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Medicinal Chemistry I
Lecture 14
Quick Review
A chiral center is defined as an atom in a
molecule that is bonded to four different
chemical species, allowing for optical
isomerism.
How can we determine the
configuration of a compound?
□find the chiral center.
□determine the priority of the functional
groups according to their
atomic number.
□set the group with the lowest priority
backward.
□start counting from the group with the
first priority to the 2nd then 3rd .
□If you are counting clock wise then the
configuration is R, if you are counting
anti clock wise then the configuration is
S.
R: clock wise.
S: anti-clock wise.
Diastereomers: are very similar
compounds but are not mirror
images.
Diastereomers types:
□Cis and trans
□ compounds with more than one chiral
center.
How many isomers does a compound
with more than one chiral center
have?
number of isomers=2n
n: number of chiral centers.
e.g. Suppose a compound has three
chiral center, how many diastereomers
we have?
number of diastereomers=23
=8
If we have a compound with two chiral
centers, then the possible diastereomers
are:
S,S R,R R,S S,R
S,S and R,R are enantiomers
R,S and S,R are enantiomers
R,R and R,S are diastereomers
Diastereomers have different
physical properties so we can use this
in separation and purification of
enantiomers,, HOW?!!
Suppose we have a mixture of R and S
enantiomers. To separate them we may
use an optically active molecule with
known stereochemistry –for example we
will call it R'- now we will obtain R,R'
and S,R'.
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R,R' and S,R' are diastereomers with
different physical properties so their
separation is easier than separation of
enantiomers.
We can separate them by physical
methods depending on the difference in:
Solubility, melting point ,boiling point.
After separation break the bond between
S-R' and R-R'.
Now we have separate pure
enantiomers.
The figure above may help in clarifying
the idea.
Enantiomers have similar chemical and
almost similar physical properties.
Diastereomers have similar chemical
properties but different physical
properties.
Examples on diastereomers:
-Ephedrine
Example on a compound with more
than one chiral center.
-Tartaric acid
In Tartaric acid:
S,S and R,R are enantiomers
R,S and S,R are enantiomers
R,R and R,S are diastereomers
There is an exceptional case in
compounds with more than one chiral
center:
R,S and S,R are supposed to be
enantiomers but in some cases like in
tartaric acid they are meso-compounds.
meso-compounds means that mirror
images compounds are identical, it
happens when we have a plane of
symmetry in the compound.
)‫)هم نفس الجزيء بس بنطلع عليه من جهتين مختلفتين‬
-pseudoephedrine
So in this case instead of having 4
isomers we have 3 isomers.
Chirality is a result of asymmetry.
For example It's no way to find a plane
of symmetry in our hands !!
Plane of symmetry cancels chirality.
Threonine is an amino acid.
-They have different biological activity
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In Threonine;
First chiral center has hydroxyl and
methyl.
Second chiral center has amino and
carboxyl.
S,S and R,R are enantiomers
R,S and S,R are enantiomers
R,R and R,S are diastereomers
S,S and R,S are diastereomers
No plane of symmetry; No mesocompounds.
Study Amino acids for the midterm
exam.
Geometric isomers
E,Z isomers
-If the highest priority substitutions -on
two carbons- are on the same direction
then we call the compound Z.
-If the highest priority substitutions on
two carbons are on the opposite
direction then we call the compound E.
Cis-trans system is used when we have
two identical functional groups.
E, Z system is used when we have two
different functional groups.
Priority is according to the atomic
number.
Examples
Tamoxifen
Z isomer has anti estrogenic activity
"antagonist'
E isomer has estrogenic activity
"agonist'
E isomer has lower affinity than Z
isomer to the receptor.
Our role as medicinal chemists is to
convert a starting molecule with low
activity, unwanted physical properties
and side effects to a DRUG.
We aim to increase the biological
activity, increase affinity to the target
receptor, improve physiochemical
properties, reduce the side effects, etc..
We will concentrate on methodologies
that we can employ to convert a lead
compound into drug:
Conformational restriction; fixation or
freezing of a certain conformer.
*methods used in conformational
restriction:
-single bond to double bond.
-addition of a bulky group.
-non-aromatic ring to aromatic ring.
Acetylcholine
Has muscarinic and nicotinic effect.
Starting from acetylcholine structure and
its muscarinic activity, how can we
deign a drug with anti-muscarinic
properties?!!
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Acetylcholine displays muscarinic
activity when it is in the staggered
conformation.
Staggered: in the opposite direction.
We should fix the compound on the
staggered conformation; to preserve its
affinity toward the receptor.
We fix staggered conformation by
converting the single bond (where the
arrow points) to double bond (trans
conformation)
To design an antagonist we should
guarantee that the drug will interact and
fit with the receptor but without
activating the receptor.
So we will change some functional
groups to another that is similar in size.
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Suggestion:
-Chloride group on carbonyl groupoxygen number 2- to form acyl chloride;
size is close but we will have more
reactive compound which means more
side effects not acceptable.
of chloride to the nitrogen will actually
form salt.
-Add oxygen to the nitrogen group to
form nitro group not acceptable;
because nitro group is electron deficient
while amino group is electron donating.
-The compound is positively
chargedno absorption, so we may
remove a methyl group linked to
nitrogen (in other words convert the
quaternary amine to tertiary amine).
-We need to reserve the ionization status
of the nitrogen.
-acetylcholine is easily metabolized in
liver because it has an ester group, so we
can:
change the ester group to carboxyl
group not acceptable because the
resulted charge is problematic.
replace oxygen number 1 to methyl
group to result in ketone acceptable;
ketone group is metabolized in a lower
extent.
-convert methyl group linked to nitrogen
to ethyl group possible, but it still
have agonist activity.
-ester group is important because it
forms hydrogen bonds, so we need to
replace it with another functional group
that forms hydrogen bonds but in the
same time less susceptible to
metabolism.
-N= C (cyano-group) not acceptable;
very small in size and we will lose ionic
binding.
-we may form enol, but in fact
compounds and their enol forms are in
equilibrium in solution.
-convert the nitrogen to
amidepossible.
-We may add benzene ring possible,
but it will change the size so it will
affect the compound's fitness with the
receptor.
-aniline ringpossible.
-We may transform the nitrogen to a
cyclic structure instead of the three
methylsacceptable.
Substitute N(CH3)
with this ring
-nitrogen to sulfurnot acceptable;
different interaction with the receptor.
Enol form
-convert to ether group, by removing
oxygen number 2 (ethers are more
resistant to metabolism).
-Add chloride to the nitrogen
groupnot acceptable because addition
The above discussion is called
isosteric substitution, which is the
second method to modify structures.
Instead of discussing similarities
between molecules isosteric
substitution discusses similarities
between functional groups.
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both of them occupy the same 3D
space and form the same interactions.
In medicinal chemistry we use the
Isomers: similar compounds.
Isosteres: similar functional groups;
similar in their chemical, physical and
electronic properties.
*We are concerned with:
-Size
-Type of electronic interaction.
-Solubility.
-pka, etc..
Before start modifying our drug,
we should study the functional
groups of the receptor.
There are functional groups important
for activity and functional groups
important for the affinity.
When we want to design an antagonist
we shouldn't change functional groups
responsible for affinity, we should
modify functional groups responsible for
activity.
In case of agonist we should focus on
increasing both activity and affinity.
Pharmacophore is the functional
groups responsible for activity, their
dimensional position, their relationships
and distance between them.
Just like saying that I want in position X
a H-bond forming group and in position
Y that is 90˚ from position X I want an
ionic group and in a third site I want
hydrophobic bond.
It is important to know the
pharmacophore before starting random
changes in the structure.
We start with a lead and end with a
drug; the structure of the drug may be
very different from that of the lead BUT
biological substrate to design an
inhibiter, for example the
neuraminidase inhibitor "tamiflu" is
designed from sialic acid.
To be able to change the chemistry
without changing interaction we should
understand different properties of
different functional groups.
That’s why isosteric and
bioisosteric terms have emerged.
The first definition of these terms was in
1999, isosteric means that some
molecules with different atoms but
with similar electron distribution and
similar size have similar physical
properties.
An example: CO2 and NO2.
have similar 3D structure, similar
density, solubility and electronic
properties of the outer surface of the
molecule.
Isosteres
Functional groups or substituents have
similar size, volume and electronic
distribution.
Note here we do not talk about
molecules, we talk about functional
groups.
Example:
CH3 can be replaced by NH2
-Similar size
-NH2 form hydrogen bond but CH3 do
not.
-NH2 is ionizable.
So depending on our need we can
replace them.
-OH ad NH2
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-Both form H-bond
-NH2 is ionizable while OH is not, so if I
want to design a drug that crosses BBB
we replace –NH2 with –OH.
-Fluoride and chloride are more resistant
to metabolism.
So may be used in sustained release
drugs.
-Chloride forms H-bonds.
-amino and hydroxyl groups are
metabolized easily.
Nitrogen to form amide or with be
replaced with CH2.
To sum up, we can substitute a
certain group with an equivalent
group to change physical
properties while preserving 3D
size and affinity.
-Oxygen of the ester -in the middle of
the structure- can be replaced with
Good Luck
Done By: Banan Oqilan
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