dic

inal chemi Deshpande and Kuppast, Med chem 2016, 6:1

DOI: 10.4172/2161-0444.1000315
Medicinal chemistry
st
Me

ry
ISSN: 2161-0444

Review Article Open Access

4-aminoquinolines: An Overview of Antimalarial Chemotherapy

Shreekant Deshpande1 and Bhimanna Kuppast2*
1
Analytical Chemistry Division, Eutech Scientific Services Inc., Highland Park, NJ 08904, USA
2
Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL-60151, USA

Abstract
Malaria is a major health problem and Plasmodium falciparum strain resistance to existing antimalarials drugs
made the current approach inadequate for treatment of malaria. Drug development directed against malaria is generally
targeting blood schizonts. However, to prevent relapse, tissue schizontocides are recommended to clean residual
infection in the tissues. In spite of the available drugs, malarial chemotherapy is still insufficient and therefore new
strategies are being explored to fill the gaps. The new approaches are being used to generate new compounds as well
as combinations of drugs for development of effective and safe antimalarial therapy. This review discusses the recent
developments in 4-aminoquinoline derived new analogs and insight into design and development of new antimalarials.
Linker: alkyl, aryl,
ferrocenyl
For Lipophilicity
Reduction from
R 4-C atoms to 2-C or 3- C atoms
increases
N activity versus CQR strains
Heme binding template HN
n

Cl N

7Cl: Essential for high affinity

binding to hematin. 0
Terminal 3 Amino Group - Important for
Accumulation

Keywords: Antimalarial; 4-aminoquinoline; Quinine; Chloroquine; showing resistance. Alternative strategies to control malaria infection
Drug resistance include vector control and development of vaccines, remain inadequate
[8]. Therefore, to meet the new challenges development of novel
Introduction molecules with better therapeutic potential and safety is a very high
priority task. So far, malaria control has relied largely on a small number
Malaria remains as one of the most devastating diseases of the
of chemically related drugs, belonging to three classes of compounds:
developing world concentrated mainly in tropical regions. Despite
Quinoline and its related analogs (quinine, CQ, amodiaquine,
the huge advances in our understanding of the disease, it continues to
primaquine mefloquine, and halofantrine), the artemisinin and
be one of the greatest causes of serious illness and death in the world.
its derivatives (artemisinin, artesunate, artemether, arteether,
Approximately 156 species of plasmodium infect various vertebrates,
dihydroartemisinin), the antifolate compounds (pyrimethamine,
but only four; P. falciparum, P. malariae, P. vivax and P. ovale are known
proguanil, chlorcycloguanil, dapsone, and sulfadoxine), and most
to infect humans. Among these, P. falciparum is the cause of most severe
recently, the hydroxynapthoquinone atovaquone (Figure 1) [9,10].
and life threatening malaria in human beings. Endemic maps indicate
that P. falciparum and P. vivax account for 95% of malarial infections Challenges in Drug Development
[1-4]. P. falciparum is found throughout tropical Africa, Asia and
Latin America while P. vivax is found worldwide in tropical and some The success of malaria chemotherapy depends on thorough
temperate zones [5,6]. P. falciparum is remarkable for its high case of fatality understanding of the interaction among the three major components,
rate causing 2-3 million deaths worldwide, particularly children, and a namely human host, antimalarial drugs and malaria parasite (Figure 2).
further 300-500 million cases occur each year [7]. Malaria is transmitted by The challenge in antimalarial drug development arises in consideration
the bite of an infected anopheles mosquito and is characterized by periodic of malaria life cycle. This contains two hosts (Human host and
chills, high fever, nausea, and vomiting. The role played by the host immune Mosquitoes) and five main stages in life cycle. Once the human host is
system in resistance and healing of the disease is well established, however
the strategies involving the development of vaccine against malaria is
inadequate [8]. Currently chemotherapy of malaria depends on several
*Corresponding author: Bhimanna Kuppast, Department of Pharmaceutical
drugs, yet proper treatment is not in sight. Even though the available drugs Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove,
have the ability to cure malaria infection and control the spread. There are IL-60151, USA, Tel: +1(630)515-6968; Fax: +16305156958; E-mail: bkuppa@
several limitations which includes left over infection leading to relapse, midwestern.edu
toxicity to the host and development of resistance. Received December 15, 2015; Accepted January 11, 2016; Published January
14, 2016
Resistance of plasmodia to antimalarial drugs is now recognized as one
of the major problems in the treatment of malaria. This rapidly increasing Citation: Shreekant D, Bhimanna K (2016) 4-aminoquinolines: An Overview
of Antimalarial Chemotherapy. Med chem 6: 001-011. doi:10.4172/2161-
resistance of P. falciparum malaria parasites to most commonly used drugs 0444.1000315
such as quinine, chloroquine (CQ), proguanil and pyrimethamine has
Copyright: © 2016 Deshpande S, et al. This is an open-access article distributed
made the chemotherapy ineffective. Moreover, new and more expensive under the terms of the Creative Commons Attribution License, which permits
chemotherapeutic agents, such as mefloquine and halofantrine are also unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.

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Citation: Shreekant D, Bhimanna K (2016) 4-aminoquinolines: An Overview of Antimalarial Chemotherapy. Med chem 6: 001-011. doi:10.4172/2161-
0444.1000315

Quinoline and its related antimalarials

OH
N
OH HN HN
H3CO N N

N Cl N Cl N
Qunine Chloroquine Amodiaquine

F3C
HO H3CO
N C4H9
H 3N
C4H9 N NH2
HN
N CF3
Cl Cl
CF3

Mefloquine Halofantrine Primaquine

Artemisinin antimalarials Other antimalarials

Cl
H
Cl O
O NH2
O
O
N
H
O
H2N N OH
OR O
Pyrimethamine Atovaquone
R= H Dihydroartemisinin
R=Me Artemether NH2
R=Et Arteether NH N
R=CO(CH2)CO2H Artesunate Cl NH NH H3CO N
NH
HN H3CO HN SO2

Proguanil Sulphadoxine

Figure 1: Chemical structures of important antimalarial drugs in clinical use.

Figure 2: Interactions among the three components of malaria chemotherapy

(human host, malaria parasite, antimalarial drug).

infected, malaria parasite induces ‘pathological condition’. It is a disease

caused by multiplication of parasites in repeated cycles of growth of the Figure 3: Life cycle of malaria parasite Plasmodium falciparum.
parasite Plasmodium in the erythrocyte. Immune response induces the
protective mechanism in the host is in response to parasitic invasion.
new antimalarials requires prior knowledge of life cycle of the parasite
Malaria symptoms can develop as soon as 6–8 days after being bitten
and drug action of existing chemotherapy.
by an infected Anopheles mosquito, or as late as several months
after departure from a malaria endemic area. The effectiveness of an Malaria Life Cycle
antimalarial drug depends, principally on the interactions between
antimalarial drug and malaria parasite, i.e., ‘selective toxicity’ and ‘drug The life cycle of plasmodia has five stages that include both sexual
resistance’, and between antimalarial drug and host, the compatibility and asexual mode of reproduction in two hosts, namely a mosquito
i.e., ‘pharmacokinetics’ and ‘pharmacodynamics’. The ideal and a human (Figure 3). During a blood meal, a malaria-infected
antimalarials are drugs which are selective and show curative activity female Anopheles mosquito injects sporozoites into the human host.
without or minimal toxicity to the host [11,12]. The development of These sporozoites then migrate to the liver where they transform,

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Citation: Shreekant D, Bhimanna K (2016) 4-aminoquinolines: An Overview of Antimalarial Chemotherapy. Med chem 6: 001-011. doi:10.4172/2161-
0444.1000315

multiply, and mature into tissue schizonts, which eventually rupture, antimalarial therapy offers two important potential advantages. First,
releasing merozoites into the blood stream. To avoid the host’s immune the combination improves the antimalarial efficacy with additive
system, they invade erythrocytes. After the initial replication in the or, preferably, synergistic effect. In the case of both the artemisinin
liver, the parasites undergo asexual multiplication in the erythrocytes derivatives and atovaquone, the new agents have had unacceptable
(erythrocytic stage). In every cycle, schizonts get ruptured with failure rates when used as single agents to treat falciparum malaria but
erythrocytes and releases new merozoites into the blood stream, which they have been highly effective in combination with other established
in turn again invade the new erythrocytes. Before this stage the infected antimalarials. Second, and probably most important in the use of
individual may not have any symptoms, once RBCs get ruptured, the combination therapy is slow down the progression of parasite resistance
host immune system get exposed to parasite factors in turn stimulates to the new agents. This latter factor is a key consideration as we attempt
to release cytokines and results in the symptoms like fever and chills. to develop new therapies that will retain activity for a long period.
Ideally, a combination regimen that prevents resistance development
In case of P. vivax and P. ovale, a dormant, hypnozoite stage remains
should include at least two agents against which parasite resistance has
in the liver and causes relapses by invading the bloodstream, weeks
not yet developed and which have similar pharmacokinetics, so that low
to years later. After a number of asexual life cycles, Some merozoites
blood levels of a single agent will not be present. No such ideal regimen
develop into sexual erythrocytic forms (gametocytes). When an
is currently available, although chlorproguanil/dapsone/artesunate
Anopheles mosquito ingests male and female gametocytes during a
may prove to fit this description. Alternatively, the combination of a
blood meal from an infected host, fertilization takes place in the gut
short-acting, highly potent compound and a longer-acting agent may
of the mosquito forming zygotes. The zygotes become elongated and
prove effective, if the initial decrease in parasite burden is so great as to
invade the gut wall of the mosquito developing into oocysts. These
limit subsequent resistance development to the long-acting agent (e.g.,
oocysts grow, rupture, and release sporozoites. These invade the
artesunate/mefloquine) [19].
mosquito's salivary gland, and the mosquito is then ready to transmit
the disease during the next blood meal [13-15]. New analogs of existing drugs
Antimalarial agents are classified by the stages of the malaria life Improving upon the antimalarial chemotherapy profile of existing
cycle that are targeted by the drug. Blood schizonticides acting on the compounds by chemical modifications has been a rewarding approach.
asexual intraerythrocytic stages of the parasites. Tissue schizonticides This approach does not require development of knowledge of the
kill hepatic schizonts, and thus prevent the invasion of erythrocytes, mechanism of action or the therapeutic target of the agents that used
acting in a causally prophylactic manner. Hypnozoiticides kill persistent for combination therapy. Indeed, this approach was responsible for
intrahepatic stages of P. vivax and P. ovale, thus preventing relapses optimizing the activity and selectivity of existing antimalarials even
from these dormant stages. Gametocytocides destroy intraerythrocytic against resistant strains. For example, CQ, primaquine and mefloquine
sexual forms of the parasites and prevent transmission from human to were discovered through chemical strategies to improve upon quinine
mosquito. As there are no dormant liver stages in P. falciparum malaria [20]. More recently, 4-aminoquinoline derivatives that are closely
(malaria tropica), blood schizonticidal drugs are sufficient to cure the related to CQ appear to offer the great potency even against CQ-
infection. In cases of P. vivax and P. ovale, a combination of blood resistant strains of parasites [21,22]. A related compound, pyronaridine
schizonticides and tissue schizonticides is required [5,6]. (Figure 4), was developed in China and is now undergoing extensive
clinical trials in other areas [23]. An 8-aminoquinoline derivative,
Chemotherapeutic Approaches tafenoquine (Figure 4), offers improved activity against hepatic-stage
Drug development directed against malaria is generally targeting parasites over that of the parent compound, primaquine [24], and is
blood schizonts. However, to prevent relapse tissue schizontocides are effective for antimalarial chemoprophylaxis [25]. Since halofantrine
recommended to clean residual infection in the tissues. In spite of the use is limited by toxicity, the analog lumefantrine was developed and is
available drugs, malarial chemotherapy is still inadequate and therefore now a component of the new combination co-artemether (artemether/
new strategies are being explored to fill the gaps. The new approaches lumefantrine) [26]. New folate antagonists [27] and new endoperoxides
are being used to generate new compounds as well as combinations of related to artemisinin [28,29] are also under study.
drugs for development of effective and safe antimalarial therapy. This
review discusses the recent developments in new analogs of existing Development of Aminoquinolines Derived
drugs, especially 4-aminoquinoline derived antimalarials. Antimalarials
Combination therapy 4-Aminoquinolines derivatives were the first class of compounds
used for the successful treatment of malaria and drugs of choice for
Owing to rapid spreading of disease as well as emergence of resistance the present time also. In the 18th century, the first attempt of successful
new strategies are being explored. Among various such approaches treatment of malaria was made with use of the bark of cinchona trees
combination therapy offers several advantages. The combination therapy [30]. Gomes et al. in 1810 extracted the cinchona bark but after a decade,
has also been recommended by World Health Organization (WHO) for active ingredient of quinine (Figure 5) was isolated and made Malaria
the effective treatment of malaria. As information on pharmacokinetics as first disease for which a pure compound was used for the treatment
of antimalarials have become increasingly available, it is appropriate [31]. The structure elucidation and different synthetic routes have come
to reexamine current recommendations for effective treatment and up in near 19th century. In 1856, chemist William Henry Perkins set out
prophylaxis. In addition, antimalarial formulations and dosage forms to synthesize quinine. His efforts resulted not in quinine (the first total
can be improved [16]. This approach is to optimize therapy with existing synthesis was accomplished later in 1944), but rather in the first synthetic
agents. New dosing regimens or formulations may optimize activity. textile dye called “mauve”. Paul Ehrlich noticed that methylene blue (1)
Combination therapies, including newer agents (e.g., artemisinin was particularly effective in staining malaria parasites (Figure 5). He
derivatives, atovaquone) and new combinations of older agents (e.g., rationalized that this dye might also be selectively toxic to the parasite
amodiaquine/sulfadoxine/pyrimethamine, chlorproguanil/dapsone), [30]. In 1891, Ehrlich and Guttmann cured two malaria patients with
are under study as first-line therapies for Africa and other tropical methylene blue (1), which became the first synthetic drug ever used in
areas with widespread drug resistance [17,18]. The use of combination therapy. Although it was not used further at that time, methylene blue

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Citation: Shreekant D, Bhimanna K (2016) 4-aminoquinolines: An Overview of Antimalarial Chemotherapy. Med chem 6: 001-011. doi:10.4172/2161-
0444.1000315

evaluated in 1943 and was found safe for human subjects. After the
CF3
World War II, CQ became the foundation of malaria therapy for at least
four decades [30-33] and most successful drug in clinical use till date
N
[34-36].
OH O

N
O Mode of action of 4-aminoquinoline derivatives
HN
N OCH3 N O Mode of action of 4-aminoquinoline classes of compounds is still a
HN matter of debate despite the overwhelming importance. Various theories
NH2
Cl N
have been proposed and reviewed [1,37-39]. The consensus points out
Pyronaridine Tafenoquine that CQ interacts with the parasite’s ability to digest haemoglobin.
Figure 4: New antimalarial drugs. During its erythrocytic stages, the parasite consumes large quantities
of haemoglobin from its host cell, either for the purpose of amino acid
supply, or simply to create space inside the erythrocyte. Haemoglobin
is shuttled by vesicles to a specialized organelle called digestive vacuole
Cl (DV). A number of facts relating to the drugs action are now widely
N S N
accepted. Based on these facts several hypotheses have been raised.
N
1 Methylene blue Early biochemical studies demonstrated that CQ was able to inhibit
DNA and RNA synthesis [40-42]. However, interaction of CQ with
Cl DNA does not explain the antimalarial activity and the selective toxicity
N S N
N of this compound. Some other mechanisms have been proposed, but
N
2
they would call for higher drug concentrations than what can be
achievable in vivo and not generally regarded as convincing options
[1]. These include inhibition of protein synthesis; inhibition of digestive
HN
N
HN
N
HN
N vacuole (DV) lipase, and aspartic protease [1,37-39].
N O
A clue to the mechanism of action of CQ came from the observation
O Cl N
3, Pamaquine
Cl N
6 ,Chloroquine (resochin)
that it is active only against the erythrocytic stages of malaria parasites.
5, Mepacrine
The next phase of research concentrated on the feeding process of the
parasites, where CQ could able to inhibit the haemoglobin degradation.
NH2 N Uptake of haemoglobin and its metabolism by a series of proteases
HN
N
HN
in food vacuole of the parasite strengthen the hypothesis [43-45].
Thus, the 4-aminoquinoline derived drugs have been proposed that
Cl N
O selectively target the haemoglobin degradation which is a specific to
4, Primaquine 7, Sontoquine
parasites [46]. The free heme, which is toxic to parasite, released from
the haemoglobin degradation and a series of proteases involved were
Figure 5: The dye methylene blue (1) is the predecessor of potent synthetic drawn more attention of the researchers (Figure 6) [47-49].
antimalarial drugs
The plasmodial enzymes involved in digestion of haemoglobin
have attracted much attention as possible targets for antimalarial drug
constituted the basis for the development of synthetic antimalarials. In design. When hemereleased from haemoglobin get converted into
the 1920s, chemists at Bayer in Germany started to modify the structure ferric form, which is highly toxic to vacuolar proteases and damaging to
of methylene blue (1). A key modification was the replacement of one parasite membranes. Interestingly, parasite has a unique non-enzymatic
methyl by a dialkylaminoalkyl side chain to give compound 2. heme detoxification mechanism, in which heme released from parasite
Subsequently, this side chain was connected with different digestion is converted to an insoluble polymer, called hemozoin. It is
heterocyclic systems such as the quinoline system, yielding the first microscopically visible in the DV as malaria pigments [50].
synthetic antimalarial drug, plasmochin (3, also known as plasmoquine
or pamaquine) in the year 1925. However, under clinical evaluation, this
drug displayed multiple side effects, and was therefore not widely used. O

The congeneric primaquine (4), introduced in 1952, was better tolerated, N X N N OH N

O
O
O
making it the main representative of the class of 8-aminoquinoline Fe (II)
N Y N
Fe (III) N N
(III)
Fe N
N
(III)
N N
derived anti-malarials. Connection of the diethylaminoisopentylamino N N
O
N
Fe
N
O
side chain with an acridine heterocycle yielded mepacrine (5, also O
O
O O O
known as quinacrine), which was introduced in 1932 for prophylaxis OH HO O O O O

and treatment of malaria [30-33]. Heme Hematin haem-μ-oxo-dimer

A major success with the drug-design strategy was achieved in

1934 with the introduction of a diethylaminoisopentylamino side chain
into position 4 of a 7- chloroquinoline, yielding a compound named
resochin by the German inventors (later known as chloroquine (6).
However, after initial trials, resochin was regarded as too toxic for use
in humans and ignored for a decade. In 1936, the structurally closely Hemozoin
related sontoquin (7, later known as nivaquine) was prepared in the Figure 6: Chemical structure of haem, hematin, μ-oxo-dimer and hemozoin.
Bayer laboratories and tested in Germany. Resochin (CQ) was re-

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0444.1000315

4-Aminoquinoline derived drugs are known to inhibit the hematin

formation by complexing with ferriprotoporphorin IX (FPIX) thereby
prevents its polymerization into hemozoin, which results into parasite
death. Crystallographic information of the structure of the CQ–FP
complex is not available. Most NMR and molecular modeling studies
[36,51] show a face-to- face π staggering of the porphyrin and quinoline
systems, although a structure showing an edge-to-face complex with the
ring nitrogen atom sitting above the ring iron center has also been reported
[52]. Very recently, structure determination by NMR spectroscopy
showed CQ sitting in a central position over the outermost porphyrin
rings of a FPIX–CQ 4:2 complex [53]. Most researchers assume that the
buildup of noncrystalline FPIX, either in its free form or as a FPIX–CQ
complex, finally kills the parasite. The precise mechanism by which this Figure 7: Representation of PfCRT gene mutation a) The positively charged
toxic effect is exerted remains to be elucidated [35,54]. According to side chain of K76 of the wild-type PfCRT repels the chloroquine dication. b)
a recent theory, the FPIX–CQ complex acts on a yet to be undefined The K76T mutation removes a positively charged side chain from the CQ
resistance transporter. c) CQ resistance.
membrane target, thereby either impairing the membrane function
directly, or triggering the release of Ca2+ ions, resulting in the premature
fusion of the transport vesicles shuttling haemoglobin to the DV. In these In CQ-resistant strains, the drug is apparently removed from
prematurely fused vesicles, haemoglobin is no longer properly degraded its putative locus of action, the digestive food vacuole (Figure 7).
[55]. This hypothesis is supported by an independently conducted study The main cause of CQ resistance is a matter of intense research and
that demonstrated the inhibition of macromolecule endocytosis by more debate. Mutation in the transporter gene ‘pfcrt’ is the main culprit in
than 40% and the accumulation of transport vesicles in the parasite which codes for a protein called the chloroquine resistance transporter
cytosol upon the addition of CQ to late ring-stage parasites. (PfCRT). Because there is not much else of significance inside the DV
Since FPIX is a potential target for 4-aminoquinolines and related worthy transport, it has been proposed that the physiological role of
antimalarials, a number of studies have investigated the nature of FP this protein is the transport of amino acids or small peptides resulting
binding to 4-aminoquinolines. Structure of heme, hemozoin and their from the degradation of haemoglobin into the cytoplasm [63]. All CQ-
structural similarity with synthetic FPIX have been well documented resistant strains have a threonine residue in place of lysine at position
(Figure 6). An important difference between monomeric heme 76 of the protein. In wild-type CRT, this positively charged side chain is
(including heme aggregates) and hemozoin is their differential solubility thought to prevent access of the dicationic form of CQ to the substrate
in organic and aprotic solvents and in sodium dodecoyl sulphate (SDS) binding area of the transporter. The K76T mutation replaces the
and mildly alkaline bicarbonate solutions. This property may be useful positively charged side chain by a neutral moiety, and thereby allows
in specific estimation of hemozoin and β-hematin formation inhibition access of the CQ di-cation to the transporter, which then decreases the
assay [47-49]. concentration of CQ in the DV considerably (Figure 7).

Considerable evidence has accumulated in recent years that The K76T mutation is accompanied by up to 14 more amino acid
antimalarial drugs such as CQ act by forming complexes with FP, replacements, which are thought to restore the physiological function
the hydroxo or aqua complex of Ferriprotoporphyrin IX (Fe(III) FP), of the transporter, as, an engineered strain carrying only the K76T
derived from parasite proteolysis of host haemoglobin. Studies by mutation is not viable [64-66]. Interestingly, a CQ-resistant strain kept
Dorn et al. confirmed that CQ forms a complex with the μ-oxo dimeric under continuous drug pressure with halofantrine (Figure 1) shows
form of FP with a stoichometry of 1 CQ : 2 μ-oxo dimmers. They a S163R mutation that renders this strain halofantrine resistant but
have supported the enzymatic mechanism of hemepolymerization in restores susceptibility to CQ, most probably through re-emergence of
vivo [56-60]. Considerable data supports the hypothesis that hematin the cation-repelling positive charge in the substrate binding area of the
is the target of 4-aminoquinoline class of compounds [61]. 4-AQ are transporter [64,67]. This is in agreement with the fact that CQ resistance
weak bases and are expected to accumulate in an acidic food vacuole can be reversed in vitro by several compounds of which verapamil (8)
to many folds. Recently Egan et al. have shown that CQ, amodiaquine is the prototype (Figure 8). The common molecular feature of these
and quinine can inhibit synthetic β-hematin formation by direct so-called CQ resistance reversers are two lipophilic aromatic residues
interaction [62]. As discussed earlier, UV, NMR, mass, crystallography and a basic aminoalkyl side chain. It is believed that the aryl residues
and molecular modeling studies also support the complex formation interact with a lipophilic pocket in the substrate binding site of the
[36,51]. The isothermal titration calorimeter (ITC) is also used to CRT, while the protonated amino group restores the positive charge
explain the mechanism. that repels the CQ di-cation. The underlying molecular scaffold for CQ
resistance reversers, resembles a variety of molecules including certain
Mechanisms of resistance H1-antihistaminic agents (chlorpheniramine 9) and neuroleptics [68-
The indiscriminate use of CQ has led to the development of 71]. Recent results suggest that this mutation plays a compensateory
resistant malaria strains. They are almost spread over the entire role in CQ-resistant isolates under CQ pressure and may also have some
malaria-endangered area. Today, more than 80% of wild isolates are fine tuning effects on the degree of CQ resistance. Efforts to design
resistant to CQ [55]. The need to understand the mechanisms of action new reversers of CQ resistance are underway [61]. Thus, although CQ
of the 4-AQ antimalarials is urgent as levels of resistance to these drugs appears to already have failed as a first-line antimalarial in most of the
is on increase. This information is also highly useful for the design and world, this inexpensive, rapid acting, well-tolerated antimalarial may be
development of drugs against CQ-resistant strain of malaria. Resistance resurrected by combination with effective resistance reversers.
to CQ is more likely to involve more than one gene and altered drug An explanation of CQ resistance, focuses on the enzyme
transport rather than changes at site of drug action. glutathione reductase (GR), which might be another target of the CQ–
FPIX complex [35]. Considerably elevated glutathione levels are found

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0444.1000315

Cl
OMe O
CN
MeO OMe N O O

MeO N
N HN N
N H

verapamil (8) chlorpheniramine (9) (10)

Cl N

Figure 8: Structures of CQ resistant reversers.

in CQ- resistant strains, leading to the theory that a combination of Figure 9: Structural requirements of 4-AQs for antimalarial activity.
CQ with a glutathione reductase inhibitor might overcome resistance.
A dual drug consisting of a quinoline derivative [62] and a GR inhibitor
(10) showed activity against various CQ-resistant strains that was HN N HN N
R1
HN N
superior to the parent quinoline, but failed to produce a radical cure R2 H

in P. berghei-infected mice [72]. The presumed role of glutathione in Cl N Cl N F3C N

CQ resistance could also be the rationale behind the recently renewed 11 AQ13 IC50=59 nm 12 13 IC50=9.8 nm
O
H
N
interest in methylene blue (1), which is known to inhibit GR [73]. HN N
N
HN N N R HN N

However, very recent results showed that methylene blue and CQ O

N
Cl N Cl N N
are antagonistic in vitro [74]. In light of these results; it is not surprising
Cl
14 IC50=31.2 nm 15-17 18 IC50=0.073-1.56 um
16
that a clinical trial showed no advantage in using a combination of X X= CH2
15, R = NH-SO2R R = N

methylene blue and CQ over CQ monotherapy in an area with a high 17 X=CO

probability of CQ resistance. N O
N R
HN N X
Modifications of 4-aminoquinoline derived scaffold
HN HN H
N

Cl N Cl N
4-aminoquinoline derived antimalarial constitute in major class Cl N
19 IC50=23 nm 20 21 X = O, NH, NMe

of available antimalarial drugs broadly in clinical use. Much work has

Figure 10: AQ13 (11) and some of recently developed 4- aminoquinoline
been invested in the structural modification on the 4-aminoquinoline antimalarials (12-21).
scaffold, resulting in a large number of derivatives. Excellent reviews
have described these efforts in depth. Three different structural
modifications are able to overcome CQ resistance (Figure 9): 1) The H
H
N
HN
elongation, or more important, the shortening of the diaminoalkyl side HN n
N n
N N
chain; 2) The introduction of lipophilic aromatic moieties into the side N N
R
chain; and 3) The dimerization of two 4-aminoquinolines by a linker of Cl N
Cl Cl N

variable nature and length. Figure 9 depicts the side chain modification 22-25
26-39
26, n=1, R=piperidine, IC50= ND
on the 4-AQ and relative structure activity relationship. 22, n=1, IC50=0.16 & 0.5 µM 27, n=2, R=piperidine, IC50=0.02 & 0.21 µM
23, n=2, IC50=0.33 & 0.7 µM 28, n=3, R=piperidine, IC50=0.02 & 0.09 µM
For the sake of clarity, the discussion is organized as following 24, n=3, IC50=0.12 & 0.68 µM 29, n=5, R=piperidine, IC50=0.06 & 0.1 µM
sub headings (a) modification on 4-aminoquinoline-nucleus (b) 25, n=5, IC50=0.44 & 0.54 µM 30, n=1, R=morpholine, IC50=0.02 & 0.14 µM
31, n=2, R=morpholine, IC50=0.02 & 0.05 µM
modification on side chain analogs (c) modification on side chain 32, n=3, R=morpholine, IC50= ND
dialkylaminomethyl-phenol and d) Bisquinoline analogs. 33, n=5, R=morpholine, IC50=0.03 & 0.14 µM
34, n=1, R=n-methyl piperazine, IC50=0.005 & 0.03 µM
35, n=2, R=n-methyl piperazine, IC50=0.007 & 0.006 µM
Modifications on 4-aminoquinoline nucleus 36, n=3, R=n-methyl piperazine, IC50=0.02 & 0.02 µM
37, n=5, R=n-methyl piperazine, IC50=0.007 & 0.016 µM
The core nucleus, 4-aminoquinoline is an essential for antimalarial 38, n=3, R=n-ethyl piperazine, IC50=0.006 & 0.06 µM
39, n=5, R=n-ethyl piperazine, IC50=0.02 & 0.02 µM
activity and several attempts have been made on modifying the side
chain on the quinoline ring. The reason being that intact 4-AQ is Figure 11: Hybrid 4- aminoquinoline antimalarials (22-39).
required in hematin binding and for antimalarial activity [75]. Several
studies report, the modification on the 4-AQ nucleus leads to loss of Side chain modifications
activity with the exceptions of chloroquine-N-oxide [76]. In literature it
is evident that 7-halo substituted 4-aminoquinoline derivatives are more The diaminoalkyl side chain of 4-AQ derived antimalarials plays
active than unsubstituted analogs [77]. Further Vippagunta et al. and significant role in modulation of the activity. It is considered that, side
other groups suggested that 7-chloro-4-aminoquinoline is essential for chain would provide and modulate the required pharmacokinetic
inhibition of β-hematin formation and optimal for antimalarial activity properties for drug transport as well as basicity for accumulation in the
[75]. This evidence is further supported by Egan et al. for obligatory DV. Thus several reports depict the alteration, or more importantly the
nucleus in the inhibition of β- hematin formation. Other electron shortening, of the dialkyl side chain for the activity against CQ resistant
donor groups like NH2 or OCH3 in the place of 7-chloro group reduces strains [77,78]. A CQ derivative with a shortened side chain is AQ13
the hematin association constant and weakens inhibition of β- hematin (Figures 10 and 11). It retains activity against CQ-resistant parasites
formation, thus finally reduces the antimalarial activity. Whereas (IC50=59 nm versus 315 nm for CQ), but there is a clear correlation
electron withdrawing group like NO2 reduces the accumulation in between the susceptibility of different isolates toward AQ13 (11) and
the DV and show weaker inhibition of β- hematin formation and CQ, pointing to some degree of cross-resistance. A recently completed
antimalarial activity. dose-dependent trial in healthy volunteers suggests that the adverse
effects of AQ13 may not be different from those of CQ and that higher

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Citation: Shreekant D, Bhimanna K (2016) 4-aminoquinolines: An Overview of Antimalarial Chemotherapy. Med chem 6: 001-011. doi:10.4172/2161-
0444.1000315

These hits need to pass through pharmacology and toxicology filters to

HN NH find the most promising candidates. In the same line various analogs
(12) of AQ13 with potent antimalarial activities have been developed.
N N
Extensive investigations were done by several research groups on the
Cl N R N R modification of side chain to determine the appropriate length and size.
Stock et al. showed that the replacement of the diethylamino function
40-46
with a metabolically stable tBu group (F2bu; 13) led to a 20-fold increase
in the potency against the CQR strain [80]. Iwaniuk et al. introduced a
40, R= HN H linear dibasic side chain (14) with good improvement in the activity
44, R= N N O [81].
41, R= N O Cl Sergherart et al. have synthesized a series of 4-aminoquinoline
H
based sulfonamide library bearing a common piperazine linker. The
H 45, R= N F most effective analog (Figures 10 and 15) shows that 100 fold better
42, R= N NO2
activity than CQ [82]. Further, in one more study, they have synthesized
N1(7-chloro-4-quinyl)-1,4-bis(3-aminopropyl) piperazine derivatives
H H and screened them against CQ resistant strain of P. falciparum. All
43, R= N 46, R= N F
these compounds showed higher selectivity index than CQ and one
of the compounds (X=CO) (16) showed 5-fold higher selectivity
Figure 12: 4-aminoquinolines-1,3,5-triazine antimalarials (40-46).
index and was 5 fold more active than CQ [83]. In another series,
eleven compounds displayed higher selectivity index than CQ, among
R1 CN these one of the compounds (17) cured mice infected by P. berghei
N X R2 N
[84]. Musonda et al. have reported a new series of 4-aminoquinoline
N
HN
N
n
n n derivatives from Ugi reaction and found these analogs were active
HN
HN
against both CQ resistant and sensitive strains of P. falciparum, with the
Cl N
Cl N
best compound (18) showing an IC50 value of 73 nM against a resistant
Cl N
strain [85]. Pyrrolizidinyl moiety at the pendent nitrogen (19) was
47, n = 1; X = CH; R1 = NO2; R2 = H 55, n = 1
48, n = 2; X = CH; R1 = NO2; R2 = H 56, n = 2
57, n = 1
58, n = 2
recently reported by Sparatore et al. has showed a promising antimalarial
49, n = 1; X = CH; R1 = NO2; R2 = CH3
50, n = 2; X = CH; R1 = NO2; R2 = CH3 activity for further development. There are different research groups
51, n = 1; X = N; R1 = H, R2 = H
52, n = 2; X = N; R1 = H, R2 = H have reported potent antimalarial activity by introducing a aromatic
53, n = 1; X = N; R1 = NO2, R2 = H
54, n = 2; X = N; R1 = NO2, R2 = H group (20) in the side chain as well as lengthening the diaminoalkyl
MeO
side chain of 4-aminoquinoliners (21).
N MeO

N
Manohar et al. reported class of hydrib molecules of
H
N
n Cl
N N
HN N N
4-aminoquinolines and pyrimidine (Figure 11); 22-39) as antimalarials.
HN HN
H
All compounds were screened for in vitro antimalarial activity against
Cl
Cl N
chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2)
Cl
Cl N Cl N strains of Plasmodium falciparum [86].
59, n = 1 61, n = 1 63, n = 1
60, n = 2 62, n = 2 64, n = 2 Out of the derivatives synthesized, 11 compounds (26, 27, 30, 31,
Figure 13: 4-aminoquinolines-acridine antimalarials (47-64). and 33-39) have showed better antimalarial activity (IC50=0.005−0.03
μM) against the CQ sensitive strain. 12 compounds (27-31, and
33-39) displayed better antimalarial activity (IC50=0.01−0.21 μM)
S
Protien
against the CQ-resistant strains of P. falciparum. Generally hydrib
OH O OH
derivatives showed roughly 1.6-2.0 fold increase in activity compared to
HN [O] N Protien-SH HN pyrimethamine in case of drug resistant strains. Most active compounds
N N N
found to be 34 and 38.
Cl N Cl N Cl N
65
66 67 Bhat et al. reported series of hybrid 4-aminoquinolines-1,3,5-
Amodiaquine
triazines (Figure 12); 40-46) and screened against chloroquine
Cl sensitive RKL2 strain of Plasmodium falciparum in 96 well-microtitre
plates. However, synthesized derivatives exhibited mild to moderate
N HN antimalarial activity with no toxicity signs [87].
OH
H
HN
N
HN OH HN OH
Kumar et al. reported the modified 4-aminoquinoline derivatives–
acridine hybrids (Figure 13); 47-64) as potential compounds to
Cl N Cl N Cl N overcome the resistance of Plasmodium falciparum to aminoquinoline
68 69
Isoquine
70
and related antimalarial drugs. All the synthesized derivatives were
Tebuquine tert-butylIsoquine
evaluated for antimalarial activity against NF 54 strain of P. falciparum
Figure 14: Amodiaquine (65) and its congeners (66-70).
[88]. Compounds 47 and 48 with ethyl and propyl chain exhibited MIC
value of 10 lg/mL. Further, methyl group on phenyl derivatives lead
doses of AQ13 over CQ may be necessary to produce similar blood levels to corresponding compounds 49 and 50 with no antimalarial activity.
and AUC values [79]. Several options have come up with AQ13 success Derivative 51 with ethyl linker attached to the 1-pyridin-2-yl piperazine
and variation have been made on the lateral amino group of the AQ13. had MIC of 10 lg/mL, however 52 propyl linker resulted in remarkable
improvement in antimalarial potency with MIC value of 0.125 lg/mL.

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Citation: Shreekant D, Bhimanna K (2016) 4-aminoquinolines: An Overview of Antimalarial Chemotherapy. Med chem 6: 001-011. doi:10.4172/2161-
0444.1000315

Compound 55 with ethyl linker attached to the tetrahydroisoquinoline

exhibited MIC value of 2 lg/mL and replacement with propyl linker (56) O R
OH O X N
led the excellent antimalarial potency with MIC value of 0.031 lg/mL. R1

Compound 57 with ethyl linker attached to the 4-phenyl-piperidine- O R O O

N N N
HN N R1 HN N HN N
4-carbonitrile showed MIC value of 10 lg/mL, while addition of one H n H H

methylene unit resulted in compound 58 with excellent activity. Data Cl N Cl N Cl N

analysis revealed that propyl linker was favorable for the antimalarial 71 72 73

activity. All other derivatives were showed moderate antimalarial Figure 15: Congeners of amodiaquine (71-73).
activity.
Modifications on AQ side chain of dialkylaminomethyl-
phenol N N
N N
Enhancement of lipophilicity of the side chain by the incorporation
of an aromatic structure resulted in amodiaquine (AQ) (Figure 14); Cl
N
74
Piperaquine
N
Cl

65) with certain degree of cross resistance to CQ activity. However, Cl Cl

N
the therapeutic value of amodiaquine is significantly decreased by the
Cl O
biotransformation of its p-aminophenol moiety into a quinonimine N O N
NH N
HN Cl N N X N N
(66), a severe hepatotoxic intermediate by complexing (nucleophilic NH
Cl
N N
Cl
N N

attack by thiol groups) with proteins. Moreover, amodiaquine- Cl N N

N N
protein complexes (67) are highly immunogenic, leading to life- Cl N N Cl
75
threatening agranulocytosis. To overcome these adverse effects, several WR 268,268
76 77

anilinoquinolines have been developed to prevent the undesirable Figure 16: Piperaquine (74) and other bisquinoline analogs (75-77)
formation of toxic quinonimines and improved antimalarial activity. One
of the modifications is the exchange of the positions of the hydroxy and
diethylaminomethyl groups on the phenyl ring. The resulting isoquine activity against P. berghei [90]. For this reason, compound 75 underwent
(69) is not bioactivated and therefore does not lead to hepatotoxicity preclinical studies at Hoffmaan-LaRoche Ltd, and was found to be
[85] with significantly improved activity against CQ-resistant strains. a good inhibitor of hematin polymerization, but its phototoxicity
Furthermore, to improve upon the rapid biotransformation by precluded its further development. tris- and tetraquinolines (Figure
oxidative dealkylation in the body, tert-butylamino group is replaced 16); 76, 77) also developed by attaching 4-amino gruop to tri- and
the diethylamino moiety, resulting tert-butylisoquine (70). It promises tetramacrocycles (cyclams) ring system. However, these derivatives are
a new generation of affordable, well tolerated and effective antimalarial extruded with difficulty by proteinaceous transporter with the aim of
agents that is devoid of any cross-resistance to the chemically related reducing CQ resistance. The results suggest that increased rigidity by
CQ and amodiaquine. cyclization, yields molecules that were not more active in CQ sensitive
strains but very potent against resistant strains and were also non-toxic
Sergherart et al. have synthesized a series of 4-anilinoquinolines
[91].
(Figure 15); 71-73) with two proton accepting side chains of varying
length, which help these dicationic moieties in their likely interaction Compounds Active against Other Diseases
with carboxylate groups of haem. From this study, they concluded that
structural features of 4-anilinoquinoline, can help in circumventing A third approach to antimalarial chemotherapy is to identify
cross resistance with CQ [62]. In continuation as mentioned earlier, they agents that are developed or marketed as treatments for other diseases.
have synthesized prodrug of 4-anilinoquinolines derivatives (Figures 8 These compounds might act against orthologs of their targets in other
and 10) in which metabolically labile ester linkage of GR inhibitor was systems or by different mechanisms against malaria parasites. This
combined to amino and hydroxy functionality of amodiaquine [72]. strategy further named as ‘piggy back’ approach which is cost effective
when a molecular target present in parasites is being pursued for other
Bisquinoline analogs (commercial) indications as it indicates the identification of chemical
starting points. The advantage of these compounds is that, whatever is
Bisquinolines were introduced to overcome CQ-resistance by
the mechanism of action, they have already been developed for a human
connecting two 4-aminoquinoline moieties through linkers of various
indication, so will be quite inexpensive to develop as antimalarials.
length and chemical nature. The activity of such bisquinolines against
Specific examples of this approach include the antimalarial screening of
CQ-resistant strains has been explained by their steric bulk, which
lead series of Histone-deacetylase inhibitors [92], which were originally
prevents them from fitting into the substrate binding site of PfCRT.
developed for cancer chemotherapy, and cysteine protease inhibitors
Alternatively, the bisquinolines may be more efficiently trapped in
that are being developed for osteoporosis. It should be noted that
the acidic DV because of their four positive charges. On this basis
structure– activity relationships emerging from the parasite assays are
bulky bisquinoline compounds were synthesized and evaluated for
unlikely to be the same as those observed for the original indication.
their antimalarial activity. The most advanced representative of the
It is therefore likely, that optimized clinical candidates emerging from
bisquinolines, piperaquine (Figure 16); 74) was developed in 1960s
this strategy will be disease-specific. In many cases, however, drugs may
and heavily used in China. Widespread resistance has developed in
be quite inexpensive to produce and may be available as inexpensive
areas where piperaquine has been extensively used. However there are
antimalarials, especially after patents have expired, as has been the
indications of cross-resistance with dihydroartemisinin (Figure 1). This
case with some antibiotics. Folate antagonists, tetracyclines and other
significant finding made to develop the combination of piperaquine
antibiotics were developed for their antibacterial properties and were
and dihydroartemisinin (named Euartekin) and entered phase II
later found to be active against malaria parasites [93]. Iron chelators,
clinical trails [89]. Of the several bisquinoline analogs developed, the
which are used to treat iron overload syndromes, have documented
compound (WR 268,268) (Figure 16); 75) has shown potent in vivo
antimalarial efficacy [94]. These examples suggest that it is appropriate

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Citation: Shreekant D, Bhimanna K (2016) 4-aminoquinolines: An Overview of Antimalarial Chemotherapy. Med chem 6: 001-011. doi:10.4172/2161-
0444.1000315

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