Year Four Chemistry

Learning Centre: Medicinal Chemistry

The discipline of medicinal chemistry is concerned with research into new agents for
curing illnesses. It is naturally very related to organic chemistry by virtue that these
medicinal compounds tend to have biological activity, thus containing a substantial
number of carbon compounds.
Medicinal chemistry has various links with organic chemistry. Firstly, it acts as the
bridge between traditional and modern chemistry, by identifying the compounds in
natural cures such as the fruit of Ascelus Punduanda Wall. (which was found to be a
steroid glucoside) and subsequently, it is necessary to understand their drug action
mechanisms and plausible side effects due to interactions with other compounds in the
body. Finally, medicinal chemistry has many relations with synthesis in organic
chemistry as these compounds need to be subsequently synthesised into commercial
drugs for use. We will be covering mainly synthesis for now.
Elucidation of Compounds
There are various means of elucidating the structure of a natural compound, and more
often than note it is necessary to use a variety of these methods in order to determine
the final structure of a certain compound.
However, it would be necessary to separate the product in order to obtain a single pure
compound rather than a mixture of several compounds, which would not give the
desired results. Methods of doing this include High Performance Liquid
Chromatography (HPLC), gas chromatography, as well as simply dissolving in polar
and non-polar solutions, followed by filtration or decanting.
Following that, we can then use various types of spectroscopy to determine the
compound such as mass spectroscopy (taught in Y3 RA), UV spectroscopy, IR
spectroscopy and Nuclear Magnetic Resonance (NMR).
Ultra-Violet/Visible Spectroscopy
It measures the absorption of light by a
certain molecule, and from this is able to tell
the identity of transistion metals, organic
compounds with a high level of conjugation
and charged complexes. The absorption can
be processed by Beer-Lamberts Law, which
calculates the absorption.
I =I 0 ex , I the intensity at a point , I 0initial intensity , x path length . absorption coefficent

Infrared Spectroscopy

IR Spectroscopy is able to tell us the types of

functional groups in a certain molecule. It is able
to detct the stretching and bending of bonds as
these would absorb IR radiation of a certain
wavelength but not others. Generally, stronger
and lighter bonds would vibrate faster. Generally,
a C-H bond would have a value of about 3000 cm 1
, C-D 2200 cm-1, C-O 1100 cm-1 and C-Cl 700 cm1
.
Nuclear Magnetic Resonance
NMR makes use of a very strong electromagnet
is a machine in order to tell us about the atoms
in a molecule by means of understanding the
spin of the electrons which in turn tells us the
nature of the atoms. Currently, the main types of
NMR are 13C and 1H. In 13C NMR, there are
various regions which are able to tell us the type
of bond the carbon is attached to as well as to a
certain extent which atom it is attached to in the
case of oxygen.
HNMR Spectroscopy

Although at this stage it may not exactly be clear what are the uses of spectroscopy in
medicinal chemistry, it has many uses indeed. In fact, all the diagrams from this
previous section have been taken from a research paper entitled Isolation and
Identification of Biologically Active Compounds in Aesculus Punduanda Wall. which
was able to identify compounds and elucidate a structure in a fruit commonly used in
traditional medicine in Myanmar.
Things to Watch Out For
It is important to note that when dealing with the human body, it is not as simple as
finding any compound with the required functional group for curing an illness. It is
necessary to consider various other factors as well, which as mainly physical and
chemical barriers to a drug meeting its intended receptor as well as possible side
effects it may have on the body.
Maintaining an Equilibrium
It

is necessary to maintain an equilibrium, when put simply being the

Drug+ Receptor DrugReceptor Complex . It is advantageous to be able to have a
drug that is able to bind on to the receptor complex well, in order to allow it to take
effect. However, it is also necessary for the drug to dissociate from the receptor be
excreted from the system subsequently so that allergies can be contained and once
the patient has recovered, he does not suffer from any side-effects. There are
exceptions however to this, as certain pharmacological agents form covalent bonds
with the receptor, and as we know it is difficult to break a covalent bond. These include
acetylcholineterase and exemestene. In this case, it is necessary for the receptor to be
able to naturally break down the drug after use.

Exemestane is used to treat breast cancer in

post-menopausal women. By reducing estrogen
levels, it slows the growth of breast tumours
which require estrogen to grow.

Physical and Chemical Barriers

For most commercial drugs, they are administered by oral
means. As a result, there are several barriers that have to
be overcame before reaching the target site. The drug will
most likely be absorbed in the intestines, hence it has to be
able to first overcome the acidic stomach followed by the
alkaline intenstinal tract. Furthermore, it also needs to be
soluble, which is dependent on its size, surface area, tablet
coating and nature of crystal form. We can modify the
properties of a drug, for example when mesalamine was
found ineffective by virtue of being metabolized before
reaching the colon, mesalamine was used instead as it had similar medicinal
properties.
Drug Metabolism
It is important for a drug to be able to be metabolized without
taking too much of a toll on the liver. Moreover, it is possible
for the drug to be metabolized during its initial trip to the liver,
before it has reached most of the target cells. This is termed
as the first-pass effect, and thus requires a different form to
avoid this effect [Note the carbon furthest from the benzene
ring]. For example, lidocaine is not usually used as it has a
half-life of only 2 hours, instead tocainide is used as it has a
longer half-life of 15 hours.

pH Dependence
In certain drugs such as aspirin, its
properties are pH dependent.
Although aspirin is not soluble, its
sodium salt is much more soluble.
Thus, if the pH is lowered, the more
acidic form of aspirin is more likely
to be favoured compared to the
sodium salt, thus the seemingly
soluble aspirin may be converted
into the less soluble form at places such as the stomach and be precipitated out of the
solution.

This

pH may be

pH= p K a +log

calculated

from

the

Henderson-Hasselbach

equation

Isomerism
Although isomers may seem rather similar, in a biological sense they are very different
from each other as proteins tend to be folded in
such a way that they are asymmetrical in nature
and thus their interactions with such isomers will
also be different. For instance, ephedrine melts at
79 oC and is soluble in water, whiclest
pseudoephedrine melts at 118 oC and is only
sparingly soluble in water. Thus, drugs such as (-)epinephrine has 10 to 15 times more
vasoconstrictor activity than (+)-epinephrine. [Diagram: Left is ephedrine, Right is
pseudoephedrine]
Synthesis
Aspirin
Aspirin is formed from the synthesis of salicylic acid and acetic anhydride in the
prescence of a phosphoric acid catalyst. This is a form of an esterification process,
with the H+ from the acid being able to cause the aceti anhydride to possess an alcohol
functional group which would then take part in a reaction with the salicyclic acid.
Mechanism

Metronidazole
Metronidazole is an antibiotic used against anaerobic bacteria and protozoa. Although
the synthesis may seem rather complicated, we may see certain understandable parts.
For instance, from 1 to 2, it is very similar to the nitration of benzene or toluene that
has been taught, whereas for 2 to 3 we can think of it as the chlorinated alcohol and 2
undergoing an alkylation reaction.
Mechanism

Caffeine
Believe it or not, caffeine can actually be synthesised from uric acid through several
steps as depicted over here. Although obviously commercially coffee is derived from
natural origins, it is interesting to see how a waste product can become an edible
compound through careful manipulation. In the first step, we basically use formamide,
derived from formic acid, as a reducing agent to remove a ketone group, and
subsequently we add methyl groups to three parts of xantine to get caffeine.
Mechanism

Physiological Action
There are generally two types of biological hormones,
lipid-soluble and water-soluble ones. The lipid soluble
ones would enter the target cell whereas the water
soluble hormones would be detected by a receptor on
the cell membrane. This has to do with the phospholipid
bilayer making up the cell membrance, however we
shall not be elaborating further.
In the case of cocaine, it is a weak base, which may be
converted into an acid salt. Cocaine is not only lipid
soluble, in the acid salt form it is charged and this
allows it to enter the cell membrane through small
pores as well as through the phospholipid bilayer.
Hence, this makes it most penetrating to brain cells, the
same for nicotine, marijuana and heroine. As a result, it
is harmful to a persons physiological and psychological
state.
However, there are nonetheless certain drugs which face difficult crossing the bloodbrain barrier if intended. This can be solved by means of a technique to invent a
special form called prodrugs, which improves the bioavalability of a drug, in other
words makes it easier to cross blood-organ barriers by masking it with lipid-soluble
substances. An example would be fexofenadine, which replaced terfenadine over the
small risk of a serious side effect. Terfenadine was in fact the first non-sedating
antihistamine to be commercially made available.

Hands-On Kit
For the purpose of demonstrating how we can relate to the chemistry of compounds
which once seems so alien to us, we will be performing the hydrolysis of aspirin
which you have just learnt the synthesis process in order to get back its original
reactants.
In the hands-on kit, you will find two cups, an aspirin tablet as well as solutions of
both an acid and acetone.
Add the tablets to the acetone
and crush them well. Decant
the clear liquid away allow it
to evaporate for possibly a
few days. You may stop once
you observe crystals of
aspirin.
Next, add the water and HCl
in
approximately
equal
volumes. Cover the cup with
the lid provided and place some ice over it. [This is to prevent loss of vapour by
causing it to re-condense.] Heat the solution for sufficient amount of time at about
60oC. A white precipitate should be evolved. Allow the solution to dry for a few more
days, and after filtering one should get salicylic acid. Please do note however that
this is a rather crude means of hydrolysis and may not result i n fine results, however
do it for the experience, maybe?
Aspirin Crystals
Salicylic Acid Crystals

White precipitate

Reaction [Without Catalyst, which may be a base or

acid] :
Essentially, aspirin acts as an ester with its
functional group attached to the benzene ring. This
produces salicylic acid as a product.

[Source: crscientific.com]

Questions:
1. What is the mass of salicylic acid required to produce 30 mg of aspirin?
2. What is the ratio of ephiderine to ephiderine HCl (pKa 9.6) in the intestinal tract at
pH 8.0? [Ephiderine may be regarded as conjugate base]
3.

4.

Thalidomide is a drug displaying optical isomerism,

with one isomer having medicinal value and the
other harmful to the body. However, the issue is that
both isomers can be converted in-vitro from one
enantiomer to another. Identify the chiral atom and
draw its enantiomer.

Complete the following reaction for the synthesis of paracetamol. [Hint: 1 and 2 are
isomers]
1

5.

Histamine is a bodily compound with the following chemical structure. However,

there are several other bodily compounds which act as competitive inhibitors to its
action. Given that the following structure is an antihistamine, explain via its
chemical structure why it is useful in reducing the action of histamine. [Left
Histamine,
Right

Antihistamine]

6. DOXP is one of the compounds produced in a series of synthesis reactions to

produce antimalarials. It is produced from pyruvic acid and glyceraldehyde-3phosphate with only CO2 as a by-product. [Hint: DOXP has a 5-carbon chain.]

Pyruvic Acid

Glyceraldehyde-3-phosphate

Answers:
1. [Simple Question] From learning centre, molecular formula of aspirin is C 9H8O4.
Its molar mass is 180 g mol-1, thus 0.167 mmol of aspirin and salicylic acid each
is needed. Salicylic acid is of the formula C 7H8O3, with molar mass 138 g mol-1,
hence 23.0 mg of salicylic acid is needed.
2. [Simple Question] By Henderson-Hasselbach equation,
8.0=9.6+ log

[ ephedrine ]
[ ephedrine HCl ]

=1.6

[ ephedrine ]
[ ephedrine HCl ]

=0.025

3. [Moderate Question]

The carbon attached to the nitrogen but not oxygen is chiral. [(R)-thalidomide is a
sedative whilst (S)-thalidomide causes birth defects.]
4.

[Moderate/Hard Question] The students should be expected to know this as for the first
step, it is a commo`n nitration step and since the OH group is electron withdrawing,
the NO2+ group would be more likely substituted into the 1,3 positions. They can infer
from the final product that 2 is the 3 substituted product. As NaBH 4 is a source of
hydride ions and a reducing agent, it will reduce the NO 2 group to an NH2 group.
5. [Hard Question] Both the histamine and antihistamine have a particular similar
structure, namely the C CH 2 CH2 N group which interacts with the
same receptor as histamine. As a result, when both are present near a receptor,
they will compete to interact with the receptor and this competition results in
reduced interaction between histamine and receptor.

6. [Hard Question]
Requires knowledge that if CO2 is a by-product, it would mean that there the
bonding site be such that it is possible for one atom to lose a C and O atom
while the other an O.

[Note: Error in glyceraldehyde-3-phosphate as carbon numbered 4 should have an

OH group attached]