This document provides information on various anti-malarial agents. It discusses the life cycle of Plasmodium parasites and the four species that cause malaria in humans. It then describes various classes of anti-malarial drugs including those derived from natural sources like cinchona alkaloids and artemisinin, as well as synthetic agents like chloroquine, primaquine, mefloquine, and antifolate drugs. For each class, it provides details on examples, mechanisms of action, structure-activity relationships, resistance issues, and pharmacological properties. The document aims to comprehensively cover the major therapeutic options available to treat malaria.

1. Anti-malarial agents
Ravish Yadav

2. Introduction
• 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 is caused by four species of the one-cell protozoan of the
Plasmodium genus. They are:
1. Plasmodium falciparum: This species is estimated to cause approximately
50% of all malaria. It causes the most severe form of the disease
2. Plasmodium vivax: This species is the second most common species
causing about 40% of all malarial cases.
3. Plasmodium malariae: Although causing only 10% of all malarial cases,
relapses are very common.
4.Plasmodium ovale: This species is least common.

3. Life-cycle of plasmodium

4. • The mosquito stores the sporozoite form of the protozoan in its salivary
glands. Upon biting the patient, the sporozoites are injected into the patient’s
blood
• Within minutes after being injected into the patient’s blood, the sporozoites
begin entering hepatocytes where they become primary schizonts and then
merozoites. At this point, there are no symptoms.
• Depending on the Plasmodium species, the merozoites either rupture the
infected hepatocytes and enter systemic circulation or infect other liver cells.
• Merozoites in systemic circulation now infect the patient’s erythrocytes where
they reside for 3 to 4 days before reproducing. The reproduction stage in the
erythrocyte can either produce more merozoites or another form called
gametocytes.

5. • the newly formed merozoites or gametocytes burst out of the infected
erythrocytes.
• The new merozoites infect additional erythrocytes and continue the cycle of
reproducing, bursting out of the erythrocytes, and infecting more
erythrocytes.
• The debris from the destroyed erythrocytes is one of the causes of severe
fever and chills.
• The conversion of merozoites results in male and female gametocytes.
• After entering the mosquito, they “mate,” producing zygotes in the mosquito’s
stomach. The latter reside in the mosquito’s stomach endothelium oocysts.
• Eventually, they migrate as sporozoites to the mosquito’s salivary gland where
the cycle begins again when the mosquito bites a human.

6. • Drugs Used to Prevent and Treat Malaria
There are four possible sites for drug therapy at this stage of the disease.
1. Kill the sporozoites injected by the mosquito and/or prevent the sporozoites
from entering the liver.
2. Kill the schizonts residing in hepatocytes and/or prevent them from
becoming merozoites.
3. Kill the merozoites in the blood and/or prevent them from developing into
gametocytes.
4. Kill the gametocytes before they can enter the mosquitoand reproduce into
zygotes.

7. Life-cycle of plasmodium

8. Classification of Antimalerial Drugs
1. Drugs from natural Origin
a. Cinchona Alkaloids-
eg. Quinine, Quinidine
b. Artimisinin and its derivatives
eg. Artemisinin, Artemether, Artesunate
2. Synthetic Antimalerial agents
a. 4-Aminoquinolines- eg. Chloroquine
b. 8-Aminoquinolines- eg. Primaquine
c. Quinolinemethanols- eg. Mefloquine
d. Miscellaneous agents- eg. Halfantrine
e. DHFR inhibitors- eg. Pyrimethamine, Proguanil, cycloguanil, atovaquone,
sulfadoxine
3. Combination Therapy- eg. Sulfadoxine and pyrimethamine
Atovaquone and proguanil, Artemether and lumefantrine

9. CINCHONA ALKALOIDS
• 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).
• Their numbering system is based on
rubane.

10. CINCHONA ALKALOIDS

11. Stereochemistry:-
•They have 4 streogenic centers at C3, C4, C8 and C9.
•The stereochemistry differs at positions 8 and 9 with
quinine (and cinchonidine) being 8S,9R and quinidine (and
cinchonine) being 8R,9S.
•The absolute configatation of quinine (and cinchonidine)
is 3R:4S:8S:9R and of quinindine (and cinchonine) is
3R:4S:8R:9S. They all have antimalerial activity.
•The C9 epimers (i.e. epi-series) have 3R:4S:8R:9R OR
3R:4S:8S:9S configuration and they do not possess any
Antimalerial activity.

12. SAR
• Configuration of C9 and C8 carbon plays important role in determining
antimalarial activity.
• Isomers with 8S:9R configuration have maximum antimalarial
activity.eg. Quinine
• Inversion of configuration at C9 and C8 leads to antiarrhythmic
activity. Eg. Quinidine
• C9 epimers(8S:9S and 8R:9R ) are inactive.
• Any modification of –OH group at C9 through oxidation, esterification,
diminishes the activity.
• The quinuclidine portion is not essential for the activity but alkyl
tertiary amine at C9 is essential for activity.

13. Quinine & quinidine
• Historically, quinine has been the main treatment for malaria until the advent of
World War II.
• The stereoisomer, quinidine, is a more potent antimalarial, but it is also more
toxic.
• Quinine is lethal for all Plasmodium schizonts (site 2 in Fig. 7.1) and the
gametocites (site 4) from P. vivax and P. malariae, but not for P. falciparum.
• Today, quinine’s spectrum of activity is considered too narrow for prophylactic
use relative to the synthetic agents. So many a times it is administered in
combination with pyrimethamine and sulfadoxine, doxycycline, or mefloquine
depending the specific form of malaria and geographical location.
• The stereoisomer, quinidine, is a schizonticide, but its primary indication is
cardiac arrhythmias. It is a good example where stereochemistry is important
because it provides a significantly different pharmacological spectrum.

14. Toxicity of cinchona alkaloids
• A toxic syndrome is referred to as cinchonism.
• Symptoms start with tinnitus, headache, nausea, and disturbed vision.
• If administration is not stopped, cinchonism can proceed to involvement of
the gastrointestinal tract, nervous and cardiovascular system, and the skin.

15. 4-Aminoquinolines
• The 4-aminoquinolines are the closest of the antimalarials that are
based on the quinine structure.
• They are 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.
• A significant difference cinchona alkaloids is replacing the 6-methoxy
on quinine with a 7-chloro substituent.
• Chloroquine can be considered the prototypical structure of 4-
aminoquinolines of which hundreds have been evaluated, but only
about three to four are still in use.
• Eg. Chlorquine, Hydroxychlorquine, Amodiaquine.

16. 4-Aminoquinolines
• Chloroquine can be considered the
prototypical structure of the 4-
aminoquinoline series of which
hundreds have been evaluated, but
only about three to four are still in
use.

17. MOA
• Its main site of action appears to be the parasite involving the erythrocyte’s
lysosome.
• ferriprotoporphyrin IX, which is released by erythrocytes containing
Plasmodium, act as a chloroquine receptor.
• The combination of ferriprotoporphyrin IX and chloroquine causes lysis of
the parasite’s and/or the erythrocyte’s membrane.
• Finally, there is evidence that chloroquine may interfere with Plasmodium’s
ability to digest the erythrocyte hemoglobin or the parasite’s nucleoprotein
synthesis.
• The mechanism is based on the drug entering the erythrocyte’s lysosome,
which has an acid environment, where it becomes protonated. The
protonated (positively charged) chloroquine is now trapped inside the
lysosome because the pore that leads out of the lysosome is also positively
charged. This leaves chloroquine bound to the patient’s hemoglobin
preventing the parasite from processing it properly.
• In general, chloroquine and the other 4-aminoquinolines are not effective
against exoerythocytic parasites. Note that each of the mechanisms require
that the parasite be inside the erythrocyte. Therefore, chloroquine does not
prevent relapses of P. vivax or P. ovale malaria

18. Resistance
• The increase in P. falciparum resistant to chloroquine is due to mutations in
pfcrt gene that codes for a transporter protein.
• The result of the changes in the gene is that the pore through which
chloroquine might exit the lysosome is no longer positive charged, allowing
protonated chloroquine to exit the lysosome
• There are at least eight mutations that have been identified in the pfcrt
gene, and it is postulated that resistance occurs because of an accumulation
of these mutations.

19. 8-Aminoquinolines
• The other major group of antimalarial drugs based on the cinchona
alkaloid quinoline moiety is the substituted 8- aminoquinolines.
• The first compound introduced in this series was pamaquine. The other
examples are pentaquine, isopentaquine, and primaquine.
• But only primaquine is used among the series.

20. SAR
1. all have a 6-methoxy moiety same as quinine.
2. the substituents are on the quinoline are located at position 8
rather than carbon-4 as found on the cinchona alkaloids.
3. All agents in this series have a four to five carbon alkyl linkage or
bridge between the two nitrogens.
4. They have one asymmetric carbon(exception-pentaquine). In vitro
and in vivo studies indicate that the stereochemistry at the
asymmetric is not important for antimalarial activity

21. Primaquine
• is the only 8-aminoquinoline
currently in use for the
treatment of malaria.
• Its spectrum of activity is one of the narrowest of the currently used
antimalarial drugs being indicated only for exoerythrocytic P. vivax malaria.
• Primaquine also inhibits the gameocyte stage.
• MOA:- Primaquine appears to disrupt the parasite’s mitochondria. The
result is disruption of several processes including maturation into the
subsequent forms. An advantage is destroying exoerythrocytic forms before
the parasite can infect erythrocytes.

22. Quinolinemethanols- eg. Mefloquine
• Strong blood schizontocide active
against P.vivax & P.falciparum, but does
not affect hepatic forms of the parasite.
• Mefloquine is a schizonticide acting
before th parasite can enter the
erythrocyte.
• There is some evidence that it acts by
raising the pH in the parasite’s vesicles
interfering with its ability to process
heme.

23. Artemisinin and Derivatives
• Artemisinin is a drug used to treat
multi-drug resistant strains of
falciparum malaria. The compound (a
sesquiterpene lactone) is isolated from
the plant Artemisia annua. Not all
plants of this species contain
artemisinin. Apparently it is only
produced when the plant is subjected to
certain conditions, most likely biotic or
abiotic stress.

24. Artemisinin
• The weed Artemisia annua has been used for many centuries in Chinese
herbal medicine as a treatment for fever and malaria. In 1971, Chinese
chemists isolated from the leafy portions of the plant the substance
responsible for its reputed medicinal action. The compound, artemisinin
(qinghaosu, arteannuin), was determined by X-ray crystallography to be a
sesquiterpene lactone bearing an endoperoxide

25. Structure and name
• 3R,5aS,6R,8aS,9R,12S,12aR)-
Octahydro-3，6，9-trimethyl-
3，12-epoxy-12H-pyrano[4，
3-j]-1，2-Benzodioxepin-10
（3H）-one
• The key structure characteristic
appears to be a “trioxane”
consisting of the endoperoxide
and doxepin oxygens.

26. Structure modification
• With the reduction of artemisinin to
dihydroartemisinin, an asymmetric
carbon forms, and it is possible to form
oil-soluble and water-soluble prodrugs.
Both stereoisomers are active. The
chemistry froming each of the
artemisinin pro-drugs results in the
predominance of one isomer. The
βisomer predominates when producing
the nonpolar methyl and ethyl ethers,
whereas the αisomer is the
predominant product when forming the
water-soluble hemisuccinate ester.

27. The Derivatives of Artemisinin

28. The Derivatives of Artemisinin
O
O
O O
OMe
O
O
O O
OCOCH2CH2COOH
• 1987, artemether, artesunate were approved for new drug for
treatment of malaria in China.

29. Mechanism of Action, SAR
• The artemisinin appear to kill the parasite by a free radical
mechanism. Not by the generation of reactive oxygen species,
but by virtue of a free-radical associated with the endoperoxide,
possibly involving a carbon radical. The radical in turn produces
oxidative damage to the parasites membrane.
• The endoperoxide is essential for activity; deoxyartemisinin, in
which the dioxy bridge has been reduced to mono-oxy, is
completely inactive.

30. Blood schizontocide, active
against strains resistant to
chloroquine, pyrimethamine,
quinine.
Only in hospitalized pateint, to
monitor their ECG
Cross-resistance in falicparum
infection occurred .
Absorbed orally slowly ,
t½=11-12day
Absorption  with meals,
elimination in feces.

31. ADR:-abdominal pain, headache, transient in hepatic enzymes, cough,
pruritus, lengthening of QT interval.
May cause hemolytic anemia & convulsions.
Reserved for infection caused by resistant organisms.
Contraindications:
with mefloquine.
Patients with cardiac conduction defects.
In pregnancy → embriotoxic in animals

32. Type 1 antifolates sulphonamides &
sulphones , compete with PABA.
Type 2 ,pyrimethamine &
proguanil inhibition
of dihydrofolate reductase.

33. Have slow action against the
erythrocytic forms of the
parasite.
Pyrimethamine is used in
combination with either dapsone
or sulfadoxine.
• High resistance

34. Sulfonamides & sulfones are active
against the erythrocytic forms of
P.falciparum.
Pyrimethamine -sulfodoxine is used
for chloroquine –resistant malaria.
Pyrimethamine & proguanil are
slowly orally absorbed.
t½ of pyrimethamine =4d,
proguanil=16h.
Proguanil is metabolized to an active
metabolite ,cycloguanil which is
excreted in urine.