This document summarizes antimalarial drugs. It describes the four species of Plasmodium that cause malaria and their life cycles. It then discusses the four sites where drugs can act against the parasite. The main classes of antimalarial drugs are described - quinolines, 9-amino acrydines, 2,4-diamino pyrimidines, biguanides, and miscellaneous drugs. Key drugs like chloroquine, primaquine, pyrimethamine, and artemisinins are explained along with their mechanisms of action.

1. ANTIMALARIALS
PREPARED BY :
VASAVI VYKUNTAPU
19AC1R0082

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. The causative
agent is a group of parasitical protozoa of the Plasmodium genus transmitted by the female
Anopheles mosquito.
• Malaria is caused by four species of the one-cell protozoan of the Plasmodium genus.
• 1.Plasmodium falciparum: This species is estimated to cause approximately 50% of all malaria. It
causes the most severe form of the disease and, because patients fee 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.
• 2.Plasmodium vivax: This species 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.
• 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 MALARIA PARACITE
• There are four phases in this cycle:
1.Pre Erythrocytic phase,
2.Erythrocytic phase,
3.Schizogony phase,
4.Sexual phase.

4. 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 mosquito and reproduce into zygotes. Some
have argued that the focus at this stage should be on the male gametocytes. This would block
the female gametocytes from mating.

5. CLASSIFICATION OF ANTIMALARIALS
• 1. Quinolines,
a. Cinchona alkaloids : Cinchonin , Cinchoninin, Quinine, Quinidine.
b. 4-amino quinolines : Chloroquine , Hydrochloroquine , Mefloquine
, Amodiaquine.
c. 8-amino quinolines : Primaquine , Pamaquine.
2. 9-amino acrydines
a.Quinacrine.
3. 2,4-diamino pyrimidines
a. Trimethoprim,
b. Pyramethamine.

6. • 4. Biguanides
a. Proguanil,
b. Cycloguanil.
5. Miscellaneous
a. Artemether,
b. Artesunete,
c. Atovaquone.

7. • 1. QUINOLINES DERIVATIVES :

9. MOA OF QUINOLINES :
• Quinolines mainly act by
1. Inhibition of polymerase enzyme.
2. Weak base hypothesis.
3. Interchelation of DNA.
SAR OF QUINOLINES :
1. The dialkyl amino group with 2-5 carbon atoms at side chain particularly
the 4-diethyl
amino methyl butyl amino side chain is optimal for the activity.
2. The amino group present in the side chain should always be teritiary.
3. The OH substitution on teritiary amine decreases the toxicity.
4. Presence of chlorine at 7th position is optimal for the activity.

10. 2. 9-AMINO ACRYDINES:
• Qunacrine is no longer available in the United States. It can be considered one of the most toxic of the
antimalarial drugs even though, at one time, it was commonly used. It acts at many sites within the cell
including intercalation of DNA strands, succinic dehydrogenase and mitochondrial electron transport, and
cholinesterase. It may be tumorgenic and mutagenic and has been used as a sclerosing agent. Because it is
an acridine dye, quinacrine can cause yellow discoloration of the skin and urine.
MOA :
1.It inhibites the intercalation of DNA.

11. 3. 2,4-DIAMINO PYRINIDINES:
• Pyrimethamine:- It is used as immunosuppressive agent. It is combined
with sulfonamide for treatment of falciparum malaria.

12. 4. BIGUANIDES :
Proguanil: It is a pro drug. It is a slow acting erythrocytic schizontocide
which also inhibits the pre erythrocytic stage of p.falciparum gametocytes
exposed to proguanil are not killed but failed to develop properly in
mosquito.
* Resistance to proguanil develops rapidly due to mutational changes in the
plasmodial DHFRase enzyme.

13. 4. MISCELLANEOUS :
• Artesunete: First line drug for uncomplicated falsiparum malaria. Not
effective against multidrug resistant strains which are non responsive to
s/p.
• Artemether: Clinical efficacy 95 -99% must be administered with fatty
food or milk to allow absorption. Quickly reduces parasite bio-mass,
resolve symptoms.