Antimalarial

1. Antimalarials
By- Ms. Aishwarya Gangwar
Assistant Professor
M.M. College of Pharmacy,
Maharishi Markandeshwar (Deemed to be University)
Mullana, Ambala- Haryana, India
Mobile: +91-9827813303

2. Malaria
 Malaria is derived from two Greek words, “mala” and “aria” which
means bad air.
 Malaria is one of the most widespread disease caused by plasmodium
parasite.
 It is caused by an insect vector, female anopheles mosquito that carries
the parasite in the stomach and salivary glands.

3. Malaria
 Malaria is caused by four species of unicellular protozoan belonging to
the genus Plasmodium:
oPlasmodium falciparum
oPlasmodium vivax
oPlasmodium malariae
oPlasmodium ovale

4. Possible Sites of Malarial Drug Therapy

5. Possible Sites of Malarial Drug Therapy
There are four possible sites for drug therapy at different stages of the disease-
 Kill the sporozoites injected by the vector mosquito and prevent them from
entering the liver.
 Kill the schizonts residing in the hepatocytes and prevent them from becoming
merozoites.
 Kill the merozoites in blood and prevent them from developing into
gametocytes.
 Kill the gametocytes before they can enter the mosquito and reproduce into
zygote.

6. Classification
Anti-Malarial Drugs
S. No. Class Example
1 Chinchona Alkaloids Quinine, Quinidine, Cinchonine, Cinchonidine
2 4-Aminoquinolines Chloroquine, Hydroxychloroquine,
Amodiaquine
3 8-Aminoquinolines Pamaquine, Primaquine
4 Biguanides Proguanil, Cycloguanil,
5 Quinoline Methanol Mefloquine
6 Aminopyridines Pyrimethamine
7 Acridines Quinacrine
Miscellaneous Artemisinin, Artesunate, Artemether,

7. I. Chinchona Alkaloids
Quinine and Quinidine
 Quinine is the chief alkaloid of chinchona bark.
 Quinine and quinidine are optical isomers.
 Both of them primarily acts as a blood schizonticide.

8. Cinchonine and Cinchonidine
 It is obtained from Cinchona officinalis.
 Both are optical isomers.
 These antimalarial agents acts as a blood schizonticide.

9. II. 4-Aminoquinolines
Chloroquine
 It is a white or almost white crystalline powder.
 It is freely soluble in water.
 It prevents the polymerization of toxic heme released during proteolysis
of hemoglobin in the Plasmodium digestive vacuole.

10. Hydroxychloroquine
• It is a white or almost white crystalline powder which is freely soluble in
water.
• It is an antimalarial drug which is also used in the treatment of
rheumatoid arthritis.
Amodiaquine
• It similar to chloroquine in structure and activity.
• It has been used as both an antimalarial and an anti-inflammatory agent.
• The mode of action of amodiaquine has not yet been determined.

11. III. 8-Aminoquinolines
Primaquine
• It is a tissue schizonticide.
• It is an orange crystalline powder which is soluble in water.
• Half life is about 3 to 6 hours.
Pamaquine
• It is closely related to primaquine.
• Pamaquine formerly used for the treatment of malaria.

12. 1,4-dibromopentane 4-bromo-1-phthalimidopentane
8-amino-6-methoxyquinoline
Primaquine

13. IV. Biguanides
Proguanil
It is a white crystalline powder .
It is slightly soluble in water.
Proguanil is a prophylactic antimalarial prodrug of cycloguanil.
Cycloguanil
• Cycloguanil is a dihydrofolate reductase inhibitor, and is a
metabolite of the antimalarial drug proguanil.

14. V. Quinoline Methanol
Mefloquine
• It is used in the prophylaxis and treatment of malaria caused by
Plasmodium falciparum and Plasmodium vivax.
• It is effective against chloroquine-resistant forms of Plasmodium
falciparum.
• Mefloquine is an antimalarial drug acting as a blood schizonticide.

15. VI. Aminopyridines
Pyrimethamine
 It forms colorless crystals or almost white crystalline powder.
 It is practically insoluble in water.
p-chlorobenzyl cyanide Methylproponate
Guanidine
Enolic ether of α-propionyl-
p-chlorophenyl acetonitrile Pyrimethamine

16. VII. Acridines
Quinacrine
 Quinacrine is a derivative of acridine that is chemically and clinically very
similar to 4-aminoquinolines.
 It is also known as Mepacrine.
 It has also been used as an anthelmintic and in the treatment of giardiasis
and malignant effusions.

17. VIII. Miscellaneous
Artemisinin
 It is a rapid acting, effective and safe for treatment of severe malaria.
 It is an antimalarial lactone derived from qinghao (Artemisia annua or sweet
wormwood).
Artesunate
 Artesunate is artesunate is an artemisinin derivative indicated for the initial
treatment of severe malaria.
 World Health Organization recommends artesunate as first line treatment for
severe malaria.
 Artesunate was developed out of a need for a more hydrophilic derivative of
artemisinin.

18. Artemether
• Artemether is an artemisinin derivative that is artemisinin in which
the lactone has been converted to the corresponding lactol methyl
ether.
• Artemether is an antimalarial agent used to treat acute
uncomplicated malaria.
Atovaquone
 It is a hydroxynaphthoquinone (ubiquinone analog) that has
antimicrobial and antipneumocystis activity, but it is also used in
antimalarial protocols.
 It is a highly lipophilic drug that closely resembles the structure of
ubiquinone.

19. SAR of Quinine Antimalarials
 Asymmetry at position 3 and 4 is not essential for antimalarial activity.
 The configuration at position 8 and 9 affect the juxtaposition of the
hydroxy group and the non-aromatic hydrogen atom, a relationship that is
associated with antimalarial activity.
 For antimalarial activity, the distance between the oxygen and the non-
aromatic nitrogen should be 3 Å.

20. SAR of Quinine Antimalarials
 The presence of methoxy group in quinine is not essential for antimalarial
activity and its replacement by a halogen, especially chlorine enhances its
activity.
 A further increase in activity resulted from the introduction of a phenyl
group at position 2’. The blocking of this position of the quinoline ring
was based on attempt to increase its activity by preventing biological
oxidation at this position.

21. SAR of Quinine Antimalarials
 Pharmacological activity is usually enhanced by the introduction of a
halogen at position 8.
 Modification of the secondary alcohol at C-9, through oxidation,
esterification diminishes its activity.
 The quinuclidine portion is not necessary for activity, however an alkyl
tertiary amine attached at C-9 is important for activity.

22. SAR of 4-Aminoquinolines
 A dialkylaminoalkyl side chain having 2-5 carbon atoms between the
nitrogen atoms, particularly 4-diethylamino-1-methylbutyl amino side
chain is optimal for activity as in chloroquine and quinacrine.
 The tertiary amine in the side chain is important for activity.
 The introduction of an unsaturated bond in the side chain was not
detrimental for the activity.

23. SAR of 4-Aminoquinolines
 The 7-chloro group in the quinoline nucleus is optimal and methyl group
in position 3 reduces activity, and an additional methyl group in position
8 completely abolishes activity.
 The substitution of a hydroxy on one of the ethyl groups on the tertiary
amine (Eg. Hydroxyquinoline) generally reduces toxicity and increases
and increases the plasma concentration. This is one of the metabolite of
chloroquine.

24. SAR of 4-Aminoquinolines
 Incorporation of an aromatic ring in the side chain (Eg. Amodiaquine)
gives a compound with reduced toxicity and activity.
 The d-isomer of chloroquine is somewhat less toxic than its l-isomer.
 The quinoline ring system seems to be inherently more active than the
acridine for a given side chain.

25. SAR of 8-Aminoquinolines
 Compounds with high chemotherapeutic index had a 6-methoxy group in
quinoline nucleus and it may be substituted by –H, -OH, or low –OR
groups.
 2,4-Propylaminoquinoline or 6-methoxy analogs of 8-diethylamino
propylaminoquinoline were all active.
 The introduction of a second methoxy group at position 2 or 5 increases
the therapeutic index.

26. SAR of 8-Aminoquinolines
 Optimal activity was obtained with 2,6-methylene groups between the
two nitrogen of the side chain. Homologs with an even number of
methylene groups were found to be less active than those with an odd
number.
 The extent of the substitution of the terminal amine is not as critical as 4-
aminoquinolines and the terminal aliphatic amino group may be primary,
secondary or tertiary.

27. SAR of 8-Aminoquinolines
 Primaquine is the drug of choice, is having a primary terminal amine. But
the aromatic amine must be secondary in nature for optimum results.
 Additional substituents in the quinoline nucleus at the 4- and 5- position
may be beneficial such as 5-phenoxy derivatives.

28. Thank you!!!