of the drug fits into a
hydrophobic cleft on the receptor composed of
the hydrocarbon side chains of the amino acids
valine, isoleucine, and leucine" are commonly
used to explain why a nonpolar substituent at a
particular position on the drug molecule is
important for activity.
• Over the years, the concept of hydrophobic bonds
has developed. There has been considerable
controversy over whether the bond actually exists.
Thermodynamic arguments on the gain in entropy
(decrease in ordered state) when hydrophobic
groups cause a partial collapse of the ordered
water structure on the surface of the receptor have
been proposed to validate a hydrophobic bonding
model.
• Problems with this concept.
1. The term hydrophobic implies repulsion. The
term for attraction is hydrophilicity.
2. There is no truly water-free region on the
receptor. This is true even in the areas populated
by the nonpolar amino acid side chains.
The alternate approach is to consider only the
concept of hydrophilicity and lipophilicity;
water molecules solvate polar moieties,
effectively squeezing the nonpolar residues
toward each other.
5. Dispersion (Vander Waal) forces
Attractive forces that arise between particles as
a result of momentary imbalances in the
distribution of electrons in the particles.
These imbalances produce fluctuating dipoles
that can induce similar dipoles in nearby
particles, generating a net attractive force.
• Van der Waals' forces are attractive forces created by the
polarizability of molecules and are exerted when any two charged
atoms approach each other very closely.
• Their strength is inversely proportional to the seventh power of the
distance. Although individually weak, the summation of their
forces provides a significant bonding factor in highermolecular
weight compounds.
• For example, it is not possible to distill normal alkanes with more
than 80 carbon atoms because the energy of 80 kcal/mol required
to separate the molecules is approximately equal to the energy
required to break a carbon-carbon covalent bond.
• Flat structures (aromatic rings) permit close approach of
atoms. With van der Waals' forces of 0.5- kcal/mol for
each atom, about six carbons (a benzene ring) would be
necessary to match the strength of a hydrogen bond.
• The aromatic ring is frequently found in active drugs,
and a reasonable explanation for its requirement for
many types of biological activity may be derived from
the contributions of this flat surface to van der Waals'
binding to a correspondingly flat receptor area.
Drug-Receptor Bonds and Selectivity
 Drugs which bind through weak bonds to their
receptors are generally more selective than drugs
which bind through very strong bonds.
 This is because weak bonds require a very precise fit
of the drug to its receptor if an interaction is to occur
 Only a few receptor types are likely to provide such a
precise fit for a particular drug structure.
 To design a highly selective short acting drug for a
particular receptor, we would avoid highly reactive
molecules that form covalent bonds and instead
choose molecules that form weaker bonds.
Correlation of Solubility and
Partition Coefficient with Biological
Activity