Pharmaceutical Pharmaceutical

Chemistry I Chemistry II

Antibacterial drugs 1) Antimalarial Agents

Chemotherapeutic

2) Antimycobacterial Agents
3) Antiprotozoal Drugs
agents

4) Antifungal Drugs
5) Antihelmintics and
ectoparasitic infections
6) Antiviral Drugs
7) Anticancer Drugs
8) Cholinergic drugs

Pharmaceutical Pharmaceutical
Chemistry III Chemistry IV
Drugs affecting CVS, Drugs affecting CNS, hormones and
antihistaminics and NSAIDs related drugs, and vitamins
Antimalarial Drugs
Tutorial 1
 Learning Outcomes
Know the different species of Plasmodium and the life cycle of plasmodium parasite.

Classify the Antimalarial drugs according to spectrum of activity and according to their
chemical structure..

Know the structure of quinine, its basic properties and stereochemistry.

Know the structure of quinidine and its diasteromeric relationship to quinine

Know the impact of metabolic blockers on half life (Mefloquine).

To compare chloroquine and primaquine (essential drugs used in malarial infections)

Know the different combination therapies for chloroquine resistant P.falciparum and
Artemisinins as the most recent class in antimalarial therapy.
 Malaria

Malaria is caused by the Plasmodium parasite

It is transmitted only by Anopheles female
mosquitoes
The parasite infect the liver and red blood cells.
Malaria is characterized by attacks of high
fever, chills, nausea and vomiting.
Malaria can kill by infecting and destroying
red blood cells (anaemia) and by clogging the
cerebral vessels (cerebral malaria) or other vital
organs.
Malaria is caused by four species of
Plasmodium protozoa
 P. Falciparum  P. Vivax
 P. Malariae  P. Ovale
P. Facliparum
 Erythrocytic cycle merozoites Primary
is completed in 48 liver stages
h (except P.
malariae 72 h)
RBCs
Secondary
merozoites liver stages
(Hypnozoites)
Vivax, Ovale
 within minutes bite from infected female
sporozoites invade Anopheles mosquito →
hepatocytes in liver sporozoites from
mosquito´s salivary
they multiply (asexually), glands enter the
and transform into circulation
schizonts and then
merozoites (no symptoms)
merozoites rupture the Liver life cycle
hepatocytes and enter the completed in
bloodstream 48 hours
(except P.
* malariae 72
hours)
merozoites infect patient´s
erythrocytes, reside there gametocytes
3-4 days and reproduce via (the only
schizonts to more RBCs sexual forms)
merozoites or gametocytes infect the
both bursting out (fever mosquito
and chills), then merozoites “mating“ in its
infect more erythrocytes stomach
*P. vivax, ovale: merozoites infect other liver cells building a reservoir of hypnozoites
that can produce secondary schizonts months or years after primary attack (relapsing
8
malaria)
The life cycle is explained to
understand the stages of the
infection and the treatment but
you will not be asked to
draw/mention the cycle

9
 Antimalarial Drugs
Inhibitors of
Quinoline
Tetrahydrofolate Others Artemisinins
Derivatives
Synthesis
A) 4-substituted B) 8- Pyrimethamine Halofantrine Artemisinin
Quinoline Amino- Sulfadoxine Lumefantrine Dihydroartemisinin
Quinine quinolines
Proguanil Atovaquone Artemether
Quinidine
Cycloguanil Doxycycline Artemsunate
Mefloquine Primaquine Trimethoprim Tetracycline
Chloroquine Pamaquine
Hydroxychloroquine Tafenoquine
Amodiaquine
(Quinacrine
Pyronaridine)

You have to know all the drug

names in the table
2) Explain, why a combination therapy is more effective against
malaria than a monotherapy (two reasons)?

 None of the antimalarials is effective against

all liver and red blood cells stages of the life
cycle. So complete cure requires more than
one drug

 To decrease the development of resistance

3) a) Consider the structure of quinine and name all structural
elements present. Which moieties are essential for the antimalarial
activity?

Tertiary amine

Aromatic ring important

(not necessarily quinoline)

Quinine has 4 chiral centers

Which moieties are essential for the antimalarial activity?

Tertiary amine, aromatic ring

b) Assign the pKa values of 4.2 and 8.8 to the quinoline and quinuclidine moieties.
Which nitrogen is protonated in quinine hydrochloride?

*
*
pKa = 8.8
quinidine.
quinine
Quinine Quinidine
pKa = 4.2

Explain the “stereochemical relationship” between quinine and quinidine.

Diastereomers (opticalisomers, not mirror image, not superimposable)

What is the major indication of quinidine?

 Cardiac arrythmias
quinine.HCl
quinine hydrochloride

In quinine.HCl only the quinuclidine ring is protonated (the more basic one)
4) The quinoline derived antimalarial drug mefloquine has a considerably longer half-life
than quinine (20 days versus 11 hours). Explain by metabolism.

Quinine Mefloquine
Half-life 11 hours Half-life 20 days
2´-CF3 group
blocks the
quinine site of
metabolism
metabolism

(major)
5) Draw the structures of chloroquine and primaquine. What is the major difference in the
antimalarial activity of both drugs?
Chloroquine
Lethal for the erythrocytic forms of all
Plasmodium species (except for the
resistant forms of P.falciparum) – drug of
choice for prophylaxis and treatment.
 No activity against latent liverforms of
P.vivax and P.ovale.
Since mid-90s increasingly ineffective
due to resistant Plasmodium strains
Primaquine
Active against exo-erythrocytic forms of
P.vivax & P.ovale and also the hepatic
stages of P.falcipare
 Drug of choice against relapsing P.vivax
and P.ovale (eradicates the hypnozoites
remaining in the liver “radical cure”)
6) Why is the quinoline ring in chloroquine more basic than in quinine?
Explain using the concept of a vinylogous amidine.

The quinoline ring in chloroquine more basic than in quinine due to extra resonance
stabilization of the protonated form by the nitrogen at no.4 :

Functional
group:
vinylogous
amidine
amidine

vinylogous amidine
18
7) Carboxyprimaquine is the major metabolite of Primquine. Explain
its formation by mechanism

Primaquine

deamination

Aldehyde

oxidation
Carboxyprimaquine
9) Draw the mechanism for the metabolic formation of cycloguanil
from the prodrug proguanil

Proguanil
prodrug
Biguanide

metabolism

Cycloguanil
Proguanil

Cycloguanil
Triazine
 endoperoxide
10) Draw the structures of dihydroartemisinine, artemether and
artemsunate. (Artemisinin will be given in the questiom)

Lipophilic Hydrophilic

Which of these three drugs is the most lipophilic and which is the most hydrophilic ?

Why are these drugs not used for malaria prophylaxis?

 Because of short t1/2 and danger of resistance development.

Artemisinin-based combination therapy (ACT) is the most effective

of the known anti-malarial treatments
8) Explain why amodiaquine is more likely to cause hepatoxicity than pyronaridine by an
appropriate metabolic reaction.
Why are patients with low glutathione levels expected to be at higher risk of
hepatotoxicity caused by these drugs?

pyronaridine amodiaquine

Amodiaquine is hepatotoxic
Amodiaquine is hepatotoxic

Toxicity

Quinonimine
toxic metabolite

Detoxification by GSH
Therefore patients with low glutathione levels
expected to be at higher risk of
hepatotoxicity
amodiaquine
pyronaridine

less hepatotoxic than amodiaquine

because of the steric hindrance at
p-aminophenol group
 Study Guide (tut 1)
 The life cycle is explained to understand the stages of the infection and
the treatment but you will not be asked to draw the whole cycle or part
of it.
 You have to know all the drugs’ names in the classification table.
 Drugs to be memorized : chloroquine, primaquine.
 Other drugs in the tut and the lecture slides are to be recognized when
they are drawn to you,
 You will be given the structure of Artemisinin and asked to draw the
other derivatives but not from scratch)
 The metabolic reactions outlined for primaquine, cycloguanil and
amodiaquine are of course to be understood and you may be asked to
draw these reactions
 Synthetic pathways in the lectures are to be understood well, and you
may be asked to draw these reactions.