2. Malaria
Malaria is a serious tropical disease spread by mosquitoes. If it isn't diagnosed and treated
promptly, it can be fatal. Much before chemotherapeutic use, it was believed that malaria
was caused by a miasma which arises from stagnate water at night. Ronald Ross in 1897
first time demonstrated the presence of malaria parasite in the wall of the stomach of female
anopheles mosquito. A single mosquito bite (female Anopheles mosquitoes) is all it takes for
someone to become infected.
3. Etiology
Malaria is caused by a type of parasite known as Plasmodium. There are many different
types of Plasmodia parasites, but only 5 (P. falciparum, P. vivax, P. ovale, P. malariae and
P. knowlesi) cause malaria in people. The most common worldwide is P. vivax and the
deadliest is P. falciparum.
The Plasmodium parasite is mainly spread by female Anopheles mosquitoes, which mainly
bite at dusk and at night. Female Anopheles mosquitoes feed on human blood in order to
nourish their own eggs. When an infected mosquito bites a person, it passes the parasites
into the bloodstream.
4.
5. While taking its meal (usually between dusk and dawn), an infected mosquito injects
immature forms of the parasite, called sporozoites, into the person’s bloodstream. The
sporozoites are carried by the blood to the liver, where they mature into forms known as
schizonts.
Over the next one to two weeks each schizont multiplies into thousands of other forms
known as merozoites. The merozoites break out of the liver and re-enter the bloodstream,
where they invade red blood cells, grow and divide further, and destroy the blood cells in the
process.
6. The interval between invasion of a blood cell and rupture of that cell by the next generation
of merozoites is about 48 hours for P. falciparum, P. vivax, and P. ovale. In P. malariae the
cycle is 72 hours long.
P. knowlesi has the shortest life cycle (24 hours) of the known human Plasmodium
pathogens, and thus parasites rupture daily from infected blood cells.
7.
8. Patients who are bitten by malaria-carrying mosquitoes experience no symptoms until 10 to
28 days after infection. The first clinical signs may be any combination of chills, fever,
headache, muscle ache, nausea, vomiting, diarrhoea and abdominal cramps. Chills and fever
occur in periodic attacks; these last 4 to 10 hours and consist first of a stage of shaking and
chills, then a stage of fever and severe headache and finally a stage of profuse sweating
during which temperature drops back to normal. The classic attack cycles, recurring at
intervals of 48 hours (tertian malaria) or 72 hours (quartan malaria), coincide with the
synchronized release of each new generation of merozoites into the bloodstream. The
parasite continues to multiply, unless the victim is treated with appropriate drugs or dies in
the interim.
9. Symptoms
Symptoms of malaria can develop as quickly as 7 days after bitten by an infected mosquito.
Typically, the time between being infected and when symptoms start (incubation period) is 7
to 18 days, depending on the specific parasite you're infected with. The initial symptoms of
malaria are flu-like and include:
▪ A high temperature of 38 °C or above
▪ Feeling hot and shivery
▪ Headaches
▪ Vomiting
▪ Muscle pains
▪ Diarrhoea
▪ Generally feeling unwell
10. With some types of malaria, the symptoms occur in 48-hour cycles. During these cycles,
patient feels cold at first with shivering. Patient then develop a high temperature,
accompanied by severe sweating and fatigue. These symptoms usually last between 6 and 12
hours.
The most serious type of malaria is caused by P. falciparum. Without prompt treatment, this
type could lead to you quickly developing severe and life-threatening complications, such as
breathing problems and organ failure.
11. Complications of malaria
Malaria is a serious illness that can get worse very quickly. It can be fatal if not treated
promptly. It can also cause serious complications, including:
▪ Severe anaemia – where red blood cells are unable to carry enough oxygen around the
body, leading to drowsiness and weakness.
▪ Cerebral malaria – in rare cases, the small blood vessels leading to the brain can become
blocked, causing seizures, brain damage and coma.
The effects of malaria are usually more severe in the pregnant women, babies, young
children and the elderly. Pregnant women in particular are usually advised not to travel to
the malaria risk areas.
12. Malaria risk areas
Malaria occurs in more than 100 countries and territories, mainly in tropical regions of the
world, including following:
▪ Large areas of Africa and Asia
▪ Central and South America
▪ Haiti and the Dominican Republic
▪ Parts of the Middle East
▪ Some Pacific islands
▪ Malaria is not found in the UK – it may be diagnosed in travellers who return to the UK
from risk areas.
13. In areas with high transmission (such as Africa south of the Sahara), the most vulnerable
groups are:
▪ Young children, who have not yet developed partial immunity to malaria.
▪ Pregnant women, whose immunity is decreased by pregnancy, especially during the first
and second pregnancies.
▪ Travellers or migrants coming from areas with little or no malaria transmission, who lack
immunity.
15. Distribution of malaria cases worldwide (2019)
Nearly half the world’s population lives in areas at risk of malaria transmission in 87
countries and territories.
According to the World Health Organization’s World Malaria Report 2020; there were an
estimated 229 million malaria cases in 2019 across 87 malaria endemic countries, declining
from 238 million in 2000 across 108 countries.
According to the World Malaria Report 2020; there were an estimated 409000 deaths due to
malaria in 2019, declining from 736000 deaths in 2000 due to malaria epidemic.
16.
17.
18. Distribution of malaria deaths worldwide (2019)
In 2019, an estimated 409,000 people died of malaria; most were young children in sub-
Saharan Africa.
An estimated 94% of deaths in 2019 were in the WHO African Region. Within the last
decade, increasing numbers of partners and resources have rapidly increased malaria control
efforts.
This scale-up of interventions has saved millions of lives globally and cut malaria mortality
by 44% from 2010 to 2019, leading to hopes and plans for elimination and ultimately
eradication.
19.
20. Preventing malaria
There's a significant risk of getting malaria if you travel to an affected area. It's very
important you take precautions to prevent the disease. Malaria can often be avoided using
the ABCD approach to prevention:
Awareness of risk: find out whether you're at risk of getting malaria before travelling.
Bite prevention: avoid mosquito bites by using insect repellent, covering your arms and
legs, and using an insecticide-treated mosquito net.
21. Check whether you need to take malaria prevention tablets: if you do, make sure you take
the right antimalarial tablets at the right dose, and finish the course (antimalarials reduce risk
of infection by about 90%).
Diagnosis: seek immediate medical advice if you develop malaria symptoms, as long as up
to a year after you return from travelling.
22. Antimalarial drugs
Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agents
(chemotherapeutic agent), which can be used for prophylaxis, treatment and prevention of
relapses of malaria. The aims of using antimalarial medications in relation to malarial
infection are:
a) To prevent clinical attack of malaria (prophylactic).
b) To treat clinical attack of malaria (clinical curative).
c) To completely eradicate the parasite from the patient’s body (radical curative).
d) To cut-down human-to-mosquito transmission (gametocidal).
23. Classification
Quinine and analogues: Quinine and its analogues are alkaloids obtained from cinchona
bark (Cinchona officinalis, family: Rubiaceae).
N
R
N
CH=CH2
H
H
H
O
H H
N
R
N
CH=CH2
H
H
O
H
H H
-R -R
Quinine -OCH3 Quinidine -OCH3
Cinchonidine -H Cinchonine -H
33. Artemisinin and its derivatives: The artemisinin derivatives are the newest antimalarial
drugs and are structurally unique when compared with the compounds previously and
currently used. Artemisinin is a natural product extracted from dry leaves of Artemisia
annua (Family: Asteraceae, sweet wormwood).
Artemisinin O
O
O
CH3
CH3
H
H
C
H3
H
O
O
38. Mechanism of action
Quinine and analogues: The mechanism of action of quinine and its derivatives is
interference with the parasite's ability to digest haemoglobin.
Quinine is an erthyrocytic schizontocide against all species of plasmodia. It gets
concentrated in acidic vacuoles of blood schinzonts and causes pigment changes; inhibits
polymerization of haeme to hemozoin (by raising pH of vacuoles due to its basic nature).
Free haeme itself or haeme-quinine complex damages plasmodia parasite membranes and
kills it.
39.
40. 4-Aminoquinolines: Chloroquine is an erthyrocytic schizontocide against all species of
plasmodia.
Plasmodia derive nutrition by digesting haemoglobin in their acidic vacuoles. Chloroquine is
actively concentrated by sensitive intra-erythrocytic plasmodia; higher concentration is
found in infected RBCs than in non-infected ones.
By accumulating in the acidic vacuoles of the parasite and because of its weakly basic
nature, it raises the vacuolar pH and thereby interferes with degradation of haemoglobin by
parasitic lysosomes.
41. Polymerization of toxic haeme generated from digestion of haemoglobin to non-toxic
parasite pigment haemozoin is inhibited by the formation of chloroquine-haeme complex.
Haeme itself or its complex with chloroquine then damages the plasmodial membranes and
kills it.
42.
43. 8-Aminoquinolines: Although mechanism of action of primaquine is unclear, primaquine
can generate reactive oxygen species due to oxidative nature of its metabolites. As a result,
cell-destructive oxidants can be formed leading to oxidative damage to critical cellular
components of the malaria parasite (it also act by interfering with electron transport in the
mitochondria of the parasite).
44.
45. 9-Aminoacridines: The exact mechanism of antiparasitic action of quinacrine is unknown;
however, quinacrine binds to DNA in vitro by intercalation between adjacent base pairs,
inhibiting transcription of DNA to RNA.
46. Biguanides: Proguanil is a relatively slow-acting erythrocytic schizontocide for both P.
falciparum and P. vivax. In addition, it also inhibits the pre-erythrocytic stage of P.
falciparum.
Gametocytes exposed to proguanil are not killed but may fail to develop properly in the
mosquito.
Proguanil is cyclized in the body to a triazine derivative (cycloguanil) which inhibits
plasmodial dihydrofolate reductase-thymidylate synthase in preference to the mammalian
dihydrofolate reductase.
47.
48. Aminopyrimidines: Aminopyrimidines (pyrimethamine and trimethoprim) are particularly
useful in cases of chloroquine-resistant P. falciparum strains when combined with
sulfadoxine.
They act 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. They act primarily on schizonts during erythrocytic phase,
and now-a-days is only used in concert with a sulfonamide.
49.
50. Artemisinin and its derivatives: Artemisinins are the prodrugs of biologically active
dihydro-artemisinin which is active during the stage when the parasite is located inside the
red blood cells.
The endo-peroxide bridge in the structure of artemisinin derivatives appears to interact with
the haeme in the parasite.
Iron mediated cleavage of the endo-peroxide bridge releases highly reactive free radicals
that bind to membrane proteins, damage endoplasmic reticulum, and inhibit protein
synthesis resulting in lysis of the parasite (P. falciparum).
51.
52. Atovaquone: Atovaquone is a rapidly acting schizonticide for P. falciparum and other
plasmodia.
Atovaquone possesses a novel mode of action against P. falciparum through inhibition of
electron transport system at the level of cytochrome bc1 complex (interfering ATP
synthesis).
Atovaquone also causes collapse of the parasite mitochondrial membrane potential in P.
falciparum.
53.
54. Structure activity relationships
Quinine and analogues:
1. Secondary hydroxyl group at C-9 is important for antimalarial activity. Any modification
in the secondary alcohol at C-9 through oxidation, etherification, etc., diminishes
antimalarial activity.
N
R
N
CH=CH2
H
H
H
O
H H 1
2
3
5
4
6
8
7
9
1’
2’
3’
4’
5’
6’
7’
8’
55. 2. Presence of methoxy group at C-6’ in quinine is not essential for antimalarial activity of
quinine derivatives. Replacement of methoxy group by a halogen, especially chlorine
enhances activity.
3. A further increase in antimalarial activity resulted from the introduction of a phenyl group
at position 2’.
4. High activity without photo-toxicity could be attained by blocking C-2’ with a
trifluoromethyl group (-CF3). This discovery had eventually led to the development of
mefloquine.
56. 5. The quinuclidine part in quinine is not necessary for the antimalarial activity. However,
an alkyl tertiary amine linked to C-9 is required for activity.
6. Introduction of halogen at C-8 resulted in increased antimalarial activity of the quinine
derivatives.
7. Vinyl group at C-3 is not essential for antimalarial activity. Assymmetry at C-3 and C-4
is not essential for activity.
57. 4-Aminoquinolines:
1. Chloro group at C-7, tertiary amine and diamino alkyl side chain are essential features for
antimalarial activity.
2. The d-enantiomer of chloroquine is somewhat less toxic than the l-enantiomer of
chloroquine.
3. The ‘NH’ group at C-4 of the quinoline nucleus determines basicity of the 4-
aminoquinoline derivatives.
1
2
3
4
5
6
7
8
N
R
1
NH-R
2
Cl
58. 4. Basic quinoline ring with chloro group at C-7 is required for binding with haeme
(optimum for antimalarial activity).
5. Introduction of methyl group at C-3 (R1) reduces antimalarial activity of the 4-
aminoquinoline derivatives.
6. Substitution of a hydroxyl group (-OH) on one of the ethyl groups in tertiary amine
generally reduces toxicity and increases plasma concentration, e.g., hydroxychloroquine.
This is one of the metabolite of chloroquine.
7. Incorporation of an aromatic ring in the side chain resulted in compounds with reduced
toxicity, e.g., amodiaquine.
59. 8. Presence of 2-5 carbon atoms between the two nitrogen atoms in the side chain at C-4 is
optimal for activity, e.g., chloroquine.
9. Introduction of unsaturation (double bond) in the side chain does not interfere with the
activity of the molecules.
60. 8-Aminoquinolines:
1. Methoxy group at C-6 is responsible for optimum activity but this group is not essential
for antimalarial activity.
2. If we replace the methoxy group at C-6 by hydroxyl group, it will show comparable
(same) activity. While when ethoxy group is attached it will show low or negligible
antimalarial activity.
3. If methoxy group at C-6 is replaced by methyl group the compound will become inactive
(less activity).
1
2
3
4
5
6
7
8 N
O
C
H3
NH-R
1
R
2
R
3
R
4
61. 4. Additional substitution on the quinoline nucleus tends to decrease both activity as well as
toxicity.
5. The reduction of quinoline nucleus (hetro ring) at C-1 and C-2 into 1,2,3,4-tetra hydro
derivative showed same pharmacological effect but its potency and toxicity were
decreased (required high dose).
6. In amino side chain, there are two amino groups, for optimum activity; the distance
between the two nitrogens of amino side chain should be 4-6 carbons. The greatest
activity was achieved in alkyl groups containing 5 carbon atoms.
7. Any substitution on the quinoline ring (especially at C-3 and C-7) will lead to decrease its
antimalarial activity.
62. 9-Aminoacridines:
N
Cl
O
CH3
NH-R
1. Acridine nucleus is essential for antimalarial action but it is less potent as compared to the
quinoline nucleus.
2. The presence of methoxy substituent at C-2 position and chloro substituent at C-6
position play an important role in antimalarial activity.
3. Carbon chain at C-9 position between two nitrogen atoms should consist of 4-6 carbon
atoms for optimal antimalarial activity.
63. 4. In the side chain, the terminal nitrogen atom should be tertiary. Its replacement with
primary or secondary nitrogen resulted in reduced activity.
5. Replacement of methoxy group at C-2 position with ethoxy group resulted in increased
toxicity.
6. Replacement of chloro group at C-6 position with other halogens resulted in reduced
antimalarial activity.
7. Introduction of a nitrogen atom at C-1 position resulted in good anatimalrial activity and
rapid onset of action, e.g., azacrine.
64. Biguanides:
Cl
N
H
N
NH
H
N
NH
H
CH3
CH3
R
1. Substitution of chloro group at para position (C-4) of the phenyl ring resulted in
antimalarial activity (e.g., proguanil).
2. Substitution of chloro group at both meta and para position (C-3 and C-4) of phenyl ring
resulted in good antimalarial activity (e.g., chloroproguanil).
3. Removal of the phenyl ring of proguanil resulted in reduced biological activity
(antimalarial activity).
65. 4. Replacement of isopropyl group with small or large alkyl groups resulted in reduced
activity. Isopropyl group showed optimal activity.
66. Dihydro triazines:
N N
N
C
H3
C
H3
Cl
NH2
NH2
1. Primary amino groups at C-1 and C-3 are essential for antimalarial activity. Replacement
or substitution of the primary amino groups with secondary or tertiary amino groups
resulted in decreased antimalarial activity.
2. Replacement of methyl groups at C-5 of the triazine ring with bulky groups resulted in
decreased antimalarial activity.
3. Presence of hydrophobic group such as chloro group at para position of the phenyl ring at
C-6 resulted in optimal activity.
67. Aminopyrimidines:
N
N
R
1
R
2
NH2
NH2
1. Two primary amino groups at C-2 and C-4 are essential for antimalarial activity.
Replacement or substitution with secondary or tertiary amino group resulted in decreased
antimalarial activity.
2. Electron withdrawing group at para position of aromatic ring at C-5 resulted in increased
activity.
68. 3. An aromatic ring is directly attached with pyrimidine ring for maximum activity.
Insertion of carbon or nitrogen between the two rings resulted in decreased antimalarial
activity.
4. Substitution at C-6 of the pyrimidine ring with electron releasing groups such as methyl
or ethyl resulted in increased activity.
69. Artemisinin and its derivatives: Artemisinin serves as lead compound for the development
of new antimalarials with improved properties.
O
O
OR
CH3
CH3
H
H
C
H3
H
O
O
1. Derivatisation of the carbonyl lactone demonstrated that it is a possible region of
modification that can be modified in order to improve pharmacokinetic parameters of
artemisinin derivatives. This was demonstrated by the semi-synthetic prodrugs.
Compared to artemisinin itself, prodrugs artemether, artesunate and dihydroartemisinin
are more active.
70. 2. Alkylation of the hydroxyl group gives oil-soluble derivatives such as artemether and
arteether.
3. Esterification of the hydroxyl group with succinic acid gives the water-soluble derivative
such as artesunate.
4. Reduction of the carbonyl group of lactone ring to alcoholic group resulted in better
pharmacokinetic properties, e.g., dihydroartemisinin.
5. Removal of endo-peroxide bridge of artemisinin resulted in vastly reduced antimalarial
activity, e.g., deoxyartemisinin.
71. Synthesis of Chloroquine
Synthesis: Synthesis of chloroquine (7-Chloro-4-(4-diethylamino-1-methylbutylamino)-
quinoline) can be performed in following three steps:
(a) Preparation of 4,7-dichloroquinoline (i.e., nucleus): 3-Chloroaniline is reacted with
ethoxymethylene malonic ester to prepare (3-choroanilino)-methylene malonic ester, which
then undergoes high-temperature heterocyclization to make ethyl ester of 7-chloro-4-
hydroxyquinolin-3-carboxylic acid. Hydrolyzing this with sodium hydroxide gives 7-chloro-
4-hydroxyquinolin-3-carboxylic acid, which when heated at 250-270 °C is decarboxylated,
forming 7-chloro-4-hydroxyquinoline. Treating this with phosphorus oxychloride 4,7-
dichloroquinoline.
72. Cl NH2
+
O
O
H5C2-O
H5C2
O
O
C2H5
Cl N
H
O
O
C2H5
O
O
H5C2
Δ
Cl N
OH
O
O
C2H5 NaOH
Cl N
OH
OH
O
Cl N
OH
250 °C
Cl N
Cl
3-Chloro
aniline Ethyoxymethylene
malonic ester
(3-Chloroanilino)-methylene
malonic ester
7-Chloro-4-hydroxyquinoline-3
-carboxylic acid ethyl ester
7-Chloro-4-hydroxyquinoline-
3-carboxylic acid
7-Chloro-4
-hydroxy
quinoline
4,7-Dichloro quinoline
POCl3
73. (b) Preparation of 1-diethylamino-4-aminopentane (i.e., side chain): Alkylating
acetoacetic ester with 2-diethylaminoethylchloride gives 2-diethylaminoethylacetoacetic
acid ester, which upon acidic hydrolysis (using hydrochloric acid) and simultaneous
decarboxylation results in 1-diethylamino-4-pentanone. Reductive amination of this
compound with hydrogen and ammonia using Raney nickel gives 1-diethylamino-4-
aminopentane.
74. Acetoacetic ester
+
CH2 N
CH2
N
H2 CH CH2
CH3
C2H5
C2H5
1-Diethylamino-4-pentane
O
C
H3 OC2H5
O
CH2 N
CH2
Cl
C2H5
C2H5
2-Diethylaminoethyl
acetoacetic ester
CH2 N
CH2
CH
C2H5
C2H5
OC2H5
O
O
CH3
Na HCl
-CO2
CH2 N
CH2
C
H3 C CH2
O
C2H5
C2H5 H2, NH3
Raney
Ni
1-Diethylamino-4-pentanone
2-Diethylaminoethyl
chloride
75. (c) Condensation of 4,7-dichloroquinoline (nucleus) and 1-diethylamino-4-aminopentane
(side chain): Chloroquine (13) is synthesized by reacting 4,7-dichloroquinoline (7) with 1-
diethylamino-4-aminopentane (12) at 180 °C.
Cl N
Cl
1-Diethylamino-4-amino
pentane
+ CH2 N
CH2
N
H2 CH CH2
CH3
C2H5
C2H5
4,7-Dichloro
quinoline
N
Cl
N
H C
H (CH2)3 N
CH3
C2H5
C2H5
Chloroquine
76. Therapeutic uses:
1. Chloroquine causes rapid fever clearance and disappearance of parasitaemia in patients of
malaria caused by all P. ovale and P. malariae, most P. vivax and some P. falciparum
that are still sensitive. It is the drug of choice for clinical cure of vivax, ovale and
malariae malaria. However, its use for P. falciparum is restricted to few areas that still
have susceptible P. falciparum, but not in India. It is no longer used as a suppressive
prophylactic in India, and such use is made only in vivax predominant countries or in
those which have chloroquine-sensitive P. falciparum.
78. Synthesis of Pamaquine
IUPAC Name: 8-(4-Diethylamino-1-methylbutylamino)-6-methoxy quinoline
Synthesis: Chloroquine can be synthesized starting from 4-anisidine by using following
three steps:
(a) Preparation of 8-amino-6-methoxyquinoline (nucleus): 4-Anisidine on acetylation to
gives 4-acaetamidoanisole which on nitration (HNO3 in presence of H2OS4) yields 3-nitro-4-
acetamidoanisole followed by hydrolysis to give 3-nitro-4-anisidine (4). This product on
treatment with glycerol in presence of concentrated H2SO4 and nitrobenzene on cyclisation
(Skraup synthesis) give 6-methoxy-8-nitroquinoline. Reduction of this compound gives 8-
amino-6-methoxy quinoline.
80. (b) Preparation of 1-diethylamino-4-aminopentane (i.e., side chain): Alkylating
acetoacetic ester with 2-diethylaminoethylchloride gives 2-diethylaminoethylacetoacetic
acid ester, which upon acidic hydrolysis (using hydrochloric acid) and simultaneous
decarboxylation results in 1-diethylamino-4-pentanone. Reductive amination of this
compound with hydrogen and ammonia using Raney nickel as a catalyst gives 1-
diethylamino-4-aminopentane.
81. Acetoacetic ester
+
CH2 N
CH2
N
H2 CH CH2
CH3
C2H5
C2H5
1-Diethylamino-4-pentane
O
C
H3 OC2H5
O
CH2 N
CH2
Cl
C2H5
C2H5
2-Diethylaminoethyl
acetoacetic ester
CH2 N
CH2
CH
C2H5
C2H5
OC2H5
O
O
CH3
Na HCl
-CO2
CH2 N
CH2
C
H3 C CH2
O
C2H5
C2H5 H2, NH3
Raney
Ni
1-Diethylamino-4-pentanone
2-Diethylaminoethyl
chloride
82. (c) Condensation of 8-amino-6-methoxyquinoline (7) and 1-diethylamino-4-
aminopentane (12): Pamaquine is synthesized by condensation of 8-amino-6-
methoxyquinoline with 1-diethylamino-4-aminopentane.
N
NH2
O
CH3
8-Amino-6-methoxy
quinoline
+ CH2 N
CH2
N
H2 CH CH2
CH3
C2H5
C2H5
1-Diethylamino-4-amino
pentane
N
N
H C
H (CH2)3 N
CH3
C2H5
C2H5
O
CH3
Pamaquine
83. Therapeutic uses:
Pamaquine is effective against the hypnozoites of the relapsing malarias (P. vivax and P.
ovale); and it is also very effective against the erythrocytic stages of all four human
malarias. One small clinical trial of pamaquine as a causal prophylactic was disappointing
(whereas primaquine is an extremely effective causal prophylactic). Pamaquine is more
toxic and less efficacious than primaquine; therefore, pamaquine is no longer routinely used,
and of the two, only primaquine is currently recommended by the World Health
Organization for the casual treatment of malaria.