Chapter 7: Antimalarial Drugs

(Medicinal Chemistry & Pharmacology)

Syllabus:
Antimalarials: Etiology of malaria.
Quinolines: SAR, Quinine sulphate, Chloroquine*, Amodiaquine, Primaquine
phosphate, Pamaquine*, Quinacrine hydrochloride, Mefloquine.
Biguanides and dihydro triazines: Cycloguanil pamoate, Proguanil.
Miscellaneous: Pyrimethamine, Artesunete, Artemether, Atovoquone.
7.1. MALERIA
Malaria is a protozoal disease infected by Plasmodium specieses (P. falciparum, P. vivex,
P. malariae and P. ovale).
Malaria is transmitted in human via a bite from an infected female Anopheles mosquito
(Vector).
P. vivex, P. malariae and P. ovale produce the mild forms of malaria by destroying red
blood cells in peripheral capillaries and thus, causing anaemia
The most dangerous is the P. falciparum. In this case, the infected red blood cells become
sticky and form lumps in the capillaries of the deep organs of the body and cause
microcirculatory arrest
This disease still affects about 200 million people and causes at least 2 million deaths per
year.

Symptoms: Fever, Shivering, Joint pain, headache, vomiting, convulsion and coma. After
mosquito bite, Symptoms occurs at 7-9 days

Two important phases of the parasite life cycle are the following:
1. Asexual cycle—occurs in the infected host.
2. Sexual cycle—occurs in the mosquito.

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 Source: https://www.malariasite.com/life-cycle

7.2. ANTIMALARIAL DRUGS

Based on Clinically Uses of Drugs

I) Sporozoitocides (caused prophylaxis): Primaquine, Chloroguanil,

Pyrimethamine* (*reserve for P. falciparum)
II) Tissue Schizonticides, Radical curative & Preventing Relapse: Primaquine
III) Blood Schizontocides:
a. Slow Acting: Proguanil, Pyramethamine
b. Rapid Acting: Chloroquine, Mefloquine, Quinine, Atovaquone
IV) Used in Prophylaxis: Proguanil, Chloroquine, Mefloquine, Atovaquone
V) Use in Clinical Attack: Chloroquine, Mefloquine, Quinine, Atovaquone
VI) Gametocytocides: to prevent transmission
a. For P. vivex, P. malariae and P. ovale: Chloroquine, Quinine
b. For P. falciparum: Primaquine

Based on Chemical Nature

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1) Cinchona alkaloid: Quinine, Quinidine, Cinchonine

2) Quinoline-methenol: Mefloquine, Cinchona alkaloids (Quinine and Quinidine).

Mefloquine
3) 4-Aminoquinolines: Chloroquine, Amodiaquine, Piperaquine.

4) 8-Aminoquinolines: Primaquine, Pamaquine, Bulaquine.

5) 9-Amonoquinoline (Acridines): Quinacrine, Mepacrine

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6) Nephthoquinone: Atovaquone.
7) Biguanides: Proguanil, Chlorproguanil.

8) Diaminopyrimidines: Pyramithamine.

9) Sulfones and Sulfonamides: Dapsone, Sulfamethopyrazine, Sulfadoxine.

10) Endoperoxides: Artemether, Artesunate, Arteether- Sesquiterpine lactones
11) Amino alcohols: Halofantrine, Lumefantrine.
12) Tetracyclines: Tetracycline, Doxycycline
13) Mannich Base: Pyronaridine.

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 7.3. SAR of Quinoline

Quinine (-) 8S9R; Quinidine (+) 8R9S

Cinchonine (+) 8R9S; Cinchonidine (-) 8S9R

a) Asymmetry at 3 & 4 is not essential for antimalarial activity.

b) At C-8: addition of halogen (Cl, F, Br), enhance the activity
c) At C9 (2o alcohol): modification of 2o alcohol by oxidation (=O) or esterification (-OR)
diminishes activity
d) At C4: Quinuclidine portion is not essential for activity, so it can be replaced. E.g., 4-
amino quinolines (Chloroquine, Amodiaquine, Piperaquine)
e) At C6: -OCH3 or -H replaced with -Cl, -CF3 increase the activity
f) introduce a phenyl (not alkyl) group at C-2 position in quinoline ring increase the
activity by blocking the metabolic oxidation (Quinoline→2hydroxy quinoline). But it
may enhance the phototoxicity. Therefore, recently discover a highly active drug
without phototoxic by addition of -CF3 at C-2 position (Mefloquine)

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 7.4. SAR of 8-Amino Quinoline

Pentaqione -(CH2)5-NH-CH(CH3)2
Quinoclide -(CH2)3-CH(CH3)-NH(C2H5)2

a) At C-6 position, -OCH3 (methoxy) group has high therapeutic index, it may be substituted
by -H, -OH group.
b) Introduce of 2nd methoxy group at C-5 or C-2 position increases the therapeutic index.
c) optimal activity was obtained with 2-6 (-CH2-) group between (NH------NH). Even no. of -
CH2 group is lesser toxic than odd no.
d) Extent substitution of the terminal amine (-NR2) is not critical as 4-amino quinoline.
Terminal aliphatic amino group may be 1o 2o and 3o. e.g., primaquine (1o amine)

7.5.SAR of 7-Chloro 4-Amino Quinoline

✓ The D-isomer of chloroquine is less toxic than its L-isomer

C-4 Position

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a) At C-4 position, the dialkylamino alkyl side chain has 2-5 carbon atoms between the
nitrogen atoms, particularly the 4-diethylamino methyl butyl amino side chain that is
optimal for activity, as in chloroquine and quinacrine.
b) The substitution of a hydroxyl group on one of the ethyl groups on the tertiary amine
(hydroxy quinoline), reduces toxicity.
c) Incorporation of an aromatic ring in the side chain (e.g. amodiaquine) gives a compound
with reduced toxicity and activity.
d) The tertiary amine in the side chain is important.
e) The introduction of an unsaturated bond in the side chain was not detrimental to activity.
C-7 Position
f) The 7-chloro group in the quinoline nucleus is optimal
C-3 Position
g) the methyl group in position 3 reduces activity,
C-8 Position
h) additional methyl group in position 8 abolishes activity.

7.6.Selected Drugs Pharmacology & Medicinal Chemistry

Quinoline Derivatives
Quinine sulphate, Chloroquine*, Amodiaquine, Primaquine phosphate, Pamaquine*,
Quinacrine hydrochloride, Mefloquine

1) Quinine sulphate

6-(methoxy quinoline-4yl)-5-(venyl quinuclidine-2yl)-methenol

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Mode of Action: Quinine (l-isomer) intercalates the DNS of the parasite. It inhibits the ability
of haemoglobin digestion of parasite thus parasite starve and build up toxic level of partially
degraded haemoglobin in itself.

The Possible Mode of Action of Quinoline derivatives

DNA interaction: Quinine intercalates the DNS of the parasite

Ferriprotoporphyrin IX: The plasmodium parasite utilizes host haemoglobin as a
source of amino acid. On digestion of the haemoglobin, the haem is released as
ferriprotoporphyrins IX and it produces haemolysis of the erythrocyte parasites. Therefore,
ferriprotoporphyrin that is released is converted into nontoxic products and they, in turn, to
haemozoites by the polymerase enzyme. The steps involved in the conversion to
haemozoites are inhibited by the chloroquine.
Weak base hypothesis: The 4-substituted quinolines have weak base and because of
this pKa they are thought to accumulate in a location, which is acidic (parasite lysosome
pH 4.8–5.2). As the extracellular fluid of the parasite is at pH 7.4, the weak base will move
towards a more acidic pH of lysosome. Once the acid–base reaction occurs, elevating the
pH in the lysozome, that in turn reduces the parasite’s ability to digest haemoglobin, thus
reducing the availability of amino acids.
Pharmacology
✓ Quinine is an erythrocytic schizontocide for all species of plasmodia, but less effective
and more toxic than chloroquine. Resurgence of interest in quinine is due to the fact
that most CQ and multidrug-resistant strains of P. falciparum still respond to it.
✓ Doxycycline or clindamycin is mostly added to it for complete parasite clearance.
✓ Quinine has no effect on preerythrocytic stage and on hypnozoites of relapsing malaria,
but kills vivax gametes
✓ Other Action: Local irritant and anaesthetics, systemically it enhances GI secretion,
Quinine is a weak analgesic and antipyretic, Cardiodepressant, antiarrhythmic and
hypotensive actions are similar to quinidine
Pharmacokinetics
✓ Rapidly and complete absorbed orally
✓ PB- 70%, to alfa-acid glycoprotein, which increases during acute malarial infection
✓ Low CSF concentration
✓ Large fraction metabolized in liver by CYP3A4 and excreted in urine (t1/2 – 10-12h)

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 ✓ Metabolism: Metabolism of liver, Quinine → 2-hydroxy quinine → 2,3-dihydroxy
quinine
Therapeutic Uses
✓ Treatment of sever P. falciparum malaria
✓ Quinidine: may also use in Supraventricular and ventricular and other arrhythmias
ADR
✓ Toxicity of quinine is high and dose related; 8–10 g taken in a single dose may be fatal.
✓ Cinchonism A large single dose or higher therapeutic doses taken for a few days
produce a syndrome called ‘cinchonism’. It consists of ringing in ears, nausea, vomiting
(due to both gastric irritation and CTZ stimulation), headache, mental confusion,
vertigo, difficulty in hearing and visual defects (due to direct neurotoxicity as well as
constriction of retinal and auditory vessels). Diarrhoea, flushing and marked
perspiration may also appear. The syndrome subsides completely if the drug is stopped.

2) Chloroquine

7-chloro-4-(diethyl amino 1-methyl butyl) amino-quinoline

MOA
➢ It interferes haemoglobin digestion ability of plasmodia species. It actively
concentrated in infected RBCs. Accumulating in the acidic vecuoles of the parasite and
because of its weakly basic nature.
➢ Polymerization of toxic haeme generated from digestion of haemoglobin to nontoxic
parasite pigment haemozoin is inhibited by the formation of CQ-haeme complex.
➢ Chloroquine also damages the plasmodial membranes
➢ Additionally, it interferes the protein and nucleic acid synthesis.
Pharmacology
✓ It is a rapidly acting erythrocytic schizontocide against all species of plasmodia;
controls most

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 ✓ clinical attacks in 1–2 days with disappearance of parasites from peripheral blood in 1–
3 days.
✓ Therapeutic plasma concentration- 15-30 ng/ml
✓ No effects on primary and secondary hepatic stages of the parasite—does not prevent
relapses in vivax and ovale malaria
✓ It has no clinically useful gametocidal activity
✓ Chloroquine-resistance among P. falciparum is now widespread in India. Resistance in
P. falciparum is associated with a decreased ability of the parasite to accumulate CQ
and increase encoding of efflux transport system (pfcrt: P.f. chloroquine-resistance
transporter gene).
✓ Presently, Chloroquine-resistance among P. vivax was first reported from Papua New
Guinea in 1989. It has now been confirmed from many countries, including India.
✓ It manifests as recurrence within 1–3 weeks of treating vivax malaria with standard
dose of chloroquine. Such cases can be treated by quinine given along with
doxycycline/clindamycin or by ACT, followed by primaquine to effect radical cure.
✓ However, CQ given in standard doses remains the first line treatment of vivax malaria
as per National vector borne diseases control programme (NVBDCP) guidelines.
✓ Other actions: Chloroquine is active against Entamoeba histolytica and Giardia
lamblia as well. It has anti-inflammatory, local irritant and local anaesthetic (on
injection), weak smooth muscle relaxant, antihistaminic and antiarrhythmic properties.
Pharmacokinetics
✓ Orally well absorbed. 50% protein bound; It has high affinity for melanin and nuclear
chromatin: gets tightly bound to these tissue constituents and is concentrated in liver,
spleen, kidney, lungs (several hundred fold), skin, leucocytes and some other tissues.
✓ Its selective accumulation in retina is responsible for the ocular toxicity seen with
prolonged use.
✓ Chloroquine is partly metabolized by liver and slowly excreted in urine.
✓ The early plasma t½ varies from 3–10 days. Because of tight tissue binding, small
amounts persist in the body with a terminal t½ of 1–2 months
ADR
✓ Toxicity of CQ is low, but side effects like nausea, vomiting, anorexia, uncontrollable
itching, epigastric pain, uneasiness
✓ Prolonged use of high doses (as needed for rheumatoid arthritis, DLE, etc.) may cause
loss of vision due to retinal damage.
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 ✓ Loss of hearing, rashes, photoallergy, mental disturbances, myopathy and graying of
hair can occur on long-term use.
✓ Intravenous injection of CQ (rarely given now) can cause hypotension, cardiac
depression, arrhythmias and CNS toxicity including seizures (more likely in children).
Contraindicated
✓ Caution In Liver damages, neurological, retinal and haematological diseases. Attacks
of seizures, porphyria and psoriasis may be precipitated
✓ CQ can be used for treatment of malaria during pregnancy: no abortifacient or
teratogenic effects have been reported.
✓ CQ should not be coadministered with mefloquine, amiodarone and other
antiarrhythmics

Uses:
✓ Treatment of Malaria (all species). It causes rapid fever clearance and disappearance of
parasitaemia in patients of malaria
✓ Extraintestinal amoebiasis
✓ Rheumatoid arthritis
✓ Discoid lupus erythematosus—very effective;
✓ Lepra reaction
✓ Photogenic reactions.
✓ Infectious mononucleosis: affords symptomatic relief.
Synthesis

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3) Amodiaquine

✓ Amodiaquine has similar action as chloroquine. Amodiaquine has tended to be

administered in areas of chloroquine resistance while some patients prefer its tendency to
cause less itching than chloroquine.
✓ Amodiaquine is now available in a combined formulation with artesunate and is among
the artemisinin-combination therapies recommended by the World Health Organization.
✓ It is used for chloroquine resistance falciparum malaria.

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4) Primaquine phosphate

Primaquine is most effective against gametocytes but also acts on hypnozoites, blood
schizonticytes and the dormant plasmodia in P. vivax and P. ovale. It is the only known drug
to cure both relapsing malaria infections and acute cases.

The mechanism of action is not fully understood but it is thought to block oxidative metabolism
in Plasmodia and binds with the nucleoproteins and interferes with protein synthesis and
intercalates readily into double-standard DNA and Inhibit both DNA and RNA polymerase.

5) Pamaquine

Pamaquine act similar as primaquine, and used in treatment of malaria caused by P. vivex and
P. ovale

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6) Quinacrine

MOA: It intercalates DNA and inhibits succinate oxidation and interfere with electron
transport.

Uses:

✓ Mainly used in treatment of malaria caused by P. vivex and P. ovale.

✓ Also used in Giardiasis caused by Giardia lamblia
✓ It is also used transcervically as a female sterilizing agents

7) Mefloquine

✓ MOA: Mefloquine is a very potent blood schizonticide with a long half-life. It is

thought to act by forming toxic heme complexes that damage parasitic food vacuoles
and interfere the ability to metabolize and utilize erythrocyte hemoglobin.
Uses:
✓ It is now used solely for the prevention of resistant strains of P. falciparum despite
being effective against P. vivax, P. ovale and P. marlariae.
✓ Mefloquine is effective in prophylaxis and for acute therapy. It is now strictly used for
resistant strains (and is usually combined with Artesunate).

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 Biguanides and dihydro triazines
A) Cycloguanil pamoate

B) Proguanil

✓ Proguanil (chloroguanide) is a biguanide; a synthetic derivative of pyrimidine.

✓ It has many mechanisms of action but primarily is mediated through conversion to the
active metabolite cycloguanil.
✓ MOA: This inhibits the malarial dihydrofolate reductase enzyme (an enzyme
essential for production of folic acid).
✓ Uses: Its most prominent effect is on the primary tissue stages of P. falciparum, P.
vivax and P. ovale. It has no known effect against hypnozoites therefore is not used in
the prevention of relapse.

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 Other Derivatives
A) Pyrimethamine

✓ Pyrimethamine is used in the treatment of uncomplicated malaria. It is particularly

useful in cases of chloroquine-resistant P. falciparum strains when combined
with sulfadoxine.
✓ It acts by inhibiting dihydrofolate reductase in the parasite thus preventing the
biosynthesis of purines and pyrimidines, thereby halting the processes of DNA
replication, cell division and reproduction.
✓ It acts primarily on the schizonts during the erythrocytic phase, and nowadays is only
used in concert with a sulfonamide.
✓ It is used for suppression or chemoprophylaxis of malaria
✓ Also used along with sulfadiazine or azithromycin for the treatment of toxoplasmosis.

B) Artesunete

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C) Artemether

✓ It is derived from the plant Artemisia annua used in Chinese traditional medicine as
‘Quinghaosu’.
✓ It is a sesquiterpene lactone with a chemically rare peroxide bridge linkage
(Endoperoxide bridge).
✓ It is active against multidrug-resistant P. falciparum. The endoperoxide bridge interact
with heam in the parasite, finally leads to inhibit protein synthesis and ultimately results
in lysis of parasitesa and it also arrest the cell cycle.
✓ It is used for suppression or chemoprophylaxis of maleria

D) Atovoquone

MOA: Atovaquone blocks the mitochondrial electron transport system at a complex III of the
respiratory chain of protozoa, thereby inhibiting pyrimidine synthesis and preventing the
nucleic acid or DNA synthesis

Uses: It is used for suppression or chemoprophylaxis of malaria and also has antipneumocystic
properties.

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