Medicinal Chemistry 3

Chapter 9: Antimalarial Agents

1. INTRODUCTION

Antimalarials are the chemotherapeutics agents which are used for the prevention and treatment of
malaria. Malaria is one of the wide spread diseases, caused by protozoan parasite of the genus
Plasmodium. The term malaria derived from mala aria (bad air) and it has been called ague, intermittent
fever, marsh fever and The fever.

2. ETIOLOGY OF MALARIA

Malaria caused by a four species of Plasmodium (Plasmodium falciparum, P. malariae, P. ovale,

and P. vivax). When female Anopheles mosquitoes infected with the parasite bites, it releases
Plasmodium sporozotes into blood. They leave the circulation and localize in the hepatocytes
(liver) whereby they transform, multiply, and develop into Primary schizonts. The primary
asymptomatic tissue stage lasts for 15 days and the tissue schizonts rupture, each releasing
thousands of merozites. The released merozites invade more erythrocytes to continue the cycle’s
synchronous rupture of erythrocytes to continue the cycle. Synchronous rupture of erythrocytes
and release of merozytes into the circulation leads to ebrile pattern attacks on day 1 and 3; hence,
the designation is ‘tertian malaria’. Some erythrocyte parasites differentiate into several forms
known as gametophytes.

When an uninfected/infected female Anopheles mosquito bites to the infected human, it ingests
gametophytes. Then the exflagellation of male gametocyte is followed by the fertilization of the
female gametocytes in the insect’s guts. The resulting zygote, which develops as an oocyte in the
stomach epithelium, eventually gives rise to infective sporozoite, which invades the salivary
glands of the mosquito. The insect then can infect another human by biting.

Parasite spends an asexual phase in human and sexual phase in female mosquito. The different
stages of parasitic life cycle (Fig.9.1) and possible site for drug therapy are given below:

1. Kill the sporozoites injected by mosquito or prevent sporozoites from entering the liver:
Primaquine and pyrimethamine.
2. Kill the schizonts residing in hepatocytes or prevent them from becoming merozoites:
Primaquine.
3. Kill the merozoites in the blood or prevent them from developing gametocytes:
Chloroquine, amodiaquine, santoquine, proguanil.
4. Kill the gametocytes before they can enter in mosquito and reproduce into zygote:
Primaquine
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Fig.9.1. Life cycle of plasmodium parasite with possible site of drug action.

3. CLASSIFICATION OF ANTI-MALARIAL AGENTS

1. Quinoline derivatives:

a) Cinchona alkaloids: Quinine, Quinidine, Cinchonine, Cinchodine

b) 4-Amino quinoline derivatives: Chlorquine, Amidoquine, Mefloquine

AMODIAQUINE

c) 8-Amino quinoline derivatives: Primaquine, Pamaquine

2. Acridine derivatives: Quinacrine, Acriquine

3. Biguanides and dihydro triazines derivatives: Proguanil, Cycloguanil

4. Miscellaneous:
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a. Diamino pyrimidine derivatives: Pyrimethamine, Trimethoprim

b. Newer antimalarial drugs: Artesunate, Artemether; Atovaquone

3.1. Quinoline derivatives: VAL2 (427)

a) Cinchona alkaloids:

b) 4-Amino quinoline derivatives:

c) 8-Amino quinoline derivatives:

Medicinal Chemistry 3

3.2. Acridine derivatives:

3.3. Biguanides and dihydro triazines derivatives:

3.4. Miscellaneous:

a. Diamino pyrimidine derivatives:

b. Newer antimalarial drugs:

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4. SAR OF QUINOLINE

1. Most of the antimalarial agents possess a quinoline ring system.

2. Secondary alcohol in structure of cinchona alkaloid is responsible for activity. While
substitution at C6 (OCH3) and –CH=CH2 group at side chain is not essential for activity.
e.g. Quinine

3. Change in configuration of 2º alcoholic group of quinine from (-) isomer to (+) isomer
result in change in activity from antimalerial to antiarrhythmic. e.g. Quinidine.
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4. Position of amino groups on quinoline nuclus develops two types of derivatives i.e. 4-
amino quinolines and 8-amino quinolines.
a) 4-Amino quinoline derivatives:
1. Introduction of chloro group at position 7 provides maximum therapeutic activity
and maximum toxicity. e.g. Chloroquine.
2. Introduction of methyl group at position 3 reduces the activity.
3. Substitution of 4 diethyl amino-1-methylbytylamino side chain at C4 is optimum
for activity. e.g. Chloroquine

4. Substitution of Hydroxyl groups at one of the ethyl group in tertiary amine side
chain reduces the toxicity and increases the plasma concentration. e.g.
Hyroxychlorquine
5. Introduction of aromatic ring in side chain increases toxicity (hepatitis and
agranulocytosis). e.g. Amidoquine
6. Introduction of two trifluromethyl moieties at positions 2 and 8 and removal of
electronegative substituents (chloro) at positions 7 of quinoline nuclus, results in
newer 4 amino quinoline derivative i.e. Mefloquine

b) 8-Amino quinoline derivatives:

1. Introduction of methoxy group at 6 positions in 8-amino quinoline nuclus is

essential for activity. e.g. Primaquine, Pamaquine
2. Four to five carbon alkyl linkage or bridge between the two nitrogens is optimum
for activity.

5. MECHANISM OF ACTION, SYNTHESIS AND USES

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Fig.9.2. Site of drug action on plasmodium parasite cell.

5.1. Quinoline derivatives:

a) Cinchona alkaloids:

Quinine: It is an alkaloid extracted from the bark of Cinchona officinalis Linne (C. ledgeriana
Moens) of the Rubiaceae family or other Cinchona species.

Uses: It is employed extensively for the suppression and control of malaria caused due to P.
vivax, P. malariae and P. ovale.

b) 4-Amino quinoline derivatives:

Mechanism of action: The plasmodium parasite utilizes host haemoglobin as a source of amino
acid. On digestion of the haemoglobin, the haematin is released as ferriprotoporphyrins IV and
it produces haemolysis of the erythrocyte parasites. Therefore, haematin that is released is
converted into nontoxic products, haemozoin by the polymerase enzyme. The steps involved in
the conversion of haematin to haemozoin are inhibited by the (Quinine and 4-Amino
quinoline derivatives) by formation of drug-heme complex. (Fig. 9.3)
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Fig.9.3. Mechanism of action of Quinine and 4-Aminoquinoline derivatives.

Chlorquine:

IUPAC Name: 7-Chloro-4-[[4-(diethylamino)-1-methyl] butyl] amino]-quinoline

Synthesis:
It is prepared by adopting the following three steps viz.,
(a) Preparation of 4, 7-Dichloroquinoline (nucleus)
(b) Preparation of 2-amino-5-diethyl amino pentane, or 1-diethylamino-4-amino pentane
(side chain).
(c) Condensation of products of step ‘a’ and ‘b’
Step (a): Preparation of 4, 7-Dichloroquinoline (nucleus):
m-Chloro aniline reacted with diethyl 2-oxosuccinate to yields diethyl-2-((3-
chlorophenyl)imino)succinate which undergoes cyclization with removal of ethanol to produce
ethyl 7-chloro-4-hydroxyquinoline-2-carboxylate. This compound undergoes hydrolysis
followed by decarboxylation and chlorination to 4,7-dichloroquinoline.
Medicinal Chemistry 3

O O
C2H5O

C2H5O CH2 -H2O CH2

+
Cl NH2 O COOC2H5 Cl N COOC2H5
m-Chloro aniline Diethyl 2-oxosuccinate Diethyl-2-((3-chlorophenyl)imino)succinate

-C2H5OH 250oC
Cyclization

OH OH

NaOH/H2O
HCl
Cl N COOH Cl N COOC2H5
7-chloro-4-hydroxyquinoline-2-carboxylic acid Ethyl 7-chloro-4-hydroxyquinoline-2-carboxylate

-CO2

OH Cl

POCl3

Cl N Cl N
7-chloroquinolin-4-ol 4,7-Dichloroquinoline

Step (b): Preparation of 2-amino-5-diethyl amino pentane, or 1-diethylamino-4-amino pentane

(side chain):
Ethylene oxide or 1-chloro-2-hydroxy-ethane reacted with diethylamine to give 2-
(diethylamino)ethane-1-ol,which is on condensation with acetone yields 5-(diethylamino)pentan-
2-one. Further on reduction with Raney Nickel followed by oximation yields 1-diethylamino-4-
amino-pentane. (side chain).
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Step (c): Condensation of products of step ‘a’ and ‘b’:

4,7-Dichloro quinoline and 1-diethylamino-4-amino pentane undergoes condensation to yields
chloroquine.

Uses: It is mainly used as an antimalarial. Chloroquine also has antihistaminic and

antiinflammatory properties. It is used to treat hepatic amoebiasis, rheumatoid arthritis, discoid
lupus erythematosus, cutanea tards, solar urticaria, and polymorphous light eruptions.

Amidoquine:

IUPAC Name: 4-[(7-Chloro-4-quinolyl) amino]-α-(diethylamino)-o-cresol.

Uses: It is used for suppressing P. vivax and P. falciparum infections being 3-4 times more
active than quinine.

Mefloquine:

IUPAC Name: DL-erythro-α-2-Piperidyl-2-, 8-bis (trifuoromethyl)-4-quinolinemethanol.

Uses: It is very effective against the erythrocytic forms of malaria. However, its use is restricted
to cases of chloloquine-resistant falciparum malaria in order to prevent the emergence of
parasites that are resistant to it.

c) 8-Amino quinoline derivatives:

Mechanism of action: While the mechanism of action of the 8-amino quinolines is unknown, it
is known that primaquine can generate reactive oxygen species via an autoxidation of the 8-
amino quinoline group with the formation of radical anion. As a result, cell destructive oxidants,
such as hydrogen peroxide, super oxide, and hydroxyl radical can be formed. The ‘drugs’ exerts
its action against the exoerythrocytic stages of P. ovale and primary exoerythrocytic stages of P.
falciparum. It has also been observed that it particularly inhibits the gametocyte stage that
essentially helps to eliminate the form required to infect the ‘mosquito carrier’. It also appears to
disrupt and destabilize the parasite’s mitochondria via several processes.

Primaquine:

IUPAC Name: 8-[(4-Amino-1-methylbutyl) amino]-6-methoxy quinoline.

Uses: In vitro and in vivo studies indicate that the stereochemistry at the asymmetric carbon is
not important for antimalarial activity. These appears to be less toxicity with the levorotatory
Medicinal Chemistry 3

isomer, but this is dose-dependent, and may not be of much importance as the doses used to treat
exoerythrocytic P. vivax malaria. It is extensively used for the radical cure of relapsing vivax
malaria, but it is not normally employed either for arresting the severe attacks of the disease or
for the suppressive therapy. It invariably kills gametocytes of all the species, or inhibits their
growth and development in the mosquito. It fails to produce any significant effect on other
erythrocytic stages, and hence, it must not be employed alone for the treatment of malaria.

Pamaquine:

IUPAC Name: 8-(4-Diethylamino-1-methylbutylamino)-6-methoxyquinoline.

Synthesis:
4-Methoxy-2-nitroaniline undergoes Skraup’s synthesis in presence of glycerol, nitrobenzene
and sulphuric acid to yields 6-methoxy-8-niroquinoline. This on reduction gives amino analog.
Condensation of this quinoline residue with 4-bromo-1-diethylamino pentane forms pamaquine.
H3CO H3CO

Glycerol/H2SO4/Nitro benzene
NH2 Skraup's synthesis N
NO2 NO2
4-Methoxy-2-nitroaniline 6-Methoxy-8-nitroquinoline

H C2H5 [H]
Br C CH2 CH2 CH2 N
H3CO CH3 C2H5
H3CO
4-Bromo-N,N-diethylpentan-1-amine
-HBr
N
H C2H5 N
NH C CH2 CH2 CH2 N
NH2
CH3 C2H5
Pamaquine 6-methoxyquinolin-8-amine

Uses: It is used in treatment of malaria but has since been superseded by primaquine.

5. 2. Acridine derivatives:

Quinacrine

IUPAC Name: 6-Chloro-9-[[4-(diethylamino)-1-methylbutyl] amino]-2-methoxy-acridine.

Mechanism of action: Quinacrine acts at many sites within the cell, including intercalation of
DNA strands, succinic dehydrogenase, mitochondrial electron transport, and cholinesterase. It
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may be tumerogenic and mutagenic and has been used as a sclerosing agent. Because it is an
acridine dye, quinacrine can cause yellow discolouration of the skin and urine.

Uses: It acts as a schizontocidal and now it is not used as an antimalarial agent. It is used in the
treatment of leishmaniasis and some tape worm infestations.

5.3. Biguanides and dihydro triazines derivatives:

Mechanism of action: Biguanides and dihydro triazines derivatives inhibits dihydrofolate

reductase enzyme and interfere in the folic acid metabolism. This leads to inhibition of the
nuclear division in malarial parasites.

Proguanil

IUPAC Name: 1-(p-Chlorophenyl)-5-isopropylbiguanide hydrochloride.

Uses: It is used mainly for prophylactic treatment of malaria.

Cycloguanil

IUPAC Name: 4, 6-Diamino-1-(p-chlorophenyl)-1,2-dihydro-2,2-dimethyl-s-triazine.

Uses: Cycloguanil is the active metabolite of proguanil. It is used mainly for prophylactic
treatment of malaria.

5.4. Miscellaneous:

a) Diamino pyrimidine derivatives:

Mechanism of action: It is a potent inhibitor of dihydrofolate reductase of the plasmodium

(mammalian enzyme is about 200 times less sensitive). Thus it blocks the synthesis of
tetrahydrofolic from dihydrofolic acid and this is essential for the synthesis of purines and
pyrimidines and hence DNA.

Pyrimethamine

IUPAC Name: 2, 4-Diamino-5-(p-chlorophenyl)-6-ethylpyrimidine.

Uses: It finds its extensive use as a suppressive prophylactic for the prevention of severe attacks
due to P. falciparum and P. vivax. It is also used in the treatment of taxoplasmosis and as an
immuno suppressive agent.

Trimethoprim:

IUPAC Name: 2, 4-Diamino-5-(3,4,5-Trimethoxybenzyl) pyrimidine.

Medicinal Chemistry 3

Uses: It has been employed in conjugation with sulphamethopyrazine in the treatment of

chloroquine-resistant malaria. It has also been used in conjugation with sulphonamides in the
treatment of bacterial infections.

b) Newer antimalarial drugs:

Artesunate and Artemether

Mechanism of action: Artesunate, kill the parasite by a free radical mechanism by virtue of a
free radical associated with the endoperoxide, possibly involving a carbon radical. It is proposed
that the heme in the form of hemozoin within the digestive vacuole is a source of Fe II, which
reacts with the peroxide to generate an oxy radical and FeIII.

Uses: It having gametocytocidal activity as well as activity against all asexual stages of the
parasites. Artemether (oil-soluble); and artesunate (water soluble) are found to be active against
the entire Plasmodium genera that cause malaria.

Atovaquone:

IUPAC Name: Trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione.

Mechanism of action: Atovaquone is a selective inhibitor of the Plasmodium’s mitochondrial

electron transport system. This deprives the cell of needed ATP and could cause the cell to
become anaerobic. Atovaquone with proguanil 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 metabolite.

Uses: Atovaquone in combination with proguanil used in treatment of malaria. It is also used to
treat pneumocystis pneumonia.

QUESTIONS

Multiple Choice Questions:

1. Quinine obtained from?

a) Cinchona bark b) Arjuna Bark c) Cinchona leaf d) Arjuna leaf

2. Chloroquine conatains a..............ring system.

a) 8-Amino quinoline b) 4-Amino quinoline

c) 9-Amino acridine d) 4-Amino acridine

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3. Primaquine conatains a ............. ring system.

a) 8-Amino quinoline b) 4-Amino quinoline

c) 9-Amino acridine d) 4-Amino acridine

4. Mepacrine conatains a ............. ring system.

a) 8-Amino quinoline b) 4-Amino quinoline

c) 9-Amino acridine d) 4-Amino acridine

5. Pyrimethamine act by inhibiting… ............. enzyme.

a) Transaminase b) Peptidase

c) Folate oxidase d) Folate reductase

6.8-amino quinoline ring is synthesized by

a) Skraup’s synthesis b) Opener oxidation

c) Grignard reaction d) None of the above

7. Malaria is caused,

a) When plasmodium uninfected female Anopheles mosquito bites to the infected human

b) When plasmodium uninfected male Anopheles mosquito bites to the infected human

c) When plasmodium infected female Anopheles mosquito bites to the infected human

d) When plasmodium infected male Anopheles mosquito bites to the infected human

8. Proguanil and cycloguanil is an example of……….

a) 8-Amino quinoline b) 4-Amino quinoline

c) 9-Amino acridine d) Biguanides derivatives

9. Primaquine show its antimalarial action by generation of reactive oxygen species via ….

a) Hemozoin b) Autoxidation c) Folate reductase d) None of the above

10. Amidoquine shows its antimalarial action by inhibition of ............ formation.

Medicinal Chemistry 3

a) Hemozoin b) Hematin c) Folate reductase d) Hemoglobin

Answers:

1 2 3 4 5 6 7 8 9 10
a b a c d a c d b a

Short answer questions:

1. Explain the mechanism of action of Chloroquine.

2. Discuss the life cycle of plasmodium.
3. Write the structure and uses of following drugs:

a) Mefloquine b) Chlorqiune c) Pamaquine d) Atovoqone

4. Write the synthesis of Pamaquine.

5. Explain the SAR of quinine.

Long answer questions

1. What is malaria? Discuss its etiology and classify antimalarial agents with suitable
examples?
2. Give the synthesis, SAR and mechanism of action of Chloroquine.
3. Define malaria? Write classification, SAR and synthesis of antimalarial agents.