UNIT-II Antimalarial drugs

Malaria fever is caused by a Plasmodium parasite and is transmitted to humans by

female Anopheles mosquito vector. Its original treatment was quinine that became the
prototypical molecule for the first generation of synthetic antimalarial drugs. One of the
most effective preventions is controlling the mosquito population, that is the vector carrying
the parasite to humans. There are three potential ways to control malaria: elimination of the
vector, drug therapy, and vaccination.

Etiology of malaria:

Dr. Ronald Ross is the pioneer who discovered the involvement of Anopheles
mosquito as the carrier of the causative protozoa Plasmodium into humans. Dr. Ross was
awarded the noble prize for this discovery in 1902. Thus the life cycle of malaria takes place
half in human beings and half in mosquitoes.

The life cycle of maria in human beings:

➢ The life cycle of malaria in human beings begins with the injection of sporozoites of
plasmodium parasite into victim’s blood with the bite of female Anopheles mosquito.
➢ The injected sporozoites immediately begin entering hepatocytes to become primary
schizonts and then to merozoites (at this point there are no symptoms of malaria fever).
➢ Further the merozoites either rupture the infected hepatocytes and enter systemic
circulation or infect other liver cells.
➢ Merozoites in systemic circulation then 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.
➢ The newly formed merozoites or gametocytes (male and female) 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
of malaria fever.

Figure 1. Stages of parasite in Anopheles mosquito and human that causes malaria.

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UNIT-II Antimalarial drugs
The life cycle of maria in Anopheles mosquito:
➢ The gametocytes in the systemic circulation of human beings enter the stomach of an
Anopheles mosquito with a bite to human beings.
➢ The gametocytes undergo fertilization in mosquito’s stomach to produce a zygote. 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.

Antimalarial drugs:

Quinolines:

Quinolines are derivatives of cinchona alkaloids such as quinine, quinidine,

cinchonine, cinchonidine produced by cinchona plant. Historically, quinine was the main
treatment for malaria until the advent of World War II. The numbering system of quinolines
is based on rubane. Besides quinine and quinidine many synthetic antimalarial drugs were
introduced under aminoquinolines category. Which includes chloroquine, amodiaquine,
primaquine phosphate, pamaquine, quinacrine hydrochloride, and mefloquine etc.

Figure 2. List of quinoline antimalarial drugs

SAR of Quinolines:

• Asymmetry at positions 3 and 4 is not essential for the antimalarial activity.

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UNIT-II Antimalarial drugs
• The configuration of the hydroxy group and non-aromatic nitrogen atom at the positions 8 and 9
is associated with the antimalarial activity.
• The presence of methoxy group on quinine is not essential for antimalarial activity, however
replacement of methoxy group with halogens enhances the antimalarial activity.
• Modification of the secondary alcohol at C-9 through oxidation or esterification diminishes the
activity.
4-aminoquinolines:
• A dialkylamino side chain, having 2-5 carbon atoms between the nitrogen atoms is optimal for
the antimalarial activity.
• The tertiary amine in the side chain is important.
• The introduction of an unsaturated bond in the side chain is not detrimental to activity.
• The 7-chloro group in the quinoline nucleus is optimal and methyl group in the position 3
reduces activity, and an additional methyl group in position 8 completely abolishes activity.
• The substitution of a hydroxy group on one of the ethyl groups on the tertiary amine generally
reduces toxicity and increases the plasma concentration.
• Incorporation of an aromatic ring on the side chain (e.g. amodiaquine) reduces toxicity and
activity.
• The quinoline ring system seems to be inherently more active than the acridine for a given side
chain.
8-aminoquinolines:
• Compounds with high therapeutic index possess a 6-methoxy group on quinoline nucleus.
• Optimal activity is obtained with 2 to 6 methylene groups between the two nitrogen atoms of the
side chain.
• The extent of substitution of the terminal amine is not as critical as in 4-aminoquinolines.
• Additional substituents on the quinoline nucleus at 4th and 5th positions may be beneficial for the
enhanced antimalarial activity.
Synthesis of chloroquine:
Chloroquine synthesis can be divided into three individual steps: which includes
1. Synthesis of 4,7-dichloroquinoline from m-chloro aniline
2. Synthesis of 4-amino-1-diethylaminopentane from 2-chloroethanol
3. Condensation of 4,7-dichloroquinoline and 4-amino-1-diethylaminopentane into chloroquine

1. Synthesis of 4,7-dichloroquinoline from m-chloro aniline

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UNIT-II Antimalarial drugs
2. Synthesis of 4-amino-1-diethylaminopentane from 2-chloroethanol

3. Condensation of 4,7-dichloroquinoline and 4-amino-1-diethylaminopentane into chloroquine

Synthesis of pamaquine:
Pamaquine synthesis can be divided into three individual steps: which includes
1. Synthesis of 8-amino-6-methoxyquinoline from p-acetamido anisole
2. Synthesis of 4-bromo-N, N-diethylpentan-1-amine from 2-methyltetrahydrofuran
3. Condensation of 8-amino-6-methoxyquinoline and 4-bromo-N, N-diethylpentan-1-amine into
pamaquine
1. Synthesis of 8-amino-6-methoxyquinoline from p-acetamido anisole

2. Synthesis of 4-bromo-N, N-diethylpentan-1-amine from 2-methyltetrahydrofuran

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UNIT-II Antimalarial drugs
3. Condensation of 8-amino-6-methoxyquinoline and 4-bromo-N, N-diethylpentan-1-amine
into pamaquine

Mechanism of action of quinolines:

A very complex mechanism is based on ferriprotoporphyrin IX, which is released by
Plasmodium containing erythrocytes, acting 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.

Biguanides and dihydro triazines:

Miscellaneous:

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