Dr.Narmin Hamaamin Hussen

1. Anti-Malarial
agents
Medicinal chemistry IV /4 th Class/2nd Semester
Lecture 7
Dr.Narmin Hamaamin

2. Antimalarial Agents
▪ Malaria, one of the most widespread diseases, is caused by a Plasmodium
parasite and is transmitted to humans by the Anopheles mosquito.
▪ It infects several hundred million people each year, results in several
million deaths annually, and is a complex disease to treat.
▪ Malaria’s name is derived from “mala aria” or bad air, and has been called
ague, intermittent fever, marsh fever, and The Fever. The name is based on
the early knowledge that malaria was associated with swamps and badly
drained areas.
▪ There are three potential ways to control malaria: elimination of the
vector, drug therapy, and vaccination.

3. ▪ Plasmodium falciparum is estimated to cause
approximately 50% of all malaria. It causes the
most severe form of the disease and, because
patients feel ill between acute attacks, debilitating
form of the disease. One of the reasons it leaves
the patient so weak is because it infects up to 65%
of the patient’s erythrocytes. P. falciparum is
responsible for most of the deaths.
▪ Plasmodium vivax is the second most common
species causing about 40% of all malarial cases. It
can be very chronic in recurrence because it can
reinfect liver cells.
▪ Plasmodium malariae: Although causing only 10% of all
malarial cases, relapses are very common.
▪ Plasmodium ovale: This species is least common

4. Gametocyte

5. Symptoms of Malaria
▪ Symptoms of malaria include fever and flu-like illness, including shaking
chills, headache, muscle aches, and tiredness. Nausea, vomiting, and diarrhea
may also occur.
▪ Malaria may cause anemia and jaundice (yellow coloring of the skin and eyes)
because of the loss of red blood cells

6. Classes Drugs
Cinchona alkaloids Quinine, quinidine
4-Aminoquinolines Chloroquine, amodiaquine, Piperaquine,
Mefloquine
8-Aminoquinolines Primaquine, tafenoquine
Biguanide Proguanil (chloroguanide)
Diaminopyrimidine Pyrimethamine
Sulfonamides and sulfone Sulfadoxine, sulfamethopyrazine, dapsone
Amino alcohol Halofantrine, lumefantrine
Sesquiterpene lactones
(Artemisia derivatives)
Artemisinin, Artemether, Artesunate,
Naphthyridine Pyronaridine
Naphthoquinone Atovaquone
Antibiotics Tetracycline, Doxycycline, Clindamycin
Fixed combinations Sulfadoxine and pyrimethamine
Atovaquone and proguanil
Artemether and lumefantrine
Classification of antimalarial agents

8. Cinchona alkaloids (quinine, quinidine) :
▪ The cinchona tree produces four alkaloids that function as prototypical molecules from which, until
recently, most antimalarial drugs were based.
▪ These alkaloids are the enantiomeric pair quinine and quinidine and their desmethoxy analogs,
cinchonidine (for quinine) and cinchonine (for quinidine).
▪ The alkaloid derived from the bark, quinine, was isolated in the mid-1820s.
▪ Quinine, a very the bitter substance has been used by millions of malaria sufferers
▪ Quinine was the first known antimalarial. It is a 4-quinolinemethanol derivative bearing a
substituted quinuclidine ring.
▪ Recently, it has been employed successfully to treat chloroquine-resistant strains of Plasmodium
falciparum and is considered to be the drug of choice for these resistant strains.
▪ Quinidine, the C-9 stereoisomer of quinine, is also an effective antimalarial but suffers from the
fact that it is considerably more toxic than quinine.
▪ Quinidine is also used as an antiarrhythmic agent
Black water fever?
Cinchonism?

9. ▪ The second class of chemicals that played a role in the development of synthetic antimalarials were the 9-
aminoacridines.
▪ 9-Aminoacridine was known to exhibit antibacterial activity, whereas a derivative of 9-aminoacridine synthesized in
1934, quinacrine, was found to possess weak antimalarial activity

10. 4-Aminoquinolines
▪ The 4-aminoquinolines are the closest of the antimalarials that
are based on the quinine structure.
▪ This group is substituted at the same position 4 as quinine and
have an asymmetric carbon equivalent to quinine’s C-9
position.
▪ Just as with quinine, both isomers are active and the 4-
aminoquinoline racemic mixtures are used.
▪ For the newest drug in this series, mefloquine, only the R, S-
isomer is marketed.
▪ A significant difference from the commercial cinchona
alkaloids is replacing the 6-methoxy on quinine with a 7-
chloro substituent on three of the 4-aminoquinolines.
Amodiaquine is no longer used in the United States.
▪ Structure– activity relationships demonstrated that the
chloro at the 8- position increased activity, whereas
alkylation at C-3 and C-8 diminished activity.
▪ The replacement of one of its N-ethyl groups with a
hydroxyethyl produced hydroxychloroquine, a compound with
reduced toxicity that is rarely used today except in cases of
rheumatoid arthritis.

11. ➢Chloroquine and Chloroquine Phosphate (Aralen):
▪ Chloroquine is the most effective of the hundreds of 4-aminoquinolines synthesized and
tested during World War II as potential antimalarials.
▪ Chloroquine is also prescribed for treatment of rheumatoid arthritis, discoid lupus
erythematosus, and photosensitivity diseases
▪ The phosphate salt is used in oral dosage forms (tablets), and the hydrochloride salt is
administered parenterally.
▪ Chloroquine is commonly administered as the racemic mixture, because little is gained by
using the individual isomers. The drug is well absorbed from the GI tract and distributed to
many tissues, where it is tightly bound and slowly eliminated
▪ Until recently, chloroquine has been the main antimalarial drug used for both prophylaxis and
treatment.
▪ Chloroquine is an excellent suppressive agent for treating acute attacks of malaria caused
by Plasmodium vivax and Plasmodium ovale.
▪ The drug is also effective for cure and as a suppressive prophylactic for the treatment of
Plasmodium malariae and susceptible Plasmodium falciparum

12. Mechanism of action:
▪ Chloroquine enters parasite cells by simple diffusion. Chloroquine then becomes protonated as the digestive vacuole is known to
be acidic (pH 5.5), chloroquine then cannot leave by diffusion.
▪ Chloroquine inhibits polymerization of heme and accumulation of heme.
▪ Chloroquine binds to heme (or fp) to form what is known as the fp-chloroquine complex, this complex is highly toxic to the cell
and disrupts membrane function.
▪ Action of the toxic compound results in cell lysis and ultimately parasite cell autodigestion

13. N-dealkylation.

14. ➢ Hydroxychloroquine
▪ Structurally, it differs solely with a hydroxy moiety on one of the N-ethyl groups
▪ Like chloroquine, it remains in the body for over a month, and prophylactic dosing is once weekly.

15. ➢ Mefloquine (Lariam):
▪ The newest of the 4-aminoquinolines, mefloquine, is marketed as the R,S-isomer.
▪ It was developed in the 1960s as part of the U.S. Army’s Walter Reed Institute for Medical Research
antimalarial research program.
▪ It differs significantly from the other agents in this class by having two trifluoromethyl moieties at positions 2
and 8 and no electronegative substituents at either position 6, (quinine) or 7, (chloroquine).
▪ It is a quinoline-methanol compound structurally similar to quinine.
▪ Mefloquine also differs from chloroquine and its analogs by being a schizonticide acting before the parasite
can enter the erythrocyte.
▪ Mefloquine is an effective suppressive prophylactic agent against Plasmodium falciparum both in
nonimmune populations (travelers coming into regions of malaria) and in resident populations.
▪ Mefloquine is teratogenic in rats, mice, and rabbits. There is an FDA-required warning that this drug can
cause exacerbate mental disorders and is contraindicated in patients with active depression,
carboxymefloquine

16. ➢ Amodiaquine.
▪ Amodiaquine is no longer marketed in the United States, but it is available in Africa.
▪ Mechanistically, it is very similar to chloroquine and does not have any advantages over the
other 4-aminoquinoline drugs.
▪ When used for prophylaxis of malaria, it had a higher incidence toxicity of hepatitis and
agranulocytosis than that was chloroquine.

17. Amino alcohol
➢ Halofantrine (Hafan):
➢ Lumefantrine:
▪ Halofantrine, a member of the 9-phenanthrenemethanol class
▪ Halofantrine is considered to be an alternative drug for the
treatment of both chloroquine-sensitive and chloroquine-resistant
Plasmodium falciparum malaria, but its efficacy in mefloquine-
resistant malaria can be questionable.
▪ It is generally believed that halofantrine acts through a mechanism
similar to that of the 4-aminoquinolines.
▪ Cardiovascular toxicity includes orthostatic hypotension and dose-
dependent lengthening of QTc intervals
▪ Lumefantrine, an effective erythrocytic schizonticide, is a derivative of
halofantrine that has been reported to exhibit antimalarial activity when
combined with artemether in the treatment of multidrug-resistant Plasmodium
falciparum.
▪ Lumefantrine has a relatively long half-life of 3 to 6 days, which makes it ideal for
combining with the short half-life artemisinins.
▪ The drug is quite lipophilic, and a diet rich in fat increases the bioavailability of the
drug

18. 8-Aminoquinolines:
➢ Pamaquine/primaquine:
▪ Pamaquine, an 8-aminoquinoline, was first introduced for the treatment of
malaria in 1926 and has since been replaced with primaquine.
▪ Primaquine is active against latent tissue forms of Plasmodium vivax and
Plasmodium ovale, and it is active against the hepatic stages of Plasmodium
falciparum.
▪ The drug is not active against erythrocytic stages of the parasite but does
possess gametocidal activity against all strains of plasmodium
CYP3A4
(99%)

19. ➢ Tafenoquine:
▪ Tafenoquine is a new 8-aminoquinoline derived from primaquine which is reported to exhibit reduced
toxicity, a prolonged half-life (2-3 weeks) and is active against the erythrocytic stages of the malaria
including chloro-quine resistant strains.
▪ The drug may also have activity against liver stages of the disease and gametocytes.

20. Diaminopyrimidine (Folate synthesis antagonists):
➢ Pyrimethamine (Daraprim):
▪ Pyrimethamine is a potent inhibitor of DHFR. The drug has been shown to have
a significantly higher affinity for binding to the DHFR of plasmodium than to the
host enzyme (>1,000 times in Plasmodium berghei) and, as a result, has been
used to selectively treat plasmodium infections
▪ The combination of pyrimethamine with a long-acting sulfonamide, sulfadoxine,
which blocks dihydrofolate synthesis by blocking the incorporation of PABA into the
dihydrofolate, is called Fansidar, which produces sequential blockage of
tetrahydrofolate synthesis similar to that reported for treatment of bacterial
infections

21. Naphthoquinone
➢ Atovaquone–proguanil
▪ Atovaquone and proguanil HCl are administered in combination in the
ratio of 2.5 atovaquone to 1 proguanil HCl.
▪ The two drugs together exhibit synergy in which proguanil reduces the
effective concentration of atovaquone needed to damage the mitochondrial
membrane and atovaquone increases the effectiveness of proguanil but not
its active.
▪ Proguanil was developed decades earlier as a folic acid antagonist and
functions as a prodrug. The active form of proguanil is cycloguanil, which
acts as a DHFR inhibitor

22. Artemisinins:
▪ The most recent additions to the drug therapy for malaria are artemisinin and its
derivatives. Isolated from Artemisia annua (qinghao, sweetworm wood), this material
has been used by Chinese herbalists since 168 bc ▪ Arteether (Ethyl ether of dihydroartemisinin),therapeutically equivalent to
quinine in cerebral malaria.
▪ A longer t1/2 & more lipophilic than artemether favouring accumulation in brain

23. Antibiotics:
▪ Various antibiotics have proven useful in the treatment of malaria. They can be
used alone as prophylaxis or in combination with quinine or artesunate as
treatment measures. The most commonly used antibiotics are doxycycline,
clindamycin, and azithromycin.

24. Sulfonamides and sulfone

25. ➢ Fixed Combination
➢ Antimalarial therapy combination drugs currently in use
▪ The concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve
therapeutic efficacy and also delay the development of resistance to the individual components of the combination
➢ Chloroquine (CQ) plus sulfadoxine pyrimethamine (SP)
➢ Amodiaquine (AQ) plus sulfadoxine- pyrimethamine (SP)
➢ Atovaquone-proguanil
➢ Mefloguine- sulfadoxne pyrimethamine (MSP)
➢ Quinine plus tetracycline or doxycycline
➢ Verapamil

26. Development of Vaccines
▪ The complex nature of the parasite and its interactions with human red blood
cells provide a large number of antigenic sites for the immune system. A T-cell
response that includes both CD4+ and CD8+ T cells and production of
interferon and nitric oxide synthase induction is additional evidence that the
human immune system does detect the parasite and responds accordingly.
▪ An ideal vaccine should, at a minimum, be effective against both P.
falciparum and P. vivax, the two species responsible for 90% of malarial
cases.
▪ A malaria vaccine is a vaccine that is used to prevent malaria. The only
approved vaccine as of 2015 is RTS, S, known by the brand name Mosquirix.
It requires four injections, and has a relatively low efficacy. Due to this low
efficacy, the World Health Organization (WHO) does not recommend the
routine use of the RTS, S vaccine in babies between 6 and 12 weeks of age.
▪ The Oxford vaccine is the first to meet the WHO goal of 75% efficacy against
the mosquito-borne parasite disease. Larger trials are now beginning,
involving 4,800 children in four countries.