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212 Pharmaceutical Chemistry
primaquine, lumefantrine and halofantrine), antibiotics, antifolates, arylaminoalcohols,
artemisinines and inhibitors of the respiratory chain, etc. (Fig. 9.2). These drugs are reported
to be active against erythrocytic stage of infection. For example, primaquine kills
intrahepatic forms and gametocytes along with erythrocytic stage. Quinoline and
chloroquine drugs act as heme polymerase inhibitors but exact mechanism is still unknown.
These drugs mostly accumulate in the parasite food vacuoles and result in the form of
complex with heme which prevents crystallization (or hemozoin formation).
OH
MeO
HO
N
HN
N
HN
N
N
Quinine Chloroquine Amodiaquine
HN
N
OMe
Primaquine
Cl
NH
2
Mefloquine (stereoisomer)
Fig. 9.2: Antimalarial drugs currently in use
CF
HO
N
N
H
N
CF
3
3
Cl
Me
N
Me
O
O
O
O
O
Artemisinin
Me
Quinolines are alkaloids and belong to the oldest class of antimalarial drugs, for example,
quinoline series compound quinine was the first compound isolated from the bark of the
Cinchona tree and used in the treatment of malaria; however in severe cases it is used in
combination with antibiotics. Quinine is used to detoxify the heme, but the exact mechanism
is still not understood. Recent studies reported that quinine is losing its resistance gradually
but still is a drug of choice, for example, treatment failed in patients suffering from severe
malaria in North India even after five days of starting the treatment.
Quinine derivative chloroquine (CQ) was synthesized in 1934 and in the 1950s, it was
introduced for the treatment of uncomplicated/nonsevere malaria and chemoprophylaxis.
Time to time use of CQ gradually develops resistance towards P. falciparum, thus policy
makers have removed CQ from antimalarial therapies, however, despite its resistant
property, it is a drug of choice for P. vivax in Afghanistan. It is believed that CQ involves
with the detoxification of ferriprotoporphyrin-IX (FP a heme metabolite) and kills the
malaria parasites. CQ-resistance is associated with a parasitic protein, which is known as
CQ-resistance transporter (Pfcrt), and the mutated form of the Pfcrt-gene is able to reduce
the CQ accumulation in the digestive vacuole of the pathogen (Fig. 9.3). There are some
examples related to multidrug resistance gene-1 (pfmdr-1) which is also associated with
resistance to CQ.
Antimalarial Agents 213
Fig. 9.3: Host erythrocyte: Quinoline-containing drugs act primarily in the malaria parasite’s food vacuole by
preventing the detoxification of heme (FV = Food vacuole, Hb = Haemoglobin, CQ = Chloroquine)
Gradually CQ got resistant and thus in counter, amodiaquine (AQ) was developed in
1960. AQ easily gets metabolised in des-ethylamodiaquine (DEAQ, structurally similar to
CQ). This also helps to understand the cross-resistance observed after treatment with AQ
where parasites reported to harbour mutations on Pfcrt and Pfmdr1 gene.
Key points:
Malaria is an acute infectious disease caused by four species of the protozoal genus
Plasmodium, viz., P. falciparum, P. malariae, P. ovale, and P. vivax.
The parasite is transmitted to humans through the bite of female Anopheles mosquito.
P. falciparum is the most dangerous species, causing a severe disease. P. vivax causes
a milder disease.
Resistance acquired by the mosquito to CQ, many insecticides and other drugs has
led to new therapeutic challenges, especially in the case of P. falciparum.
9.3.1 Classification of Antimalarial Agents
Antimalarial drugs can be classified as follows:
(a) Tissue Schizontocidal drugs
214 Pharmaceutical Chemistry
(i) Causal drugs: Eliminate liver stage from initiating erythrocytic stage.
(ii) Hypnozoitocidal: Radical cure of exoerythrocytic hypnozoites caused by
P. ovale and P. vivax after the treatment of acute erythrocytic phase.
(b) Blood Schizontocidal drugs
(c) Clinical cure: Fast action on erythrocytic stages; example: artemisinin and quinolines
(d) Suppresive therapy: Slow suppressive action on erythrocytic stages.
(e) Gametocytocidal drugs: Destroy sexual erythrocytes and prevent transmission to
mosquitoes.
(f) Sporontocidal drugs: Oocyst and sporozoites stage.
(g) Chemoprophylaxis
(i) Causal: Eliminate liver stage from initiating erythrocytic stage.
(ii) Clinical or suppressive: Eliminate or prevent merozoites in erythrocytes.
9.3.2 Chloroquine
Chloroquine (CQ) was first known as ‘Resochin’ after the
discovery in 1934 by Hans Andersag et al., in Germany (his
native was Italy), but it was thought to be toxic to humans thus
HN
ignored or unrecognized for a decade. It was introduced first
in 1947 for its clinical uses by USA and found to have great
potency to kill malaria parasite. Later, it was found to be far
Cl
N
Chloroquine
superior to the other contemporary synthetic antimalarials.
Thus, after this discovery CQ became the choice of drug in the antimalarial chemotherapy
for almost another four decades.
After this discovery it was used globally to treat uncomplicated infections caused by P.
falciparum. In 1955, World Health Organization (WHO) launched CQ as a part of the Global
Malaria Eradication campaign. CQ has potent activity against the susceptible strains of P.
falciparum and P. vivax and also in the blood stages of P. malariae and P. ovale. Gradually,
resistance was developed to P. falciparum in most malaria-endemic countries which declined
its use, however it remains effective for the infections caused by P. ovale, P. vivax and P. malariae.
Despite extensive research during the past five decades, scientists are unable to
understand the exact mechanism how CQ kills the infected malaria parasite. It is believed
that CQ inhibits DNA and RNA biosynthesis and also induces dissimilation of ribosomal
RNA, rapid degradation of ribosomes and protein synthesis. The inhibition of DNA
replication was considered due to understanding of antimicrobial effect of CQ. It is also
reported that CQ accumulates in acidic food vacuole of parasite with very high
concentration. Once, CQ accumulates in the food vacuole, it is thought to inhibit the
detoxification of heme. CQ becomes protonated (to CQ
2+
) due to acidic nature of the
digestive vacuole which has pH 4.7 and it can’t exit from the vacuole by diffusion.
N
Antimalarial Agents 215
Hemozoin is capped with CQ and leads to the heme formation by preventing further
bio-crystallization of heme. Then, CQ binds to heme [or Fe(II)-porphyrin or FP] resulting
in the highly toxic FP-CQ complex which is responsible to disrupt membrane function.
Both these (FP and its toxic FP-CQ complex) together lead to the cell fusion and ultimately
the autodigestion of the parasite cell and forms its own metabolic products.
Thus, gradually P. falciparum developed resistance to CQ due to the excess administration
and many intrinsic entomological, parasitological, epidemiological factors which now
spread to all the endemic countries and limit its low cost effective use.
Key points:
CQ prevents polymerization of heme to heamozoin (or crystallization), leading to
death of the parasite.
Effective in the treatment of extra-intestinal amebiasis (especially amebic liver
abscess).
It has anti-inflammatory action, therefore, can be used in rheumatoid arthritis.
Used in sensitive vivax malaria only.
Resistance to it has developed (especially CQ-resistant against P. falciparum).
9.3.2.1 Mechanism of Resistance
The development of resistance to CQ is very slow and it can take almost 15-20 years to
develop through various mutations in several genes while the exact mechanism of CQ
resistance is still uncertain. Low amount of CQ is accumulated in the food vacuole from
CQ resistant parasites as compared to the sensitive parasites. Previous report indicates
that CQ resistance is generally associated with an elevated level of drug efflux. It is believed
that drug resistant parasites are responsible to release preaccumulated CQ which are 50
times faster than the CQ-sensitive parasites. The rate of drug efflux is reduced by using
verapamil to form the CQ-resistant parasites. Basically, verapamil is known to reverse the
p-glycoprotein mediated efflux of particular drugs in the multidrug resistant tumor cells.
Thus, the action of verapamil indicates CQ-resistance might be caused through efflux of
CQ by plasmodial p-glycoprotein.
In 1999, Bray et al. have suggested that the reduced affinity of CQ to heme leads to low
level of CQ uptake which causes CQ resistance. In another study, a cross-resistance
between CQ-resistant & CQ-sensitive strains of P. falciparum was analysed by Wellems et
al. (1991), and also identified a CQ-resistance which located within a 400-kb segment of
chromosome-7. It is also reported (Su et al., 1997) that putative CQ-resistance are located
at 36-kb region and also identified eight potential genes in this region. Previously it was
considered that cg2 (polymorphic protein at parasite periphery) are responsible for
CQ-resistance but now cg2 have been ruled out by another gene called Pfcrt (P. falciparum
chloroquine resistant transporter) within this region.
216 Pharmaceutical Chemistry
t
9.3.2.2 Specification
Name : 4-N-(7-chloroquinolin-4-yl)-1-N,1-N-diethylpentane-1,4-diamine
Molecular formula : C
18H26
ClN
3
Molecular weight : 319.87 g/mol
Melting point : 87–92°C
Physical state : Odourless, white or off-white crystalline powder, bitter in taste.
Solubility : Slightly water soluble, soluble in chloroform, ether and dilute acids.
9.3.2.3 Synthesis of Chloroquine
O
Cl NH
COOEt
+
2
COOEtO
AcOH
o
40
C
Cl N COOEt
COOEt
H
Cl NHCOOE
OEt
250 oC
–
-EtOH
POCl
O
Cl COOEt
3
Cl NCl
N
H
Cl
RNH
N
180 oC
KOH/EtOH
Cl COOK
2
O
N
H
Me
HN
Chloroquine
NEt
2
270 oC
–
-CO
2
O
Cl
N
H
Alternate method
Me
NEt
NH
2
+
Cl NCl
N
Me
Cl
NEt
'
2
HN
Chloroquine
9.3.2.4 Mechanism of Action
CQ is alkaline in nature and high concentration of CQ reaches into the food vacuoles of the
parasite thereby pH level goes basic. CQ acts as heme polymerase enzyme inhibitor of the
parasite which helps to converts the toxic heme into non-toxic hemozoin (Fig. 9.3) while
few suggested that formation of drug-heme complex intercalation of the drug with the
parasitic DNA etc. Some reports stated that CQ interferes with the biosynthesis of nucleic
acids.
2
Antimalarial Agents 217
9.3.2.5 Absorption, Metabolism and Excretion
Almost all the antimalarial drugs rapidly absorbed in the tissues through gastrointestinal
tract. It has a large distribution volume due to extensive sequestration in tissues of liver,
spleen, kidney, and lung, etc. Approximately 55% of the drug in the plasma is bound to
non-diffusible plasma constituents. Therapeutic blood levels persist for 6-10 days and
elimination half-life is 1-2 months. Half of the drug is excreted unchanged by the kidneys,
remaining is converted to active metabolites in the liver. The main matabolites of CQ are
desethyl chloroquine and bisdesethyl chloroquine. Desethyl chloroquine found one fourth
of the total material appearing in the urine while bisdesethyl chloroquine, a carboxylic
acid derivative, and other metabolic products found in small amounts and yet are
uncharacterized (Fig. 9.4). Slightly more than half of the urinary drug products can be
accounted for as unchanged CQ.
H
HN
NH
HN
2
N
NCl
Bisdesethyl chloroquine
Fig. 9.4: Active metabolites of chloroquine
NCl
Desethyl chloroquine
9.3.3 Quinine
Quinine is an alkaloid isolated from Cinchona bark tree mostly
found in South American continent. Quinine has an amazing
history for centuries. An Augustinian monk named Calancha
from Lima (in 1633) wrote about the drug curativeness of
Cinchona powder in “fevers and tertians”. Then around 1640,
MeO
HO
quinine found its way to Europe and it was known as ‘Jesuit’s
bark’. Later Cardinal de Lugo helped to popularise the bark in
Rome and named it Cardinal’s bark. Later Pelletier & Caventou
Quinine
isolated Quinine and Cinchonine from the tree Cinchona in 1820.
9.3.3.1 Specification
Name : (R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxy quinolin-4-yl)methanol
Molecular formula : C
20H24N2O2
Molecular weight : 324.42 g/mol
Melting point : 177°C (with some decomposition)
Physical state : Odourless, bulky white amorphous powder or crystalline alkaloid
(crystal turns brown on exposure to air), very bitter taste.
Solubility : Soluble in ether, chloroform, glycerol and acids
N
N
218 Pharmaceutical Chemistry
9.3.3.2 Synthesis of Quinine (Robert B. Woodward, 1944)
OEt
CHO
EtO
100°C, 30 min
OH
OEt
NH
EtO
2
N
OH
H2SO4, H
0°C to RT, 48 h
Pomeranz-Fritsch
2
Isoquinoline Synthesis
N
O
Piperidine, CH
OH
EtOH, H
100
°C, 6 h
O
2
O
2
Betti Reaction
N
N
OH
H2, Ni (Raney)
200 atm
EtOH,
150°C, 16 h
Ac
N
Me
NH
2
Reflux, 48 h
CO2Et
BzCl, K2CO
3
CHCl3, H2O
Reflux, 2 h
Schotten-
Baumann Reaction
NaOMe, MeOH
220
°C, 16 h
Ac
N
Me
OH
MeI, K
2CO3
EtOH
Bz
N
CO2Et
N
Me
OH
CrO3,
AcOH, H
0-50
2
°C, ON
O
2 steps
Jones oxidation
Ac
N
Me
NMe
CO2Et
MeO
NaOEt,
82°C, 14 h
Claisen
Condensation
H
3
elimination
O OEt
, PtO2,
2
4 atm
AcOH,
RT, 18 h
Ac
N
NaOH,
H
O
2
180°C,
60 min
Hofmann
N
MeO
Me
O
H
N
H
N
Me
OH
EtONO,
NaOEt
EtOH,
0°C, 18 h
CO2H
O
N
Ac
N
Ac
O, MeOH
2
40-50°C
2 steps
Ac
N
Me
NOH
CO2Et
H
HCl, EtOH
N
Reflux
Fischer
esterification
Bz
N
HCl, H2O
CO2Et
Reflux, 4h
The enantiomers were
resolved with(+)-tartaric acid
& dibenzoyl-(+)-tartaric acid
Me
OH
, PtO2,
H
2
3 atm
AcOH, RT,
40 h
CO2Et
MeO
O
N
Quinotoxin
NH
1. NaOCl
2. H
2
PO
N
O
MeO
4
NaBH
4
MeO
HO
N
Quinone
Quinine
N
N
Antimalarial Agents 219
9.3.3.3 Mechanism of Action
Quinine is weak basic in nature, acts as a blood schizonticide and gametocytocidal activity
(in case of P. vivax and P. malariae). It usually deposits in the food vacuoles of P. falciparum
and is less effective and more toxic than CQ. It acts as a heme polymerase inhibitor thus
helps in accumulation of toxic heme in food vacuole.
9.3.3.4 Absorption, Metabolism and Excretion
Quinine can be given orally or intramuscularly with good gastrointestinal absorption.
After 1-3 hours of oral dose, plasma concentrations go up and plasma half-life is about 11
hours. The volume of distribution of quinine contracts and in the result low clearance takes
place while elimination half-life increases in case of acute malaria. Therefore, after 48 hours
of administration quinine must be reduced.
Many factors (viz., age, immunity, pregnancy and disease severity) influence the
therapeutic responses and pharmacokinetic properties of quinine. Approximately 80% of
quinine is converted into stable metabolite 3-hydroxyquinine, which contributes ~15% of
antimalarial activity formed by cytochrome P450 3A4. The clearance of quinine is reported
to be significantly reduced during malaria, liver and renal diseases. Its reduction in liver
disease condition has been shown to be predominantly as a result of disease-induced
dysfunction in hepatic mixed-function oxidase activity (majorly CYP3A) that leads to
impairing the conversion of quinine to its major metabolite 3-hydroxyquinine, but the
effect on 3-hydroxyquinine disposition is still unknown.
OH
N
O
HO
MeO
3-hydroxyquinine
OH
N
N
HO
HO
N
O-desmethylquinine
Fig. 9.5: Metabolites of quinine
OH
N
MeO
HO
2-Quininone
N
MeO
N
O
H
HO
N
H
3-hydroxy-2'-quininone
Quinine is mostly metabolised in the liver whereas only about 10% is excreted unchanged
in the urine. Renal excretion of quinine and its metabolites (viz., 3-hydoxyquinine,
2-quininone, O-desmethylquinine and 3-hydroxy-2’-quininone) is in the form of
glucuronide-conjugate (Fig. 9.5).
9.3.3.5 Adverse Effects
Quinine is a more toxic drug than chloroquine. Quinine includes a typical syndrome
known as cinchonism. Headache, nausea, ears ringing and loss of vision due to neurotoxicity
(photophobia, blurred vision, diplopia and blindness, etc.) are the common side effects of
quinine. Other symptoms like rashes, vomiting, confusion, abdominal pain, sweating,
220 Pharmaceutical Chemistry
diarrhoea, angioedema, coma, respiratory arrest and hypotension may be observed.
Over-dose of quinine can cause renal failure and sometimes death. During pregnancy
it can cause massive haemolysis and haemoglobinuria, hypoprothrombinemia and
agranulocytosis. Quinine helps to stimulate insulin secretion which can cause hypoglycemia.
It has severe infection during pregnancy.
9.3.4 Artemisinin
Artemisinin or Qinghaosu (“ching-how-soo”) is phytoconstituent
Me
obtained from Chinese medicinal herb sweet wormwood (Artemisia
annua). It has been used in the treatment of fever in China for more
than 1000 years. Before 340 AD in Eastern Jin Dynasty, Ge Hong
documented the anitmalarial value of Artemisia annua in ‘Handbook of
Prescriptions for Emergency Treatments’ (Zhou Hou Bei Ji Fang).
Artemisinin was first isolated from Artemisia annua as an active
Me
O
O
O
O
Artemisinin
Me
O
antimalarial pharmacophore in 1971. The WHO has recommended
high priority to development of fast acting Artemisinin derivatives specially used for the
treatment of cerebral malaria and it also has good control of multidrug resistant P. falciparum
malaria, thus WHO has recommended this drug in high priority to the malaria eradication
programme. Artemisinin has a poor bioavailability thus limiting its effectiveness. Therefore,
some similar drugs have been developed such as artesunate is a water soluble ester and
artemether and arteether (artemotil) are two oil soluble compounds (Fig. 9.6).
Me
O
O
O
Me
OEt
Me
O
O
O
O
O
Artesunate
Me
Me
O
O
Me
OH
O
Artemether
Fig. 9.6: Pharmacophore similar to artemisinin
Me
O
O
O
OMe
Me
Me
O
Arteether
Artemisinin contains an internal peroxide bridge and an example of sesquiterpene
lactone (a compound made up of three isoprene units bound to cyclic organic esters),
which provides a specific structural prototype as compared to other classical antimalaria
drugs, viz., chloroquine, proguanil, sulfadoxine and quinine. Artemisinins are specially
used to treat complicated parasite arising due to P. falciparum. They mostly kill parasites
more rapidly than conventional antimalarial drugs. Artemisinins are also active against
both the sexual and asexual stages of the parasite cycle. Artemisinin is generally given
in combination with mefloquine, amodiaquine, sulfadoxine/pyrimethamine or
lumefantrine due to its short life and this effective combination therapy is now a widely
used drug choice for the treatment of P. falciparum parasitic infection.
Antimalarial Agents 221
9.3.4.1 Antimalarial Activity
The antimalarial activity and toxicity of the artemisinins is because of the peroxide
bridge in the core. They specifically act by inhibiting a P. falciparum encoded sarcoplasmicendoplasmic reticulum Ca-ATPase. Previously, it was believed that it inhibits toxic heme
in food vacuoles. They usually start acting within 12 hours of administration and prevent
progression of the disease by inhibiting the trophozoites stage. It is used to kill free
moving parasites in the bloodstream before they are isolated in the deep microvasculature and also effective against the CQ-resistant strains of P. falciparum which
makes it more unique and specific. Clinically, metabolic product of artemisinin is
dihydroartemisinin (elimination half-life of 45 min), that also acts as an antimalarial
agent. Artemisinin sister drugs, artesunate and artemether are also found active against
parasites more effectively than chloroquine, sulfadoxine and pyrimethamine. It has been
reported that the survival rate of artemether and artesunate is found to be similar to
quinine. Thus, it is concluded that artemisinin is a better drug to kill parasites much
faster than the quinine in patients suffering from severe malaria with less clearance of
parasites.
9.3.4.2 Gametocytocidal Action
Artemisinin drugs are also used in the reduction of gametocytogenesis which further lead
to reduction in transmission of malaria and thus these facts are significant to prevent the
parasitic infection. These drugs especially act on the ring stages and on the early stage
(stage I-III) gametocytes, thus preventing the gametocyte development. One comparative
study showed over 5000 patients in Thailand reported that artemisinin is more effective as
compared to Mefloquine.
9.3.4.3 Specification
Name : (3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-
epoxy[1,2]dioxepino[4,3-i]isochromen-10(3H)-one
Molecular formula : C
15H22O5
Molecular weight : 282.33 g/mol
Melting point : 156-157°C
Physical state : Colourless needles or white crystalline powder
Solubility : Soluble in methanol, ethanol, DMF, DMSO, acetone, chloroform,
dichloromethane, and ethyl acetate; while almost insoluble in water.
9.3.4.4 Synthesis of Artemisinin from Pulegone
Me
O
Me Me
Pulegone
Alkaline
HOOH
THF
Me
O
Me Me
Me
NaSPh
O
THF
O
SPh
MCPBA
DCM
Me
OO
Me Br
O
S
PhO
LDA