Option D medicinal chemistry SL

Option D- Medicinal Chemistry
SL & HL- R.Hughes 2017
Note: an excellent precursor to studying this topic is to watch the movie- ‘The constant gardener’

Topic outline…..
Lesson 1- Our dependency on drugs….
Lesson 2- Bioavailability- How effective is your drug?
Lesson 3- Making Aspirin (P).
Lesson 4- Purifying Aspirin (P).
Lesson 5- Penicillin- The first antibiotic.
Lesson 6- The ‘innocent’ little poppy.
Lesson 7- Ouch! My stomach hurts
Lesson 8- pH and buffering.
Lesson 9- The war against viruses!
Lesson 10- Green Chemistry☺

D1- Pharmaceutical products and drug
action.

Lesson 1- Our dependency on drugs.
Level 4: State the definitions for the key terms
of medicinal chemistry.
Level 7: Explain why we have such a lengthy
drug development process and the F.D.A.
Level 5/6: Describe the different ways of
administering drugs and give examples.

Starter…..
List off as many medicines/drugs that you can
think of….
Do you think all of these do exactly what they
say they do?
How can we apply science and chemistry to
measure monitor the efficacy of the drugs we
prescribe…...

Keyterms(note: pre-print for students)
Metabolism: The intricate balance of thousands of different biochemical reactions
occurring simultaneously in the body.
White blood cells: The body’s natural secondary line of defense against invading
pathogenic microbes (bacteria, fungi & viruses).
Medicine: Substance which improves health.
Drug: may positively improve (therapeutic) or negatively affect your health (side
effect).
Placebo: Preparation with no active ingredient. Can ‘trick’ patient into feeling
better.
Tolerance: when repeated doses of a drug result in smaller physiological effects.
Addiction: Patient/user gets withdrawal symptoms when drug is not available.

Keyterms
Bioavailability: The fraction of the administered dosage that reaches the
bloodstream.
First pass effect: Drugs which are taken orally have to first pass through the
digestive system where up to 80% of the drug can be altered/metabolised (by
enzymes), before reaching the bloodstream (resulting in very low bioavailability).
Enzymes: biological catalysts which can speed up the metabolism of drugs in the
body.
Dosing regime: How much and how often.
Pharmaceutics: The science of dosage form design.
Rational drug design- The modern approach of finding new drugs by identifying
target molecules (e.g. receptors) in the body and designing molecules(lead
compounds) to bind to it.

The drug development process.
Establishment of the
Food and Drug
administration (F.D.A.)
https://www.youtube.co
m/watch?v=fX2Kj14PzD
0

Now the process takes just a bit longer….
Pearson pg. 868

Administration of drugs- pharmaceutics
(pg 862 Pearson)

Parenteral modes of administration-
which do you think will have the fastest effect?
Pearson pg. 863

And so the pharmaceutical
industry was born…..

Lesson 2- Bioavailability- How effective is your drug?
Level 4: Recall the 3 factors which influence the bioavailability of a
drug in the body.
Level 7:Explain how the therapeutic window of a drug influences its
development as a marketable drug.
Level 5/6: Justify why the term toxic dose 50% (T.D. 50) is used for the
upper limit of a drug in humans and not lethal dose 50% (L.D. 50)

Starter…..
What do you think is the most lethal poison
known to us?
https://www.youtube.com/watch?v=flv0ql218
-A

Bioavailability
• The fraction of the administered
dose that reaches the bloodstream.
• 3 factors influencing it:
1. Mode of administration.
2. Solubility.
3. Functional groups present.

2. Solubility of the drug
Morphine
More polar, less soluble in lipid
environment, therefore finds it hard
to pass across cell membrane of
small intestine.
Better to administer intravenously.
Codine
Less polar, more soluble in lipid
environment e.g. passes across cell
membrane of small intestine.
Can be quite effective as an oral
administration.

3. Functional groups present
Recall covering the following functional groups from T10- Organic chemistry. *Functional groups can
influence: solubility, reactivity, charge and intermolecular bonding of a drug molecule.
Note: The IB are
very specific
when it comes to
the names of
these functional
groups, so be
careful!

Dosage - How much and how often?
• Calculations of dosage must take
bioavailability into account, as well
as possible side-effects and
potential problems of tolerance and
addiction.
• Other factors to consider include:
age, sex, weight, diet, environment
and interaction with other drugs the
patient is already taking.
• The main problem is keeping the
levels of drug within the
therapeutic window.

Quantifying the therapeutic window- Therapeutic index (T.I.).
In humans In animals

The larger the therapeutic
window/index, the safer the drug.
(a)Penecillin (b) Warfarin- blood thinning drug used in rat
poison and for peolpe with blood clotting problems.

D2- Aspirin and Penicillin.
3 lessons

Lesson 3- Making Aspirin.
Level 4: State the word equation for the
synthesis of aspirin.
Level 7: Explain why a strong acid is used
in this synthesis.
Level 5/6: Outline this reaction using structural
formulae.

Fast facts about Aspirin….
1. It was the first non-steroidal anti-inflammatory drug (N.S.A.I.D.) produced in the 1800s
by Bayer pharmaceutical.
2. Made by altering salicylic acid from the bark of the willow tree.
3. After the 1st world war, Germany was forced to give up the rights to solely produce
Aspirin, allowing the allied forces to benefit from its profits.
4. It is considered the most widely used drug in the world with over 100billion standard
tablets being produced each year!!$$$
5. Can be described as an analgesic or antipyretic drug as it ease pain by reducing
inflammation and fever. It controls the inflammatory response by inhibiting the release
of prostaglandins (‘pain molecules’).
6. Its structure is given in section 37 of the data book, along with some other drug
molecules.

Aim: To synthesise Aspirin.
•See Pearson method for this practical on scidrive.
Note will take full lesson, get started early!

Lesson 4- Purifying Aspirin.
Level 4: State what the steps are in the recrystallisation
process.
Level 7:Interpret the IR spectra of salicylic acid and
aspirin and be able to distinguish them from each
other.
Level 5/6: Describe how aspirin can be chemically
modified into a salt to improve its aqueous
solubility.

Aim: To purify a sample of Aspirin.
•See Pearson method for this practical on scidrive.
Note will take full lesson, get started early!

Lesson 5- Penicillin-The first antibiotic.
Level 4: Identify the beta-lactam ring in
penicillin.
Level 7: Explain why there is such a strain
on the beta-lactam ring in penicillin.
Level 5/6: Discuss the effects of chemically
modifying the side chain of penicillin.

Starter- A brief history of penicillin.
1. Fleming- Discovers the action of the mould.
2. Chain& Florey- Discover how to make large amounts of
penicillin.
3. Hodgkin- Deduces the structure of penicillin G from x-ray
crystallography( in databook section 37).
https://www.youtube.com/watch?v=0ZWjzcsTd5M

The structure of penicillin
• In section 37 of d.book.
• Made by combining the amino acids
cystine and valine (who's structures you
can see in section 33).
• Key point of focus is the R group which
can vary from one penicillin antibiotic to
the next.
• The presence of the ‘beta-lactam’ ring.
Taken from pg 877 Pearson.

A closer look at the β-Lactam ring.
• 4 atoms make up the ring, 3 C and
1 N. (make this ring with molymods)
• 2 of the carbons are sp3 hybridised
(i.e. have 4 single bonds) should have
bond angles of 109.5°.
• The other carbon is sp2 hybridised
and should have a bond angle of
120°.
• However, the ring is strained because
of the 90° angles between these
atoms- try it and see what happens! From pg 877 Pearson

How penicillin works….
• Once the beta-lactam ring breaks, the carbonyl
carbon of the amide group acts like a ‘hook’ in
your body and will hook onto the bacterial
enzyme- transpeptidase.
• This prevents the bacterium from building the
cross links it needs to hold its wall together and
so it bursts and dies!
• Cool fact- The polypeptide chains used to build
the cross-links to strengthen bacterial cell walls
contain the amino acid d-alanine. Only its
optical isomer L-alanine is found in humans, so
penicillin selectively targets bacteria and is
generally not toxic to animals!- Lucky!
From pg 877 Pearson

Antibiotic resistance and new generation penicillins
• Because of over-prescription of antibiotics
and unfinished courses of them, we are
encouraging the generation of ‘super-
bugs’
• They are resistant because they have the
enzyme penicillinase/beta-lactamase
which opens the beta-lactam ring and
renders it inactive.
• Next generation penicillin molecules are
developed to prevent this enzyme from
binding to it, by modifying the R group.
e.g. (a)- methicillin and (b) oxacillin.
Note: M.R.S.A.= Methicillin Resistant Staphylococcus
Aureus- what do we do now?!!
From pg 878 Pearson.

Lesson 6- The ‘innocent’ little poppy.
Level 4: Compare the structures of
morphine, codeine and diamorphine.
Level 7: Explain the increased potency of diamorphine
compared to morphine based on their chemical
structure and solubility.
Level 5/6: Outline the pros and cons of using
opiates as analgesics.

Starter- Where do opioids come from?
https://www.youtube.com/watch?v=5xmeH_E
dPRA

Print out (in
colour) for
students with
slide 42 on the
back- from pg
881 Pearson.
Note- all 3
structures are
in section 37 of
d.book

The blood-brain barrier (B.B.B.)
• The blood is a predominantly aqueous
environment.
• The brain is surrounded by a fatty
membrane/layer known as the blood-
brain barrier (b.b.b.)
• The best narcotics (pain killers acting on
the brain) are therefore not too polar and
not too non-polar, i.e. ‘just right’ for
crossing this barrier.
• Out of the 3 opiates, Heroin is the best at
crossing the b.b.b. (can you see why from
using section 37 of the d.book?)

Deriving codeine and diamorphine from morphine
e.g. CH3I
CH3COOH or
*(CH3CO)2O
Note: *(CH3CO)2O is the condensed formula for ethanoic/acetic
anhydride. Can you remember where else we might have used
this reagent in this topic? Can you draw what it would look like?
Makes it less polar
so crosses bbb
faster, but this group
doesn’t allow it to
bind as well to
opioid receptors.
Much less polar and so
crosses bbb fastest.
However, these two
ethanoate groups must
be returned to OH groups
in the brain if the
molecule is to be able to
bind to the opioid
receptors. A ‘pro-drug’
From pg 882
Pearson

A short history of opioids….. 8min.
https://www.youtube.com/watch?v=4MIseokX
cxY

D4-pH regulation of the stomach
2 lessons

Lesson 7- Ouch! My stomach hurts
Level 4: State some of the ways that the
pH of the stomach can change.
Level 7: Explain how Proton pump inhibitors and
H2 receptor inhibitors work to control the pH
of the stomach.
Level 5/6: Write balanced equations for the
neutralisation of HCl using antacids.

Starter- stomach acid can be a real pain!
https://www.youtube.com/watch?v=TdK0jRFp
WPQ
Q. So do any of you know why we have stomach acid of pH 1-2
in there in the first place?!

A closer look at the structures of the stomach.
1. HCl is generated by parietal cells in the
gastric glands in the lining of the stomach.
2. This gives a pH of 1-2.
3. This kills off *MOST bacteria and allows the
digestive enzymes of the stomach to do
their job.
4. Certain factors can increase this production
of HCl:
● Stress/alcohol/taking
aspirin/caffeine/smoking.

Preventing the over-production of HCl in the stomach.
1. Blocking stomach acid production.
• Histamine is a hormone which can
increase the release of HCl in the
stomach.
• It achieves this by binding to ‘H2
’
(histamine receptors) in the parietal
cells of the stomach.
• A drug which blocks/antagonises this
hormone-receptor interaction is
Ranitidine (Zantac) see section 37 of
d. book.
Histamine
Ranitidine

Preventing over-production of HCl in the stomach.
2. Blocking stomach acid secretion.
• H+ ions are pumped into the stomach from the
parietal cells across the cell membrane through
a gastric proton pump.
• As H+ ions come across, K+ ions are exchanged
to replace the loss of +ive charge.
• Since there is a lot of H+ already inside the
stomach, this process is against the
concentration gradient and so requires energy
through the hydrolysis of A.T.P.
• Drugs which inhibit this pump include
omeprazole (Prilosec) and esomeprazole
(Nexium).

Antacid equations to know…
1. Calcium hydroxide + hydrochloric acid-->
2. Magnesium hydroxide + hydrochloric acid-->
3. Aluminium hydroxide + hydrochloric acid-->
4. Sodium hydrogen carbonate + hydrochloric acid
5. Sodium carbonate + hydrochloric acid
Note: All of the bases are weak bases. Why do you think you
can’t use a strong base?

P.P.I.s Vs. Antacids.
Mylanta~ treating the symptoms.
Vs.
Treating the source/cause
(omeprazole )Prilosec

*Heliobacter pylori & Barry
Marshall
https://www.youtube.com/watch?v=V_U6czb
DHLE

Lesson 8- pH and buffering.
Level 4: Define what a buffer is and why
they are necessary in the body.
Level 7: Explain how the blood buffers
against changes in pH due to drug or
food intake.
Level 5/6: Solve buffer problems using the
Henderson- Hasselbalch equation.

The pH of your blood can change…
• The pH of your blood MUST rest
around 7.4.
• Certain drugs, foods, lack of exercise,
can affect this pH.
• A pH lower than 7.4 is known as
‘acidosis’ and above it is known as
‘alkalosis.’ This can result in death!
• A buffer system exists in your blood
to keep the pH around 7.4 despite
small amounts of acid or base being
added to it.

What is a buffer?
A solution/system which maintains a certain pH by neutralising
the addition of small amounts of a strong acid/base.
e.g. CH3COOH/CH3COO-
e.g. NH3/NH4
+

Making buffer systems.
Way 1:
Weak acid+ conjugate base salt (in solid form or *solution).
Or.
Weak base + conjugate acid salt (in solid form or *solution).

Making buffer systems
Way 2:
Add a strong base to a weak acid
( ½ neutralisation/1/2 equivalence point/midpoint)
At this point you will have equal amounts of the weak acid and it’s
conjugate base because:
e.g. CH3COOH + NaOH
Similarly, you can make a buffer system by adding just the right amount of a strong acid to a weak base.

The Henderson- Hasselbalch equation
• Henderson (American) & Hasselbalch (Danish) were
studying acidosis in the blood.
• Their equation is in section 1 of the d.book☺
• pKa of weak acids you will find in section 21 of d.book.
• *The concentrations of weak acid and conjugate base
may be diluted if two solutions are being mixed.
• You do not have to worry about dilution factor if a solid
salt of the acid is added to ‘supplement’ the
concentration of weak base.

Example #3 (pg. 891 Pearson)
0.15 mol.dm-3

Homework for more practice!
See worksheet 3.7 on buffers on drive☺

D5-Antiviral medications
1 lesson.

Lesson 9- The war against viruses!
Level 4: Draw a labelled diagram of the
structure of a virus Vs. a bacterium.
Level 7: Compare and contrast the structure of
sialic acid to the two anti-flu drugs.
Level 5/6: Outline why viruses like influenza and
H.I.V. are so difficult to treat.

Starter-
Trailer to the constant gardener:
https://www.youtube.com/watch?v=1l1lzzfpW
FU

Viruses Vs. Bacteria
• Viruses are much smaller than bacteria.
• They are very difficult to classify as living.
• They are ‘parasitic’ in nature in that they need another living cell to thrive.
• They can contain either DNA or RNA.

Viral replication.
• In order to find out ways of stopping viruses, we need to
understand the various steps of its replication and
‘reproductive’ process.
Q. Can you suggest any points at which you could attack
the virus?
1. Stop it from binding to the host cell.
2. Prevent DNA/RNA transcription/copying.
3. Prevent release of newly formed viral particles from
infected cell.

Drugs against viral infection
Vaccines- prevention against infection.
• E. Jenner (1800s):
https://www.youtube.com/watch?v=jJwGNPRmyTI
• A small amount of the virus ‘attenuated’ is injected into the
patient in order to illicit a mild immune response.
• The immune system generates antibodies against this
pathogenic particle.
• Immune memory is generated which can deal with the full virus
should it meet it in the future.
• In 1980 the W.H.O. declared smallpox to be eradicated from all
parts of the world!
• Vaccine comes from the Latin word ‘vacca’ (for cow☺)
• Often raises controversy amongst people- should we be obliged
to vaccinate ourselves?- take this quick survey to see what WE
think:
• https://docs.google.com/forms/d/11Em_POw1X4KUJNpdZB8se
Cdf6XCCmPrRig0JgQUA_3Y/edit
Anti-viral – Treatment once infected.
• If a virus has overcome the body’s
immune system, it is very hard to stop!
• They have very little, in terms of
structure, to target.
• They mutate rapidly.
• Multiple drugs have to be administered to
effectively keep the virus ‘at bay’
• Average cost of drug cocktail for HIV is
$12,000 per patient /yr (For the rest of
your life……….)

Case study 1- The influenza virus.
• Between 2009-2010 250,000 people died from the
(H1N1) strain of the influenza virus (a.k.a. ‘swine flu’).
• At its height it was declared a pandemic (from the word
pandemonium).
• Some people argue that the situation may have been
over-hyped in order to increase sales of the of the flu
vaccine…….
• Do we really need the ‘flu shot?’
https://www.youtube.com/watch?v=GjzM
MqVFDH0

Anti- influenza drugs.
• Target either the H spikes (Hemagglutinin) or the N
spikes (Neuraminidase)- hence the classification of flu
viruses using the H,N nomenclature system (e.g. H1N1)
• Hemagglutinin is the protein the virus uses to dock onto
the host cell.
• The neuraminidase protein is an enzyme which the virus
uses to release itself from the host cell once it has
infected that cell:

Neuraminidase is the main target for drugs.
The enzyme- substrate complex.
• Neuraminidase is the enzyme.
• Sialic acid is the substrate.
• Q. what key functional groups have
been highlighted in the picture on
the right?
Structure of Sialic acid
From Pearson pg. 897

Anti- flu drugs Substrate- sialic acid
From pg 897 Pearson- note, both of these are in section 37 of d. book.

Case study 2- The H.I.V. virus.
• First appeared in 1981.
• Acquired Immunodeficiency Syndrome (A.I.D.S.) results from a H.I.V. infection.
• It has had pandemic status since then.
• Like flu, it can be described as a ‘retro-virus’ as its genetic material is initially in RNA format which must be
converted ‘back’ to DNA format in the host cell before it can replicate.
• This is achieved via reverse transcriptase.
Combination therapy:
https://www.youtube.com/watch?v=EYqsgAQ7yNM
Charlie Sheen and combination therapy:
https://www.youtube.com/watch?v=yvmMB4PBxp0

Anti- HIV drugs.
• Very difficult to contain- mutates
far more rapidly than flu.
• Destroys helper T-cells.
• Can lie dormant.
• Combination approach.
• Very expensive- sub-Saharan
countries struggle to afford- (see
‘constant gardener’ movie)
WHO on HIV:
https://www.youtube.com/watch?
v=n61IAf07VAQ

D6-Environmental impact of medications.
1 lesson

Lesson 10- Green chemistry.
Level 4: List off the 3 main forms of chemical
waste which threaten our environment.
Level 7: Explain the 12 principles of green
chemistry.
Level 5/6: Describe how green chemistry has
been applied to the production of Tamiflu.

Starter- The 12 principles of green chemistry.
Fun video recap☺
https://www.youtube.com/watch?v=_nvXzxglI
T0
*Print out handout on the 12 principles from Pearson for students.

3 Examples of Chemical waste
1. Solvents from pharma industry (and school
lab experiments!)
2. Nuclear waste.
3. Antibiotic waste.

1. Solvents from the pharma
industry.
Pick 2 solvents from each list and then run it through risk assess – see what it says…..
From Pearson pg. 931

2. Nuclear waste.
Low level waste (L.L.W.)
• Radioactive isotopes with short half
lives e.g. I131 in medical imaging.
• Give off small amounts of ionizing
radiation for a short time e.g. 8 days
for I131.
• Contaminated gloves, shoe covers,
paper towels and implements are
stored for these 8 days and then
disposed off as general waste.
High level waste (H.L.W.)
• Radioactive isotopes with long half
lives e.g. U238.
• Give off large amounts of ionizing
radiation for a very long time e.g. 4.5
billion years U238 !
• Store under water for 5-10 years
initially, then put into heavily
shielded containers and stored under
ground.
Check out this video: https://www.youtube.com/watch?v=HQKT4axR6RU

3. Antibiotic waste.
• In the lesson on penicillin, we learned that bacteria have become resistant to it over the many years that
it has been used- ‘antibiotic resistance’
• We then mentioned that the antibiotic methicillin (a derivative of penicillin) was developed.
• However, we now have the issue of ‘super-bug’ such as M.R.S.A. methicillin resistant staph. Aureus,
which is particularly prevalent in hospitals.
• The spread of antibiotic resistant bacteria is primarily the result of overuse/prescription of antibiotics.
• However, there are other things we are doing which don’t help either:
Nice video on resistance: https://www.youtube.com/watch?v=znnp-Ivj2ek

Making Tamiflu from The Chinese star plant.
Green chemistry principle # 7- Use of renewable feedstocks.
• Shikimic acid is the precursor to
Tamiflu.
• Tamiflu is the only known drug to
combat the H5N1 (‘avian flu’)
• The ‘waste bit’ comes from the fact
that we can’t synthesise it in the lab
and so need to grow lots of this plant
or alternatives.
• Can be produced from the
fermentation reactions of bacteria-
being researched by Roche pharma.

Why should industries bother?
It eventually becomes government policy, so
those who are ahead of the game, will stay
ahead!
https://www.youtube.com/watch?v=rIE4T2HL
W7c

End of SL content☺
Revision time!

Option D medicinal chemistry SL

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