Recent Advances in Antimalarial
Suryanaryana Vangapandu, Meenakshi Jain, Kirandeep Kaur,
Premanand Patil, Sanjay R. Patel, Rahul Jain
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research,
Sector 67, S.A.S. Nagar, Punjab 160 062, India
Published online 12 May 2006 in Wiley InterScience (www.interscience.wiley.com).
Abstract: Malaria caused by protozoa of the genus Plasmodium, because of its prevalence,
mankind. The inadequate armory of drugs in widespread use for the treatment of malaria,
development of strains resistant to commonly used drugs such as chloroquine, and the lack of
affordable new drugs are the limiting factors in the fightagainst malaria. These factors underscore
thecontinuingneed ofresearch fornewclasses ofantimalarial agents,anda re-examinationof the
existing antimalarial drugs that may be effective against resistant strains. This review provides an
in-depth look at the most significant progress made during the past 10 years in antimalarial drug
development. ? 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 1, 65–107, 2007
Key words: malaria; drug resistance; artemisinins; 4-aminoquinolines; chloroquine resistance
reversal agents; 8-aminoquinolines; quaternary ammonium salts; new structural classes of
antimalarial agents; iron chelators; target-based antimalarial agents; chalcones; natural product-
based antimalarial agents
1 . I N T RO D U C T I O N
protozoan belonging to genus Plasmodium causes malaria, one of the most severe tropical diseases.
The four identified species of the parasite responsible for inflicting human malaria are Plasmodium
falciparum,P.vivax,P.ovale,and P.malariae.Of these,P.falciparum and P.vivaxaccountfor more
than 95% of malaria cases in the world. Malaria infections caused by P. falciparum are prevalent in
the major parts of Africa, sub-Saharan Africa and East Asian countries, whereas P. vivax is the
causative species primarily of Indian sub-Continent. Interestingly, the disease can be treated in just
Correspondence to: Rahul Jain, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Medicinal Research Reviews, Vol. 27, No.1, 65^107, 2007
? 2006 Wiley Periodicals, Inc.
48 hr, yet it can cause fatal complications, if the diagnosis and treatment are delayed. The tropical
regions provide ideal breeding and living conditions for the anopheles mosquito. Malaria is re-
people that account for approximately 40% of the world’s population, in more than 100 countries.1
Every year, 300–500 million people suffer from this disease (90% of them in sub-Saharan Africa,
of these deaths occur in sub-Saharan Africa), which account for about 4%–5% of all fatalities in
the world. Malaria is known to kill one child every 30 sec, 3,000 children per day under the age
5 years.3–5Malaria ranks third among the major infectious diseases in causing deaths after
the total disease burden of the world.
other drug discovered during this period, artemisinin, is a natural product, whose medicinal
recommended only in the complicated cases of cerebral malaria. Resistance of plasmodia to
antimalarial drugs is now recognized as one of the major problems in eradication of malaria. The
rapid increasing resistance of P. falciparum malaria parasites to most commonly used drug
chloroquine has made it ineffective. Furthermore, control of malaria is hampered by emergence of
mosquitoes resistant to pesticides, and by restriction in the use of chemical sprays. Despite
of malaria in many countries, and the increased resistance of vectors to commonly used drugs and
insecticides, synthetic efforts toward new antimalarial drugs have regained importance.
This review article accommodates some of the most significant achievements observed during
discussion on: clinical features, pathophysiology, classification, mechanism of action, drug
resistance, the P. falciparum genome, and recent advances in antimalarial drug development.
2 . C L I N I C A L F E A T U R E S OF M A L A R I A
Malaria is a febrile illness characterized by fever and related symptoms. The clinical manifestations
malaria after the prepatent period (period between inoculation and symptoms that is the time when
of symptoms at regular intervals of 48–72 hr. These are called as ‘‘short term relapses.’’ Some
patientswillget ‘‘long term relapses’’after agap of20–60 daysormore.Invivaxand ovalemalaria,
these are due to reactivation of the hypnozoites in the liver. In falciparum and malariae infections,
these are called as ‘‘recrudescence’’ and are due to persistent infection in the blood.
3 . P A T H O P H Y S I O L O G Y O F M A L A RI A
prodromal illness characterized by vague aches and pains, headache, nausea, etc. At the end of
which in turn infect more RBC’s. The growing parasite progressively consumes and degrades
intracellular proteins, principally hemoglobin, resulting in formation of the ‘malarial pigment’ and
hemolysis of the infected red cell. This also alters the transport properties of the red cell membrane,
and the red cell becomes more spherical and less deformable. The rupture of red blood cells by
merozoites releases certain factors and toxins, (such as, red cell membrane lipid, glycosyl
of cytokines such as TNF and interleukin-1 from macrophages, resulting in chills and high-grade
fever. This occurs once in 48/72 hr, corresponding to the erythrocytic cycle.7
are sticky. This results in increased adhesion of red blood cells that clump together. The red blood
cells may also adhere to the wall of the minute capillaries, venules, and arterioles, thereby blocking
resulting in occlusion of blood-flow culminates in damage to vital organs like the brain, kidneys,
lungs, liver, and gastrointestinal tract which leads to the various fatally serious complications of
P. falciparum malaria. Cerebral malaria is the most serious complication of falciparum malaria.
the clogging of the cerebral microcirculation by the parasitized red blood cells. These cells develop
these deeper blood vessels. Also, rosetting of the parasitized and non-parasitized red cells and
decreased deformability of the infected red cells further increases the clogging of the
microcirculation. Obstruction to the cerebral microcirculation results in hypoxia and increased
lactate production due to anaerobic glycolysis. In patients with cerebral malaria, cerebrospinal fluid
lactate, the adherent erythrocytes may also interferewith gas and substrate exchange throughout the
brain. However, complete obstruction to blood flow is unlikely, since the survivors rarely have
any permanent neurological deficit. P. vivax and P. ovale infections are generally benign and
of P. vivax and P. ovale in the liver go into hibernation. These hypnozoites can get reactivated and
infections, relapses from the liver do not occur; however, the blood infection may remain chronic
and, if untreated, may remain chronic for years in case of P. falciparum and decades in case of
4 . C L A S S I F I C A T I O N O F A N T I M A L A R I A L A G E NT S
chemical structure (see Fig. 1).
A. Blood Schizontocides
These drugs act on the blood forms of the parasite and thereby terminate clinical attacks of malaria.
The drugs belonging to this class include chloroquine, quinine, mefloquine, halofantrine,
pyrimethamine, sulfadoxine, sulfones, tetracyclines, and artemisinin and its derivatives.
B. Tissue Schizontocides for Causal Prophylaxis
These drugs act on the primary tissue forms of the Plasmodium, which after growth within the liver
initiate the erythrocytic stage. By blocking this stage, further development of the infection can be
prevented. Primaquine and pyrimethamine (to a lesser extent) have activity against this stage.
However,since it is impossible to predict the infection before clinical symptoms begin,this mode of
therapy is more theoretical than practical.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
C. Tissue Schizontocides for Preventing Relapse
These drugs acton hypnozoitesofP.vivax andP.ovale intheliverwhich cause relapse ofsymptoms
on reactivation. Primaquine is the only prototype drug available for this stage.
These drugs destroy the sexual forms of the parasite in the blood, and prevent transmission of the
infection to the mosquito. Chloroquine and quinine have gametocytocidal activity against P. vivax
and P. malariae, but not against P. falciparum. However, primaquine has gametocytocidal activity
against all human malarial parasite species including that against P. falciparum.
These drugs prevent the development of oocyst in the mosquito and thus ablate the transmission.
Primaquine and chloroguanidine are known to have activity against this stage. The two important
concepts in the treatment of malaria include suppressive and radical treatment of the infection.
Suppressing the erythrocytic stage of the parasitic development can alleviate the symptoms of
Figure 1. Antimalarialdrugsinwidespreaduse.
malaria and it involves administration of appropriate blood-schizontocidal drugs. In all cases of
along with tissue-schizontocidal drugs.
5 . M E C H A N I S M O F A C T I O N O F K N O W N AN T I M A L A R I A L DR U G S
used drug by P. falciparum has posed major challenges to combat malaria. It is well known that
malaria parasite manifests unique features of heme metabolism. In the intraerythrocytic stage, it
utilizes the host hemoglobin to generate amino acids for its own protein synthesis, but polymerizes
de novo for metabolic use. The heme biosynthetic pathway of the parasite is similar to that of
hepatocytes and erythrocytes. However, while the parasite makes its own d-aminolevulinate
(ALA) synthase, which is immunochemically different from that of the host, it imports ALA
schizontocidal drugs such as chloroquine are known to act by interfering with the heme metabolism
of the parasite.8
The proposed mechanisms of action of chloroquine include intercalation with parasite DNA,9
impairment of lysosome function,10inhibition of heme-dependent parasite protein synthesis,11and
with the heme polymerization process that is essentially a detoxification mechanism to prevent the
stage. Fitch et al. demonstrated that the chloroquine and other 4-aminoquinolines bind to heme
strongly (Kd¼ 10?8M), and suggest that heme-chloroquine complex (HCC) could be toxic to
is a heme polymer obtained from the breakdown of hemoglobin by Plasmodium species. The
mechanism of action of chloroquine thus involves, the drug enters the food vacuole, possibly via
diffusion of the free base across intervening membranes;14accumulation of the drug in the food
forms a predominantly p–p complex with heme ferriprotoporphyrin IX [Fe(III)PPIX], which may
further enhance drug accumulation;16drug inhibits formation of hemozoin via the formation of
this complex; and drug exerts a toxic effect on the parasite in the form of the Fe(III)PPIX-drug
Recent studies suggest that a malarial histidine-rich protein (HRPII) localized in the digestive
vacuole of the parasite provides a nucleation site for initiation of hemozoin (malaria pigment)
on the growing intraerythrocytic stages carrying out hemoglobin digestion. Chloroquine inhibits
hemozoin formation that results in the buildupof significant quantities of toxic heme [Fe(III)PPIX]-
strong affinity toFe(III)PPIX.However,association with Fe(III)PPIX is necessary,butnot sufficient
for inhibiting b-hematin formation. Presence of 7-chloro group in the 4-aminoquinolines is an
essential requirement for b-hematin inhibitory activity. In turn, b-hematin inhibitory activity is
necessary, but not sufficient for antiplasmodial activity. To summarize, 4-aminoquinoline nucleus is
responsible for complexing Fe(III)PPIX, the 7-chloro group is required for inhibition of b-hematin
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
B. Sesquiterpene Endoperoxides
Mode of action of artemisinin and related 1,2,4-trioxanes involves the cleavage of endoperoxide
bridge homolytically by heme (ferriprotoporphyrin IX), a ubiquitous cellular component of
P. falciparum to give a reactive free radical intermediate that alkylate vital parasite protein
molecules.19–21Thus, the antimalarial activity of artemisinin is mediated by free radicals.22Heme
accumulates in the parasite as a result of hemoglobin digestion.23The heme iron reacts with
artemisinin to generate free radicals by hemolysis of the endoperoxide.24The interaction between
hemin and artemisinin results in membrane damage of the parasite.25Posner et al. suggested a
pathway, whereby initially formed oxygen-centered radicals undergo hydrogen abstraction to givea
carbon-centered radical.26Further studies conducted by Posner et al. suggested that abstractable
hydrogen at the 4a-position is an important requirement for good antimalarial activity.27Hayes and
them,hemeiron(II)ratherthan heminiron(III)istheinitial reaction species,andartemisininformsa
covalent adduct with hemin.29An intact tetracyclic framework appears to be required for adduct
sequence has been suggested involving initial complexation between iron and the peroxy bridge of
the compound and followed by heterolytic bond cleavage.28aKrishna et al. recently proposed that
artemisinin act by inhibiting PfATP6, the sarco/endoplasmic reticulum Ca2þ-ATPase (SERCA)
ortholog of P. falciaprum.28bWhen expressed in Xenopus oocytes, Ca2þ-ATPase activity of PfATP6
was inhibited by artemisinin with potency similar to that of another highly specific SERCA
inhibitor sesquiterpene lactone, thapsigargin. It was observed that thapsigargin antagonizes the
activity of artemisinin, and ineffective antimalarial desoxyartemisinin was found not to inhibit
The most active and common metabolite of all artemisinin compounds ‘dihydroartemisinin’ is
very effective in treating P. falciparum infected rodent malaria. It is known to alter the ribosomal
organization and endoplasmic reticulum. Changes in membrane integrity are followed by a
depression in protein synthesis. Artesunate acts via inhibiting cytochrome oxidase and DNA
synthesis by blocking the purine synthesis. In cerebral malaria, it is known to interfere with
parasitized RBC sequestration in cerebral micro vessels.19
Both humans and parasites have the ability to convert folic acid into tetrahydrofolic acid. Humans
obtain the needed folic acid from the diet. However, parasites cannot readily use exogeneously
supplied folic acid to synthesize folate co-factors. Rather, parasites synthesize these co-factors
de novo starting with the condensation of pteridine with para-aminobenzoic acid (PABA) to form
differences between humans and parasites are the basis of selective toxicity of sulfonamides, which
are PABA antagonists, and diaminopyrimidines that are inhibitors of dihydrofolate reductase. The
type-I antifolates such as sulfones and sulfonamides inhibit dihydropteroate synthase (DHPS).30On
the other hand, type-II antifolates, such as pyrimethamine and proguanil inhibit dihydrofolate
reductase (DHFR) [the pathway from 4-aminobenzoic acid to the tetrahydrofolate co-factors is
essential in the synthesis of the pyrimidine deoxythymidylate for DNA].31Antifolates attack all
growing stages of the malaria parasite, and are found to also inhibit the early growing stages in the
liver and the developing infective stages in the mosquito.
stress mechanism.32–36Itiswell knownthat the hydroxylated metabolitesof primaquine, stimulates
the hexose monophosphate shunt, increases hydrogen peroxide and methemoglobin production and
decrease glutathione levels in the erythrocyte.34–38Unfortunately, this same preoxidant property of
primaquine is probably also responsible for its hemolytic side effect.34Other potential mechanisms
include inhibition of vascular transport39,40or inhibition of the parasite enzyme dihydroorotate
inhibitors of this enzyme. In contrast to chloroquine, primaquine does not inhibit hematin
polymerization although it does bind to hematin m-oxo dimer with modest affinity.42,43The
accumulation of 8-aminoquinolines in the food vacuole is in part a function of their weak base
hematin m-oxo dimer with an affinity between that of mefloquine and quinine, suggesting that the
mode of hematin binding may also be important.42
6 . D R U G R E S I S T A N C E
Malaria was nearly eradicated by the early 60s, owing largely to concerted antimalarial campaigns
under theguidanceof WHO.45,46However,the disease has made adramaticcomeback,duetolaxity
in antimalarial campaigns, emergence of resistance by the parasite to majority of commonly used
antimalarial drugs and by the vector against the insecticides. Resistance to the commonly used drug
chloroquine is most prevalent, while resistance to most other antimalarials such as alkaloids (e.g.,
quinine), sulfonamides (e.g., sulfadoxine), and diaminopyrimidines (e.g., pyrimethamine) have
also been extensively reported.33–35The spread of multidrug resistance particularly with P.
falciparum,47,48isresponsible forthemajorityofdeathsandmostsevereforms ofdisease,including
cerebral malaria, whereas only sporadic cases of resistance have been reported in vivax malaria.
P. falciparum do not accumulate chloroquine and the parasitized red blood cells release the drug at
least 40 times faster than the sensitive strains.49,50There is an increase in the surface area of the
resistant parasites, permitting more efficient pinocytosis. Binding of chloroquine with hemoglobin
breakdown product to form toxic complexes is also prevented. Chloroquine accumulation in the
acidic food vacuole of the malaria parasite might occur by passive diffusion down the pH gradient
(ion-trapping), by import via an ATP-dependant transporter (active uptake) or by binding to
ferriprotoporphyrin IX.51The plasmodial P-glycoprotein homolog-I (Pgh-I) or the chloroquine
resistance transporter (PfCRT) modulates quinoline uptake directly by transporting drugs in and out
of the food vacuole, or indirectly, by contributing to the generation of a pH or electrochemical
gradient.52It is estimated that more than 60% of the P. falciparum strains that infect non-immune
travelers are resistant to chloroquine. The drug is expelled 40–50 times more rapidly from resistant
strains than from sensitive strains.53A single genetic locus appears to be responsible for the rapid
and cyproheptadine and hydroxyzine.54
Resistance to proguanil and pyrimethamine has developed over the past 30 years and is now
widespread.55The mechanism of resistance to these drugs is known to involve: (i) modification of
enzymes, and (iv) the use of alternative pathways.56Resistance to these drugs apparently depends
largely on point mutations in the dihydropteroate synthase and dihydrofolate reductase genes.57
Combinations of type-I and type-II antifolates have been generally effective against pyrimethamine
resistance and resistance to sulfadoxine and pyrimethamine was not a significant problem initially.
Recently it seems particularly in East Africa and South East Asia that resistance to sulfadoxine and
pyrimethamine is becoming more widespread. It might be due to higher levels of resistance to the
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
pyrimethamine component, reflected in additional mutations in dihydrofolate reductase, or is due to
the development of resistance to sulfadoxine as well.58
Reports of resistance to quinine are rare, but cases have been reported from Thailand and East
however, there are still no well-documented cases of high-grade resistance. In Thailand, more than
50% of cases in certain border areas are no longer responding to mefloquine therapy.59The
the opportunityforresistantstrainstodevelop. Topreventdevelopmentofresistancetothisvaluable
drug, it has been suggested that mefloquine should always be used in combination with another
reportedly blocked by penfluridol, but not by verapamil, whereas chloroquine resistance is reversed
by verapamil, but not penfluridol. Resistance against halofantrine is also linked to amplification of
Pfmdr 1 gene.61
Atovaquone and proguanil are synergistic in vitro and this combination in vivo produces 100%
cure rates against the most multidrug resistant P. falciparum. Atovaquone resistance is associated
with singlepoint mutations in the cytochrome bgene of P.falciparum.62Although small decrease in
sensitivity in P. falciparum can be induced in vitro, true stable resistance to artemisinin group of
documented reports on development of resistance against 8-aminoquinolines. However, sporadic
incidents of decrease in sensitivity to primaquine have been reported recently.46,63–65
7. THE P . F a l c i p a r u m G E N O M E S E Q U E N C E
P. falciparum in the year 2002.66–69The P. falciparum genome is approximately 23 Mb in length,
consists of 14 chromosomes, encodes about 5,300 genes and is extremely rich in adenosine and
thymine (AþT ¼ ?80%).69The individual chromosomes were resolved by pulsed field gel
electrophoresis and subjected to shotgun sequencing. Sequence-tagged site (STS) markers,70the
microsatellite linkage map and optical restriction maps of the chromosomes were used for the final
sequence assembly.71The information obtained by investment in sequencing of the P. falciparum
genome has been of immense scientific value. Investigations by Olliaro et al.72led to the
identification of an organelle in Plasmodium and related parasites called the apicoplast. Analysis of
the genome sequence in conjunction with transfection studies in Toxoplasma have led to the
identification of nuclear-encoded proteins that are imported into the apicoplast and the amino-
terminal sequences that direct the transport of these proteins into the organelle. The fabH gene
encoding 3-ketoacyl carrier protein synthase III, an enzyme involved in type-II fatty acid
biosynthesis, was identified on chromosome 2 in P. falciparum and shown to contain a putative
apicoplast-targeting peptide. More recently, genes encoding enzymes of the non-mevalonate
pathway of isoprenoid biosynthesis were identified in preliminary data from the chromosome
14 sequencingproject and the enzymes are localizedin the apicoplast.73Inhibitors of one enzyme in
the pathway (1-deoxy-D-xylose-5-phosphate reductoisomerase) were found to inhibit the activity of
These examples validate the early interest in plastid-localized pathways as drug targets and
demonstrate the rapidity with which potential drug targets can be identified with genome sequence
information.74Plantlike biochemical pathways in apicomplexanparasites that may not be located in
the apicoplast are also useful drug targets. These discoveries may provide a much more complete
picture of parasite biology and facilitate the development of new drugs and vaccines to combat
8 . R E C E N T AD V A N C E S I N A N T I M A L A R I A L D R U G D E V E L O PM E N T
A. Artemisinin and Its Derivatives
first-generation endoperoxide antimalarial compounds are ester or ether derivatives of artemisinin
that include dihydroartemisinin (DHA), artemether, arteether, and artesunate.76There are not many
reports of clinically significant resistance, though they suffer from poor oral bioavailability, high
incidence of recrudescence and their actions are limited to specific blood stages of Plasmodium.
There are possibilities that, like other antimalarial drugs, the artemisinin derivatives might become
second-generation derivatives that include bicyclic trioxanes (2),78tetraoxanes (3),79tricyclic
trioxanes (4),80arteflene (5),81and 11-alkyl-12-deoxy artemisinins (6–7)82(see Fig. 2).
clinical trialsinhumans.Artefleneissafe andeffective,butcharacterizedbyfrequentrecrudescence
common to all endoperoxide antimalarial agents. Considerable amount of work had been done to
improve the blood-schizontocidal activity of artemisinin because its utility has been limited due to
high recrudescence.81The efforts made by Central Institute of Medicinal and Aromatic Plants
(CIMAP),inLucknow,India todevelopafast acting bloodschizontocide specifically forthe control
of drug resistant and cerebral malaria resulted in the discovery of a/b-arteether (a 30:70 mixture of
enantiomers).83This compound exerts curative blood-schizontocidal action against P. berghei
(sensitive strain),84P. yoelii nigeriensis (chloroquine, quinine, and mefloquine resistant strain),85P.
knowlesi (mefloquine resistant strain),86and P. cynomolgi (sensitive strain).87
to be safe in subacute toxicity studies, and has no teratogenic effect in rats and rabbits.87Phase-I
completed. In all the cases, single injection of a/b-arteether was well tolerated and no tenderness,
swelling or discomfort was experienced at the site ofinjection. a/b-Arteether administered daily for
3 consecutive days as intramuscular injections, in single doses in the range 20–300 mg and in
The other potentially fast acting blood-schizontocide candidate compound under clinical
reviewed recently.89,90This review is limited to discussion on the advances made in the year 2004.
Figure 2. Artemisininandsomeimportantsyntheticperoxidederivatives.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
It has been observed that the replacement of oxygen at the C-10 position of DHAwith carbon
past decade. Apart from monomeric semisynthetic analogs, dimeric derivatives of artemisinin have
potent antimalarial and antitumor activities of synthetic and semisynthetic artemisinin-derived
dimers.90The potential drawback of these dimers is the presence of metabolically unstable C-10
acetal linkage. Jeyadevan et al.91and O’Neill et al.92have recently reported antimalarial and
0.3 nM againstK1 strain.91The isobutyricaciddimeric analog 9,on the other hand upon single dose
ip administration to mice was found to be safe and displayed a therapeutic index six times that of
It is commonly known that acetal-type DHA derivatives undergo a facile hydrolysis under the
acidicconditionsinadditiontoenzymaticoxidationresultingintheformationofDHA.Be ´gue ´ etal.93
utilized an interesting approach to the design of non-acetal derivatives that involves dehydration of
DHA to anhydrodihydroartemisinin and the 6-methyl functionalization. Derivative 10a (R ¼ H)
mice invivo versus P.berghei at a concentration of 35.5 mmol/kgusing iproute (see Fig. 3). Another
derivative 10b (R ¼ NHCH2CH2NH2) from the same series was found to be even more active
(IC50¼ 1.2 nM) than the control artemether (IC50¼ 3.5 nM), and cured 4/5 mice invivo. Recently
Bonnet-Delpon et al.94have reported that the introduction of a trifluoromethyl group on a crucial
C-10 position of artemisinin resulted in excellent in vitro and in vivo antimalarial activities.
Derivative 11 (R ¼ OH) displayed IC50value of 9.4 nM and has plasma half-life of 85.9 min
11 (R ¼ OCH3) displayed invitro antimalarial activity of 0.8 nM against P. falciparum FCB1 strain
mice from day 4 to day 25.
Tilley et al.95synthesized a series of novel epoxy endoperoxides, which were evaluated for in
vitro antimalarial activity and ability to interact with oxidized and reduced forms of heme. The most
active derivative 12 (R1¼ R2¼ c-C6H11) of the series displayed good IC50value of 0.32 mM
compared to 0.01 mM for artemisinin (see Fig. 3). Several derivatives,however, did not interact with
Figure 3. Importantsemisyntheticperoxidesreportedinyear2004.
FP-Fe(III) or interacted weakly suggesting that these epoxy endoperoxides exert their antimalarial
activities by a novel mechanism of action.
Immense efforts are directed towards development of small endoperoxide ring con-
taining synthetic antimalarials due to the fact that artemisinin suffers from high cost, poor
pharmacokinetics and recrudescence. Research efforts made by Vennerstrom et al.96led to the
discovery of a novel 1,2,4-trioxolane ring containing antimalarials 13 (see Fig. 3). Derivative 13
[R ¼ CONHCH2C(CH3)2NH2] of the series displayed in vitro IC50values of 0.39 ng/mL and
0.42 ng/mL versus chloroquine resistant P. falciparum K1 and chloroquine sensitive NF54 strains,
and was more active than artesunate, artemether, chloroquine, and mefloquine in vivo after a single
3 mg/kg dose administration against P. berghei infected mice. It has progressed through preclinical
regulatory studies and advanced to preclinical studies. Singh et al.97,98have made significant
and affordable synthesis of orally effective 6-alkylvinyl/arylalkylvinyl/cycloalkylvinyl substituted
1,2,4-trioxanes of general structure 14 (see Fig. 3). The most promising compounds 14
[R ¼ CH2CH2CH(OH)C6H4(4-Cl), CH2CH2CH(OH)C6H5, c-C3H5] of the series displayed good
invivo activity against multidrug-resistant P. yoelii in Swiss mice and cured all animals at a dose of
96 mg/kg. Finally, a series of antimalarial peroxides having a 3-methoxy-1,2-dioxane structure
15 (see Fig. 3) were synthesized by Kobayashi et al.99The most active compound displayed invitro
IC50value of 0.033 mM versus P. falciparum, and in vivo ED50of 18 mg/kg versus P. berghei
1. Bis-, Tris-, and Tetraquinolines
enhanced bulkinessandrigidityon their activity against strains ofP.falciparum expressing different
degrees of chloroquine resistance and cytotoxicity in mammalian cells. Biochemical studies have
indicated that the isolates of chloroquine resistant parasite accumulate less drug concentration than
proteins involved in the drug efflux and likely to be extruded with difficulty by a proteinaceous
transporter have been synthesized, and are found to inhibit the growth of both chloroquine sensitive
and resistant parasites with similar efficacy. However, further development of the most promising
molecules in this series, piperaquine (16a, R ¼ H), hydroxypiperaquine (16b, R ¼ OH), and
dichloroquinizine (17), has been suspended for reasons of toxicity (see Fig. 4).100
On the basis of observations that several bisquinolines such as piperaquine possess notable
activity against chloroquine resistant malaria, Vennestrom et al.101have synthesized a series of
bisquinoline analogs. The most effective compound of the series 18 (WR 268,668) (see Fig. 4), has
shown potent in vivo activity with 4/5 and 5/5 mice curative at 160 and 320 mg/kg, respectively,
against P. berghei. No other compound in the series was curative at the dose of 160 mg/kg. It is
suggestedthat the relativeorientation of the two-quinoline heterocycles is important foractivity and
This observation is consistent with molecular modeling studies, which indicate an energydifference
of less than 1 kcal/mol between the energy-minimized diequatorial and diaxial conformers of
18. Compound 18 underwent extensive preclinical evaluation at Hoffmann-LaRoche Ltd. and is a
very effective inhibitor of hematin polymerization, but its phototoxicity precluded further
With the aim of maintaining both steric hindrance and a reduction of the degrees of freedom
while introducing proton accepting and/or substitution sites Girault et al.102have designed and
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
tetrazamacrocycles (cyclams) (see Fig. 4). All these quinolines are extruded with difficulty by a
by an absence of cytotoxic effects, whereas tetraquinolines were found to be very potent against
chloroquine resistant strains and were non-cytotoxic against mammalian cells.
Vennerstrom et al.103further extended the work and synthesized a series of bisquinoline
heteroalkanediamines21(R ¼ NH/O)andfoundthatincorporationofnitrogenandoxygenatomsin
the bisquinoline bridge did not improve antimalarial activity of these compounds (see Fig. 4). They
suspected that the structural feature probably allows for rapid N-dealkylation metabolism, which
would convert these bisquinolines to monoquinolines, and subsequent loss of in vivo antimalarial
activity. Thus, compared to alkane-bridged bisquinolines, none of the heteroalkane-bridged
bisquinolines had sufficient antimalarial activity.
(n ¼ 4) has IC50value of 100 nM/g against P. falciparum invitro (see Fig. 4). The further biological
activity of all the synthesized compounds indicated them to have good activity against resistant
strains and most effective compound 22 (n ¼ 4) showing activity in the range of 120 nM/g. The
position of attachment and length of the linker chain markedly affected activity.
Figure 4. Biologicallyactivebis-,tris-,andtetraquinolines.
Cowman et al.105synthesized cinchonidine-like bisquinolines and the most active derivative 23
(n ¼ 8) appeared to have overcome the chloroquine resistance mechanism, but was toxic in animal
studies (see Fig. 4). Deady et al.106further extended this work and synthesized a series of
chloroquine-like bisquinolines 24 with a hydrocarbon linkage at the position-2 (see Fig. 4). The
length of the linker affected the activity and the most activecompound 24 (n ¼ 12) was shown to be
chloroquine (IC50¼ 540 nM) and slightly better than mefloquine (IC50¼ 30 nM). Compound 24
was also found to inhibit b-hematin formation with efficiency similar to that of chloroquine.
Studies conducted earlier have demonstrated that chloroquine resistant parasites are not necessarily
cross-resistant to amodiaquine. Furthermore, amodiaquine was found to be superior to chloroquine
with lower parasitological and clinical failure rates.107Amodiaquine can adopt a bioactive
conformation, which includes an inter-nitrogen separation of 8.3 A˚similar to that found in
chloroquine.108The same distance has been measured by X-ray crystallography within the central
iron atom and the oxygen in the carboxylate groups of heme, indicating ferriprotoporphyrin as the
possible receptor target for 4-aminoquinolines. Sergheraert et al.108synthesized a series of 4-
aminoquinolines 25–27 with two proton-accepting side chains of varying length (see Fig. 5), which
helps these dicationic moieties in their likely interaction with carboxylate groups of heme.
The comparative ability of each compound to inhibit the growth of chloroquine sensitive and
resistant strains of P. falciparum invitro has been measured, and the most potent among them being
subsequently tested against P. berghei in mice. In conclusion, this series of derivatives constitute a
be of help in circumventing cross-resistance with chloroquine.
Glutathione (GSH) protects P. falciparum from oxidation, and its elevation in parasites leads to
increased resistance to chloroquine, while reduction in GSH restores the sensitivity in resistant
P. falciparum strains. Intracellular GSH levels depend mainly on the reduction of glutathione
disulfide (GSSG) by the glutathione reductase (GR). Upon the basis of this hypothesis, Davioud-
Charvet et al.109synthesized several prodrugs, in which 4-anilinoquinolines were combined with a
GR inhibitor via a metabolically labile ester linkage. The most effective analog 28 (see Fig. 5)
Figure 5. 4-Anilinoquinolines.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
exhibited ED50values ranged between23 and 36.5 nM against six P. falciparum strains with various
degree of resistance to chloroquine. Upon evaluation against P. berghei infected mice model 28
produced a 178% excess mean survival time at 40 mg/kg for 4 days.
The toxic effect of amodiaquine is manifested by its metabolism to amodiaquine quinoneimine
(AQQI), which initiates hypersensitivity reactions. O’Neill et al.110synthesized a series of
metabolically stable analogs ofamodiaquine (AQ),inwhich30-hydroxyland40-Mannichsidechain
function were interchanged. Isoquine (29) produced excellent IC50of 6.01 nM versus K1 strain of
P. falciprum and also exhibited excellent oral in vivo ED50activity of 1.6 and 3.7 mg/kg against
P.yoeliiNSstraincomparedto7.9and7.4 mg/kgforAQ(see Fig.5).Isoquine (14)representsanew
second-generation 4-anilinoquinoline lead molecule that does not undergo in vivo bioactivation as
evident from its metabolism studies in a rat model.
3. Modified Chloroquine Analogs
Considerable data now support the hypothesis that chloroquine-hematin binding in the parasite food
vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning.107
Hematin polymerization, a unique parasite mechanism to detoxify hematin, is a non-enzymatic
process in which the hematin released from parasite digestion of hemoglobin is converted to
bonding and ionic interactions between the two carboxylates of hematin, and the charged tertiary
hematin m-oxo dimer binding as this binding is pH-independent and is nearly unaffected by high salt
concentrations. Instead, they suggested that the enthalpy driven chloroquine-hematin m-oxo dimer
binding derives largely from an energetically favorable p–p molecular recognition interaction
between the quinoline ring of drug and the metalloporphyrin ring of hematin m-oxo dimer. The
isothermal titration calorimetry, the stoichiometry data, and exothermic binding enthalpies indicate
that chloroquine and its analogs bind to two or more hematin m-oxo dimers in a co-facial p–p
determinant in its binding affinity to hematin m-oxo dimer. The initial work on the quinoline ring
modified chloroquine analogs carried out by O’Neill et al.113was further extended by Vennerstrom
et al.114They synthesized various quinoline ring modified analogs (30) to measure hematin binding
affinity, inhibition of hematin polymerization, and inhibition of parasite growth against both
chloroquine sensitive and resistant strains of P. falciparum (see Fig. 6). Based on the molecular
modeling study, they describe the structural specificity of chloroquine-hematin binding. For, 4-
aminoquinolines related to chloroquine, this data suggested that electron withdrawing functional
groups at the C-7 position of the quinoline ring are required for activity against both hematin
polymerization and parasite growth and the chlorine substitution at position 7 is optimal. It also
confirms that the alkyl side chain especially the aliphatic tertiary nitrogen atom is an important
structural determinant in chloroquine drug resistance.
bearing a common piperazine linker. The most effective analog 31 (R ¼ 4,5-dibromothiphen-2-yl)
displayed an activity 100-fold better than chloroquine (see Fig. 6). Fluorescence microscopic
different tothatofchloroquine.Inyetanotherextension,Sergheraertetal.117,118synthesized several
series of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives in the hope to
improve activity/cytotoxicity ratio. Two most effective compounds from the series 32 (X ¼ CH2)
and32(X ¼ CO)displayedremarkableimprovementinantimalarialactivity(seeFig.6).Compound
32(X ¼ CH2)producedanIC50valueof8.8nMcomparedto126nMforchloroquineanddisplayeda
infected mice.117On the other hand, compound 32 (X ¼ CO) was even more potent with IC50value
of 6.5 nM and much improved cytotoxicity profile and displayed a superior selectivity index of
4.6-fold to 32 (X ¼ CH2) and 5.3-fold to that of chloroquine.118
function with more metabolically stable side chain groups, such as tert-butyl, piperidyl, or
pyrrolidino, led to substantial increase in antimalarial activity.119Derivatives 33 [R ¼ C(CH3)3,
X ¼ Cl, CF3] were found to be most active with 4- to 20-fold increase in activity against the
chloroquine sensitive and resistant strains (see Fig. 6). The ability of these analogs to accumulate at
higher concentrations within the food vacuole of the parasite proved to be an important parameter in
increasing their potency. Synthesis of new class of Ugi adduct of 4-aminoquinolines was recently
described.120The most active derivative 34 (R ¼ c-C5H9, n ¼ 2) displayed an IC50value of 73 nM
against a resistant K1 strain. More recently, Katti et al.121synthesized a series of guanidine group
containing 4-aminoquinolines. The most active derivative 35 (R ¼ H, n ¼ 4) displayed IC50of
1.02 mM, and suppressed 76% parasitaemia on day 4 compared to 100% suppression displayed by
chloroquine (see Fig. 6).
C. Chloroquine Resistance Reversal Agents
Development of resistance to the inexpensive antimalarial mainstays, such as chloroquine, is a
serious worldwide problem, which has significantly reduced treatment options. One interesting
strategy to counteract the chloroquine resistance involves potentiating its effects using compounds
with weak antimalarial activity. Search for such agents has led to biological evaluation of various
calcium channel blockers,122antidepressants,123antihistamines,124and prostaglandin oligomers125
reversal agents (or chemosensitizers) is generally close to or higher than therapeutic dose for other
Guan et al.126have designed and synthesized a series of new resistance reversal agents against
ring systems—phenothiazine, iminodibenzyl, iminostilbene, and diphenylamine—with side chain
length between four and six carbons. Various tertiary amino groups including either non-cyclic,
Figure 6. Modifiedchloroquineanalogs.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
aliphatic amines were introduced to explore the steric tolerance at the end of the side chain. The
compounds 36–37 (see Fig. 7) showed better drug-resistant reversing activity in chloroquine-
chain of the molecule retained the chemosensitizing activity, and analogs with four-carbon side
chains showed superior activity. Furthermore, new modulators with phenothiazine ring exhibited
the best chemosensitizing activity among the four different ring systems examined. Terminal amino
function has limited steric tolerance as evidenced by the dramatic lose of the modulating activity,
possesses all three optimized structural features, which consist of phenothiazine ring and a
index of compound 36 is 0.21, which is superior to that of the best-known multidrug-resistant
reversing agent, verapamil (0.51).
Bitonti et al. have found that the 9-g-methylaminopropyl-9,10-dihydro-9,10-ethanoanthracene
(maprotiline) has shown anti-MDR activity on P. falciparum.123This study was further explored by
Alibert et al.127by synthesizing a series of 9,10-dihydro-9,10-ethano or ethenoanthracene (DEEA)
derivatives. The resistance reversal activity is expressed as IC50, which is the concentration of the
compound that leads to a 50% decrease of the IC50of chloroquine. Compounds 38–40 were more
potent thanverapamil and promethazine (see Fig. 7). These compounds except 40 are less cytotoxic
than the reference chemosensitizers. Compounds 38 and 40 are as potent as verapamil and/or
promethazine on three other chloroquine resistant strains of P. falciparum (Palo Alto from Uganda;
FCR3 fromGambia; Bres 1from Brazil).128Theresistancereversalactivity isunder the influenceof
amino group, the nature of the group associated with the amine, the length of the chain carrying the
functions, and the presence of an ethano bridge versus that of an etheno bridge. It was found that
of the quaternary ammonium group, which could be detrimental to cross membranes, lowers the
activity. Indeed, these functional groups can be ranked in a decreasing order of activity as:
amino>hydroxyl>carbamate>carboethoxy>carboxylic acid. The double bond in the ethenoan-
thracene derivatives versus the ethanoanthracene derivatives decreases the potentiating activity.
Bhaduri et al. have earlier reported a novel pyrrolidinoaminoalkane (CDRI 87/209), as a
chloroquine resistance reversal agent both in vitro and in vivo.129In search of newer molecular
and evaluation of 1-(30-diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines as
chloroquine resistance reversal agents.130Among the compounds screened in vitro, compounds
41–43 (see Fig.7) were found tobe completeinhibitorsofparasite heme oxygenasebuttheydid not
inhibit the host enzyme, while compound 41 inhibited both parasite and host heme oxygenase. The
compounds were also evaluated for their in vivo heme oxygenase inhibitory activity in P. yoelii
Figure 7. Chloroquineresistancereversalagents.
found to be higher in resistant plasmodia. Of all the compounds, 41 showed complete inhibition of
both the enzymes, while compounds 42 and 43 exhibited potent inhibition. Upon the basis of these
observations compound 41 was selected for detailed in vivo evaluation for chloroquine resistance
reversal activity. The possible mode of action of compound 41 relates to the heme or hemozoin
degradation pathway and more specifically to heme oxygenase of the chloroquine-resistant parasite
levels of the heme-chloroquine complex that is lethal to the parasite.
treated malaria with methylene blue (44)131after observing the dye’s selective staining of
intraerythrocytic plasmodia in vitro (see Fig. 8). Schuleman et al.132subsequently found that the
activity of methylene blue could be improved by replacing one of the dye’s methyl groups with the
basic dialkylaminoalkyl chain to give compound 45. The attachment of the basic dialkylaminoalkyl
chain to a quinoline ring producing the first 8-aminoquinoline antimalarial 46. The activity of 46
triggered an interest, and massive investigation of the 8-aminoquinolines, led through thousands of
variants to the first clinically used synthetic antimalarial, pamaquine (47) but its level of toxicity
warranted further investigations. In an effort to improve the therapeutic index of pamaquine,
hundreds of 8-aminoquinolines were synthesized that include pentaquine (48), isopentaquine (49),
SN-3883 (50), and primaquine (51), which ultimately became as the drug of choice for the radical
cure of the relapsing malaria (see Fig. 8).133Quinocide (52), an isomer of primaquine is later
synthesized and used in Eastern Europe and the USSR, however, is more toxic.133Primaquine has a
broad range of antimalarial activity. In addition to its radical curative activity, drug is a causal
prophylactic, a gametocytocide, a sporontocide, and can be produced at low cost.134Despite these
attributes, primaquine is far from being an ideal antimalarial. It is a poor blood-schizontocide, and
side effects such as hemolysis, methemoglobinaemia, and gastrointestinal distress. Patients with a
genetic deficiency of glucose-6-phosphate dehydrogenase (G-6PD) are particularly prone to
hemolyticreactions.133Theneed toadminister primaquine in divideddoses over anextended period
(15mg/day for14 days) has further limitedits clinical use.Primaquine is,therefore,beingusedwith
some trepidation with the desire for a safer, more effective congener.
their metabolites that are active compounds. In an early study, it was found that primaquine was
inactive against P. gallinaceum, whereas its metabolites were active. The 6-hydroxy and 5,6-
dihydroxyderivativeswerethelikelymetaboliteswhile 5,6-quinolinequinones were alsospeculated
Figure 8. 8-Aminoquinolinesandsomeputativemetabolites.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
to be active metabolites of these drugs. It has been recently shown that in rodents, a single dose of
primaquine is excreted in the urine in about 24 hr, mainly in the form of metabolites; about 4%
remains unmetabolized and only a very small quantity is retained in the tissues. The drug is rapidly
been identified as 8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline,135a product reported
earlier by the microbiological degradation of primaquine. To verify these speculations, Strother
et al.136,137synthesized many putative metabolites of primaquine, which were previously isolated
from the urine of dogs, and evaluated their antimalarial activity. However, all of these compounds
series of the possible metabolites 53–54 (see Fig. 8) of 8-aminoquinolines and evaluated their
antimalarial activity. Compounds 53–54 were evaluated for their radical curative antimalarial
activity against P. cynomolgi in rhesus monkeys at a dose of 3.16 mg/kg ?7 days. However, all of
these compounds were found to be highly toxic with no apparent activity. These findings further
confirm the fact that 8-aminoquinolines are themselves active species rather than their metabolites,
with the possibility of side effects arising from the metabolites.
Although, tremendous amount of research efforts are given for the development of a safer 8-
aminoquinoline, the success are quite few with only two compounds showing promise. Immense
partially fulfills these objectives (see Fig. 9).139Initial clinical studies show that WR 238605 is well
tolerated, has a much longer half life than primaquine and may have considerable promise as a
prophylactic drug for P. falciparum malaria in addition to its potential as a radical curative drug.
Tafenoquine, based on its promising broad-spectrum of activities, has been selected as a potential
antirelapse antimalarial drug to replace primaquine. Preclinical studies against the sporozoite-
induced P. cynomolgi B infection in rhesus monkeys established tafenoquine as an effective
days.140,141Additional studies carriedoutwithWR 238605 have shown the drug’sefficacyas causal
prophylactic agent in simian malaria model at a dose of 0.316 mg/kg ?3 days. Likewise, this
compound also has shown gametocytocidal activity with a single dose of 2.0 mg/kg, successfully
Figure 9. Recent8-aminoquinolines.
inhibiting oocyst development in mosquitoes. The compound also exhibits a significant blood-
schizontocidal activity against two simian malaria parasites, P. cynomolgi and P. fragile at a dose of
indicates that on CD100basis, the antirelapse curative dose is 3.16 times lower than that of
primaquine, whereas the causal prophylactic CD100of tefenoquine is 5.63 times lower. As a blood-
schizontocide, tafenoquine protected 83.3% of the P.cynomolgi Binfections and 91.7% of P.fragile
infected monkeys at 1.0 mg/kg dose, showing nearly 10 times higher activity compared to
primaquine. As a gametocytocidal agent, both tafenoquine and primaquine exhibited identical
activities at 2 mg/kg. Tafenoquine has also undergone detailed preclinical toxicity evaluation,
including methemoglobin producing toxicity tests in beagle dogs. Tafenoquine produced moderate
amount of methemoglobinaemia, which was reversible, indicates it has the potential to replace
primaquine based on its higher therapeutic index. Tafenoquine thus proves promising towards
the parasite residing in the hepatocytes and the red blood cells.139–141
Trouet et al.142postulated that linking the primaquine to small peptide reduces its toxicity and
in liposomes reduced its acute lethal toxicity 3.6-fold but left the efficacy unchanged. Thus,
Hofsteenge et al.144considered that a more specific target could be achieved by linking the drug to
macromolecular carrier protein. They thought that the linkage between the drug and protein carrier
should be relatively stable in the blood stream but should readily be cleaved inside the target cell. A
thiol containing primaquine derivative 8-[4-(2-amino-3-mercaptopropionamido)-1-methylbutyla-
activityin mice inoculated with P.berghei.Thecasualprophylactic activityofthe conjugate 56with
the lactosaminated serum albumin was two times higher than that of free drug; the mean causal
prophylactic doses CPD50were 6 and 13 mg of primaquine base per kg, respectively. Its acute lethal
toxicity has decreased at least 6.5-fold. The therapeutic index of this conjugatewas at least 12 times
higher than that of the free drug. This allowed the administration of a dose that cured 100% animal
(17.5 mg of primaquine), in a single dose. With unmodified serum albumin the conjugate showed an
strongly reduced toxicity.
as potential antimalarials (see Fig. 9). All the compounds were tested for radical curative activity
The most active analog 57 (R1¼ D-valine) showed blood-schizontocidal activity at 90 mg/kg but
wastoxicat180and400mg/kg.Atalowerdoseof0.316mg/kg,57(R1¼ D-valine) didnotrelapse
for 79 days against P. cynomolgi infected monkeys.
A general deficiency of 8-aminoquinolines is their tendency to produce methemoglobinaemia.
is greater than the usual 1–2%. In methemoglobin, the normal ferrous iron is oxidized to the ferric
state, which is incapable of transporting oxygen. Methemoglobinaemia can thus lead to anoxia and
death. Synthesis of a series of cyclic enaminone analogs of primaquine as prodrugs resulted in
aablaqiuine (58), which was found to be as activeas primaquinewith slightly reduced toxicity when
assayed for radical curative activity against P. cynomolgi in rhesus monkeys (see Fig. 9).146,147The
its safety profile.148MetHb toxicities of primaquine and aablaquine were compared in beagle dogs.
MetHb, whereas aablaquine at 3.75 mg/kg ?7 days produced only 3.2-fold increase. Thus, MetHb
toxicity induced by aablaquine is three to four times less compared to primaquine. Acute toxicity
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
for primaquine. Subacute toxicity studies in two hosts (rats and monkeys) have also shown that the
compound is safe and does not produce any toxic manifestations even after administration for 90
administered daily for 7 days, is safe, well tolerated and offers advantage over primaquine.
Aablaquine also showed causal prophylactic activity at 3.16 mg/kg ?3 doses against sporozoite-
induced P. cynomolgi B infection in rhesus monkeys.18This compound also exerts antirelapse
activity at 1 mg/kg ?7 days. The drug’s exact mode of action is not fully known. However, it is
believed to be acting by inhibition of protein synthesis in protozoa, and by indirectly inhibiting
as potential antirelapse and causal prophylactic drug that would be safe for the treatment of relapses
of P. vivax malaria.
Jain et al.149synthesized some amino acid derivatives 59 (see Fig. 9) of 4-mono- and 4,5-
disubstituted-8-aminoquinolines. These compounds were tested for their radical curative activity
against P. cynomolgi in rhesus monkeys, and subacute toxicity in beagle dogs. Compounds
59 (R ¼ H, R1¼ CH3, R2¼ Ala), 59 (R ¼ H, R1¼ CH3, R2¼ Lys), and 59 (R ¼ OC6H13,
R1¼ CH3, R2¼ Ala) found to be more active and less toxic than primaquine.
tissue-schizontocidal activity with improved blood-schizontocidal activity and reduced MetHb
toxicity. Jain et al.150synthesized several N8-(4-amino-1-methylbutyl)-5-alkoxy-4-ethyl-6-meth-
oxy-8-quinolinamines and their pro prodrug analogs 59 (R ¼ OC3H7to OC8H17, R1¼ C2H5,
R2¼ linker) prepared by covalently linking redox-sensitive and esterase-sensitive linkers through
the amide linkage. The most effective 8-quinolinamines of the series have exhibited in vitro and in
vivo biological efficacy superior to that of the standard drug chloroquine against both drug-sensitive
alanine, lysine, ornithine, and valine conjugated to primaquine and other 8-quinolinamine
antimalarials for their blood-schizontocidal antimalarial activity evaluation. These analogs were
synthesized with primary objective to protect primary amino function of primaquine against
metabolic process that leads to inactive metabolite 4-(6-methoxy-quinolin-8-ylamino)-pentanoic
acid. The analogs 59 were examined for blood-schizontocidal activity in vivo against P. berghei
(drug-sensitive strain) and P. yoelii nigeriensis (highly virulent multidrug-resistant strain) infected
mice models (see Fig. 9). Derivative 59 (R ¼ OC4H9, R1¼ C2H5, R2¼ Lys) showed curative
activity at 5 mg/kg in the P. berghei test and emerged as the most active compound, while 59
(R ¼ OC5H11, R1¼ C2H5, R2¼ Lys) exhibited curative activity at 50 mg/kg against P. yoelii
nigeriensis in mice and emerged as the most potent analog against multidrug-resistant strain. More
recently, primaquine-statine conjugates 59 (R ¼ R1¼ H, R2¼ statine-based inhibitor of
plasmepsin II) were synthesized by Romeo et al.152The most active compound displayed IC50
value of 4 mM versus a P. falciparum strain in vitro (see Fig. 9).
One of the main metabolic degradation pathways known for the quinoline moiety results in
oxidativebiotransformation at the C-2 position, and convertsit to 1H-2-oxoquinoline. This pathway
is supported by the isolation of 2-quininone (known to display phototoxic side effects) as one of the
major metabolite of quinine. Furthermore, high antimalarial activity associated with mefloquine is
derivedby theplacement ofaCF3groupatthe C-2positionofthe quinolinering, which preventsthe
aforementioned transformation. Upon the basis of these observations, Jain et al.153–155hypothesize
in primaquine may produce analogs with improved therapeutic efficacies due to their inability to
60 (see Fig. 9), displayed potent invitro antimalarial activity (IC50¼ 39 ng/mL), superior to that of
chloroquine (IC50¼ 113 ng/mL). Compound 60 also displayed promising in vivo antimalarial
efficacy against P. berghei when given orally at 25 mg/kg (6/6 cures) and 10 mg/kg (4/6 cures),
whereas it displayed 100% curativeactivity at a dose of 100 mg/kg and subsequently cured4/6 mice
at a lower tested dose of 50 mg/kg versus highly virulent multidrug resistant P. yoelii nigeriensis
strain. Upon in vivo MetHb-inducing properties estimation in Mastomys coucha, compound 60 did
not show any increase in MetHb compared to 3.38% increase induced by primaquine. Derivative 60
represents the discovery of a highly potent blood-schizontocidal antimalarial completely devoid of
MetHb toxicity and is currently undergoing preclinical studies. Finally, Moreira et al.156,157
described syntheses of imidazolidin-4-one derivatives 61 (see Fig. 9) of primaquine as potential
berghei in Anopheles stephensi mosquitoes in vivo, affecting the development of oocysts.
E. Quaternary Ammonium Salts
Extensive research on intraerythrocytic Plasmodium phospholipid metabolism revealed potential
of phosphatidylcholine, the major phospholipid of Plasmodium.158
Calas et al.159–161identified some essential parameters, for example electronegativity and
lipophilicity, required for polar head analogs to inhibit P. falciparum phospholipid metabolism,
leading to parasite death. QSAR analyses have indicated that lipophilicity is a major relevant
parameter for potent antimalarial activity. In this context, Calas et al. synthesized various cationic
choline analogs consisting of mono- and bis-quaternary ammonium salts 62–63 (see Fig. 10) with
distinct substituents of increasing lipophilicity. It was found that for mono-quaternary ammonium
salts, an increase in lipophilicity around the nitrogen was beneficial for antimalarial activity, since
polar head substitution (methyl, ethyl, hydroxyethyl, and pyrrolidinium), increasing the alkyl chain
length from 6 to 12 methylene groups always led to increased activity. The highest activity was
observed for N,N,N-tripropyl-N-dodecyl substitution of nitrogen (IC50¼ 33 nM).159In contrast,
with bisquaternary ammonium salts, an increase in lipophilicity of the alkyl chain between the two
nitrogen atoms (from 5 to 21 methylene groups in the nitrogen spacer) constantly increased the
21 methylene groups in the nitrogen spacer) exhibited an IC50as low as 3 pM, while 64 showed IC50
value of0.65 nM.Morerecently,Calasetal.162synthesized threeadditional seriesofmono-andbis-
thiazolium salts 65, in which polar heads are linked either from the nitrogen atom or from the C-5
position of the thiazolium ring. Seven derivatives showed IC50values in the range between 0.65 and
results indicate that developing a pharmacological model for antimalarial compounds through
choline analogs is a promising strategy.
F. New Structural Classes of Antimalarial Agents
Wiesner et al.163have reported 2,5-diaminobenzophenones as a novel lead structure of antimalarial
agents that are active against multiresistant strains of P. falciparum. They have tested a library of
compound 66 lead to the 4-propoxycinnamic acid derivative 67 with more than 10-fold improved
Figure 10. Quaternaryammoniumsalts.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
antimalarial activity (IC50¼ 340 nM).164,165Replacing the 4-propoxyphenyl residue of the
The exploratory study to address the influence of structural variation of the acyl residue at the 2-
amino function of the benzophenone core structure led to inhibitors that have a chlorine (69) or a
bromine (70) in the para position, which are equipotent (69, IC50¼ 64 nM; 70, IC50¼ 70 nM) to
methyl derivative 68.167Replacement of the para-methyl group by trifluoromethyl yielded the most
active compound 71 of this class (IC50¼ 47 nM).167Inhibitor 68 carries a polar group in the para
position of the terminal phenyl residue and this led to the hypothesis that the presence of a polar
moiety with hydrogen bond acceptor properties at the para position of the terminal phenyl group
might increases the activity. Thus, replacement of the nitro group of lead structure 68 by a
trifluoromethyl residue led to an equipotent compound 72 with an IC50value of 77 nM,168while
replacement of the nitro group by a methylsulfonyl moiety (compound 73) resulted in a twofold
improvement in antimalarial activity (IC50¼ 37 nM). The lower activity of the corresponding
ethylsulfonyl derivative 74 (IC50¼ 60 nM) may be explained by the increased bulkiness of this
moiety (see Fig. 11).
4-Aminopiperidines were reported by Brinner et al.169as a novel class of compounds that
sensitive(3D7)andresistant(W2) strainsofP.falciparum.Compound76 showed a15-foldincrease
in activity with an IC50of less than 60 nM against a multidrug-resistant strain of P. falciparum when
compared to the initial lead compound 75,while improving the activity to toxicity ratio from 11:1 to
over 78:1 (see Fig. 11).170Whereas compound 77 showed over a 10-fold increase in activity with an
IC50of75nM andanimprovedactivitytotoxicityratio of100:1.These compoundshaveacceptable
logD values and were reasonably metabolically stable in both human and murine liverS-9 fractions.
Since the discovery of the non-phototoxic, but highly effective antimalarial agent mefloquine,
the trifluoromethyl group has aroused considerable interest. Fluorine atom has high ionization
potential, high electronegativity, small size, and tightly held non-bonding electron pairs in
comparison with chlorine. Halofantrine also contains a trifluoromethyl group, compares favorably
advantage ofthisfact,Kgokong etal.171reported thatthe 1,2,4-triazino[5,6b]indolederivativeswith
a trifluoromethyl group at position 6 exhibits increased in vitro activity when compared to the
unsubstituted analogs. Thepresence ofthetrifluoromethylgroupinthe5H-1,2,4-triazolo[10,50,2,3]-
1,2,4-triazino[5,6b]indole ring system leads to promising compound 78 (see Fig. 12). Compound 78
exhibits in vitro activity against the chloroquine-sensitive strains (IC50¼ 86 mM).
Novel 5-substituted amino-2,4-diamino-8-chloropyrimido-[4,5-b]quinolines172were designed
were synthesized and evaluated by Rane’s test for blood-schizontocidal activity in mice infected by
P. berghei. Based on the mean survival time (MST) data, 79–81 (see Fig. 12) displayed curative
Figure 11. Newstructuralclassesofantimalarials.
potential comparable to chloroquine. It was observed that among the aminobenzene-sulfonamides,
the compound with bulky substitution (compound 79) was curative while among the substituted
aminophenols, the disubstituted compounds (80–81) were curative at 20 mg/kg. It shows that the
nature and size of the substituents at the 5-amino function in the pyrimidoquinoline class of
compounds significantly influences the antimalarial activity.
Thehighthroughputinsilicoscreeningofavirtuallibraryintothe structure oftheP.falciparum
lactate dehydrogenase (LDH) with the 4SCan technology yielded a series of biphenyl urea
compounds. These compounds were chemically optimized to a new structural class of sulfonyl-
phenyl-ureido benzamidines as potent antimalarial agents.173A dramatic increase in activity was
achieved with 2,3,6-trifluoro substitution of the benzyl ring (82, IC50¼ 17 nM) and a more polar p-
sulfonylamino substituent on the benzyl ring further increased activity (83, IC50¼ 7 nM) (see
chloroquine, and almost as active as amicarbalide (IC50¼ 5 nM). The compounds displayed
nanomolar activity in cell culture assay, however are micromolar inhibitors of P. falciparum
plasmepsin suggesting an unknown target other than DNA binding.
N,N0-spacer-linked oligomeric derivatives were prepared starting from three monomeric
ergolines (terguride, festuclavine, and pergolide) using different aliphatic or arylalkyl spacers and
found that N-1,N-10-spacer-linked dimerization substantially enhanced their antiplasmodial
activity.174The best activities were observed for compounds showing a distance of six carbon
spacer-linkeddepropylpergolidedimer 84(seeFig.13)exhibitedthe highest antiplasmodialactivity
of all compounds tested (IC50values ¼ 0.14 and 0.13 mM against poW and Dd2, respectively).
Unfortunately, 84 displayed toxic effects against the mouse fibroblast cell line NIH 3T3
(IC50¼ 0.1 ? 0.09
leakage ¼ 15.58 ? 0.87 mkat/L; GSH-level ¼ 8.15 ? 0.78 nmol/106cells). However, the N-1,N-
10-spacer-linked trimer of festuclavine (85), and tetramer of terguride (86) possessed remarkable
antiplasmodial activities (IC50¼ 0.54 and 1.53 mM, respectively, against Dd2) and were found free
of cytotoxic effects (see Fig. 13).
87 (0.37 mM), 88 (0.68 mM) and 89 (0.69 mM) against leishmania, P. falciparum D6 clone and W2
clone, respectively (see Fig. 14). The entire series of compounds contain a 4-benzyloxy group in the
aromatic ring and appears to enhance antimalarial activity in vitro. These compounds might
eventually prove useful as broad-spectrum antiparasitic agents.
Egan et al.176have synthesized a series of novel water-soluble 2,20-bipyridyl and 1,10-
phenanthroline benzoylthiourea complexes of platinum(II) ligands. All of these compounds are
mM)and alsoagainsthuman hepatocytesat 100
Figure 12. Newstructuralclassesofantimalarials.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
square-planar mixed-ligands and were found to form moderately strong complexes with
ferriprotoporphyrin IX in 40% aqueous DMSO (log K ranging from 4.81 to 6.24). The complexes
also inhibit b-hematin (synthetic hemozoin or malaria pigment) formation in acetate solution. The
most active antimalarial compound of the series is 90 (see Fig. 14) displayed equally strong activity
against D10 chloroquine sensitive and K1 chloroquine resistant strains of malaria parasite with an
selectivity indices >85 after cytotoxicity evaluation studies.
Prompted by the role of sugars in drug targeting and their good pharmacokinetic properties as
well as the chelating ability of hydroxamates, Mishra et al.177synthesized glycosylated hydroxamic
acids as new antimalarial agents and found most active compound 91 showing 100% inhibition of
schizont maturation at 2 mg/mL (see Fig. 14). General SAR indicates that compounds with long
straight alkyl amines were more active than the rigid or cyclic amines.
The invitro antiplasmodial activity of some dihydrostilbenamides, phtalazinones, imidazo[2,1-
a]isoindole, and pyrimido[2,1-a]isoindole derivatives related to the natural dihydrostilbenoid
isonotholaenic acid show discrete activity against Plasmodium, with representative members
showing IC50values within the 1–50 mM range.178Compounds having the imidazo[2,1-a]isoindole
skeleton were the most active and compound 92 (IC50¼ 0.017 mg/mL) (see Fig. 15) was found as
potent as chloroquine (IC50¼ 0.013 mg/mL).
In a serendipitous result, pharmacophores generated for the database searching for new non-
nucleoside inhibitors of the HIV-1 reverse transcriptase enzyme unearthed 12 new lead compounds
which were active against the P. falciparum.179The most potent compound in this wide structurally
diversified series was 93 with an IC50of 1.2?10?6M (see Fig. 15). Derivative 93 is structurally
related to gossypol known to possess antimalarial properties. Gossypol derivatives have been
reported as lactate dehydrogenase inhibitors and 93 might target the same enzyme.
The triterpenoid lupeol possesses a wide range of activities that include urolithic, anticalciuric,
and antimalarial activity against chloroquine-resistant P. falciparum. Thus, lupeol provides an
Figure 13. Newstructuralclassesofantimalarials.
Figure 14. Newstructuralclassesofantimalarials.
for their antimalarial activity. The most active compound 94 displayed ninefold increase in activity
compared to lupeol with an MIC value of 13.07 mM (see Fig. 15).
A class of new pyrimidinyl peptidomimetic agents in which core structure consists of a
substituted 5-aminopyrimidone ring and a Michael acceptor side chain were synthesized and
evaluated for invitro antimalarial activities against P. falciparum.181The new compounds exhibited
potent in vitro growth inhibitory activity (IC50¼ 10–30 ng/mL) against both chloroquine sensitive
most active compound and displayed antimalarial efficacy comparable to that of chloroquine.
The preliminary results indicated that these compounds exhibited in vivo antimalarial activity at
40–160 mg/kg dose and prolonged the life span of infected mice up to 16–24 days.
P. falciparum utilizes alternative mevalonate-independent DOXP/MEP pathway for isoprenoid
biosynthesis. The DOXP reductoisomerase is a key enzyme in the DOXP/MEP pathway and its
inhibition with fosmidomycin leads to substantial antimalarial activity in vivo. The presence of
for antimalarial drug discovery. A series of novel 30-amido-30-deoxy-N6-(1-naphthylmethyl)ade-
and were tested for antimalarial activity versus the Dd2 strain of P. falciparum and DOXP
reductoisomerase inhibition.182The results revealed that these adenosine derivatives displayed
activity against the P. falciparum parasite in the low-micromolar range. The most active compound
96 (see Fig. 16) of this series displayed an IC50of 2.8 mM and 75% of DOXP inhibition.
Bhattacharjee et al.183developedawidely applicable three-dimensional QSAR pharmacophore
model for antimalarial activity from a set of 17 substituted antimalarial indolo[2,1-b]quinazoline-
and multidrug-resistant P. falciparum strains. The pharmacophore that contains two hydrogen bond
acceptors (lipid) and two hydrophobic (aromatic) features, was found to map well onto many
well-known antimalarial drug classes including quinolines, chalcones, rhodamine dyes, Pfmrk
Figure 15. Newstructuralclassesofantimalarials.
Figure 16. Newstructuralclassesofantimalarials.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
cyclin-dependent kinase inhibitors, malarial FabH inhibitors, and plasmepsin inhibitors. The
and enabled custom designed synthesis of new potent analogs, most active of which 97 (see Fig. 16)
displayed IC50of 0.43 ng/mL versus P. falciparum.
G. Iron Chelators
The idea that iron chelation has a role in eliciting antiplasmodial effect emerged from the awareness
that many microbial pathogens depend on host-derived iron for virulence. Iron is essential for
parasitic growth and multiplication, and particularly critical enzyme, ribonucleotide reductase,
trial of the chelation therapy with desferrioxamine (98) in cerebral malaria quickly reduced the
symptoms of parasitaemia.184Inspired by these key investigations, a diverse range of iron chelators
has been synthesized, tested and found to possess antimalarial activity. For example, tris-
hydroxamate siderophores including tripodal hydroxamates (99),185,1863-hydroxypyridin-4-ones
(100),187phenolic and catecholic ligands including HBED (101),188desferrithiocin (102),189and
daphnetin (103),190a dihydroxycoumarin class of compound (see Fig. 17).
When parasites invade erythrocytes they generate low molecular weight iron pool, which must
this pool, thus reducing the rate of incorporation of iron into critical redox proteins and
metalloenzymes. This mechanism is likely to be associated with the hexadentate chelators, for
instance desferrioxamine (98), synthetic trihydroxamates (99), and HBED (101). It is well known
as the dissociated heme is potentially toxic to the parasite, due tothegeneration of hydroxyl radicals
under aerobic conditions.
Van Zyl et al.191proposed that desferrioxamine (98) somehow disrupts the hemozoin complex,
thereby generating toxic levels of the dissociated heme moieties. Interestingly, the highly effective
be noted however, that both desferrioxamine (98) and 3-hydroxypyridin-4-ones (100) inhibit the
antimalarial activity of artemisinin.192It is conceivable, therefore, that the selectivity of artemisinin
Figure 17. Ironchelators.
for infected erythrocytes is not associated with the presence of hemozoin, but rather, the elevated
induced by the simultaneous use of two chelators, typically one being hydrophilic and the other
hydrophobic and therefore, highly permeable to the parasite.193
H. Target-Based Antimalarial Agents
Target-specific antimalarial agents have been reviewed recently in considerable details.194,195Our
discussion on target-specific antimalarial agents is limited to significant advances made in the past
1. Plasmepsin I and II Inhibitors
The aspartic proteases, plasmepsins I, II, IV, and Histo-Aspartic-Protease (HAP), are present in the
food vacuole of P. falciparum. These enzymes were shown in vitro to be capable to proteolytically
cleave hemoglobin and thus are necessary for the survival of the parasite during the blood stage of
their life cycle. The most attractive target from the group of four aspartic proteases is plasmepsin II
(Plm II) and is recently reviewed.194Inhibitors of Plm II based on a C2-symmetric mannitol scaffold
were found to be selectiveversus the most homologous human aspartic protease cathepsin D. It was
determined experimentally that the stereochemistry of the central mannitol core is crucial for
inhibitory activity with a strong preference for RRRR configuration.196The enzyme tolerates a wide
variety of substituents, ranging from bromine to styrene. These compounds are inactive in the
fold. Hence Plm II can be considered as a reasonable target for future antimalarial drugs.
The drawbacks of the Plm inhibitors are obviously their peptidic backbone and their high
molecular weight, which certainly prevents them from having good pharmacokinetic properties and
than fourfold selectivity for either of the Plm could be achieved. The compounds exhibited high
104 (see Fig. 19), despiteKivalues of 115 nM (Plm I) and 121 nM (Plm II). An expansion of the P10-
side chain results in increased affinity and the most marked effect is observed when hydrogen in the
paraposition is exchanged with bromine, leading tomorethan a 20-fold increase in Plm I inhibitory
activity. The rigid biphenyl substituents in 104 seem to be accommodated easily in the flexible S10-
pocket of both Plm I and II and the high selectivity ratio versus cathepsin D is retained. Compound
104 suppressed parasite growth completely at 5 mM and displayed an ED50of 1.6 mM. The best dual
PlmI/Plm IIinhibitor,compound 105(see Fig.19)ofthis series exhibitedKivalues of0.8and6nM,
respectively and was the most active inhibitor of parasite growth in cell culture.200
Dahlgren et al.201have synthesized sets of libraries from novel reversed-statine isosteres,
Figure 18. A:Structuralrequirementsofhydroxyethylamine-basedinhibitorofplasmepsinIandplasmepsinII;(B)generalstructure
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
configuration in this carbohydrate-based template series is required to achieve Plm I inhibitory
is preferred in terms of potency. Furthermore, 106 exhibited Kivalues of 2.7 and 0.25 nM,
respectively, and displayed >100-fold selectivity against Cathepsin D.202
(see Fig. 20) exhibited promising activity towards both Plm I and II. Additionally, presence of the
in terms of potency. To assess the influence of chirality on inhibitor activity, the potent aza-based
inhibitor 107 was selected and all stereoisomers (regarding the central core) of this inhibitor were
synthesized and Kivalues were determined. Surprisingly, among all the stereoisomers, the best
inhibitor 108 (see Fig. 20) has the (R,S) syn configuration in the central part of the molecule and
exhibited invitro activity of 98% inhibition at 5 mM for Plm I (Ki¼ 250 nM) and 74% inhibition at
5 mM for Plm II (Ki¼ 1.4 nM). In another study, Greenbaum et al.203reported a series of
P. falciparum, respectively.
2. Farnesyltransferase Inhibitors
Recent studies have suggested that protein farnesyltransferase (PFT) is a promising target for the
inhibitors exhibit potent antimalarial activity against P. falciparum in vitro. In this study FTI-2148
Figure 19. PlasmepsinIandplasmepsinIIinhibitors.
Figure 20. PlasmepsinIandplasmepsinIIinhibitors.
(110, R ¼ H) (see Fig. 21), one of the most potent mammalian PFT inhibitors (IC50¼ 1 nM),
2153 (110, R ¼ CH3) potently inhibited P. falciparum growth with an ED50¼ 2 mg/mL. It is likely
of the free acid. Guided by these findings, a series of ester prodrugs of FTI-2148 was synthesized to
investigate the effect of ester moiety on antimalarial activity.205Evaluation against P. falciparum in
red blood cells showed that the ester derivatives exhibited significant antimalarial activity, and 110
(R ¼ CH2C6H5) exhibited the best inhibition (ED50¼ 150 nM). Additionally, it displayed
significant in vivo activity and was found to suppress parasitemia by 46.1% at a dose of 50 mg/kg/
day against P. berghei in mice. The enhanced inhibition potency of the esters is consistent with
improved cell membrane permeability compared to that of the free acid. The results suggest that
protein farnesyltransferase is a valid antimalarial drug target and the best antimalarial activity of
these compounds derives from a balance between the hydrophobic character and the size and
conformation of the ester moiety.
3. Pfmrk Inhibitors
A family of protein kinases [cyclin-dependent kinases (CDKs)] that control cell cycle progression
has been the potential targets for drug development. Pfmrk is a well-characterized plasmodial CDK
to inhibit Pfmrk, Li et al.206synthesized compounds containing lactam moiety with five different
structural classes as potential Pfmrk inhibitors. The most potent inhibitor is a 3-phenylquinolinone
the micro molar range. Further studies led to development of an in silico pharmacophore model by
Waters et al.207which allowed identification of several potent Pfmrk-specific inhibitors through 3D
database searches by adopting CATALYST procedures. The best compound 112 (see Fig. 21) of this
series has an IC50of 2.5 mM in the test model.
4. AdoHcy hydrolase Inhibitors
S-Adenosyl-L-homocysteine (AdoHcy) hydrolase, responsible for the hydrolysis of AdoHcy to
adenosine and L-homocysteine, has been recognized as a new target for antimalarial agents. The
malaria parasite hasaspecificAdoHcyhydrolase, which isessential forparasite proliferation andits
inhibition provides a new avenue for antimalarial drug development. Several AdoHcy hydrolase
inhibitors, such as the carbocyclic nucleoside antibiotic neplanocin A (NPA), have been shown to
(60R)-60-C-methylneplanocinA (RMNPA,113)(see Fig. 22)that effectivelyinhibited thegrowth of
malaria parasites both in vitro and in vivo.208Compound 113 displayed an EC50of 1.0 mg/kg/day
againstP.bergheiinmice,which wassuperiortothatofchloroquine(EC50¼ 1.8mg/kg/day).Ithas
shown significant invitro activity with an IC50of 0.10 mM, which was greater than that of the parent
of KATO III cells (IC50¼ 1.1 mM) compared with NPA (IC50¼ 0.22 mM) and was completely
Figure 21. PFTandpfmrkinhibitors.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
inactive in Vero cells in a stationary phase; no cytotoxic effect on the cells was observed at
concentrations up to 1,800 mM of RMNPA.
5. Carbonic Anhydrase (CA) Inhibitors
P. falciparum encodes a a-carbonic anhydrase (CA) enzyme possessing catalytic properties distinct
investigated for in vitro inhibition of the malarial parasite enzyme (pfCA) and the growth of P.
falciparum.209Several inhibitors with affinity in the micromolar range (Ki¼ 0.08–1.23 mM) were
detected, whereas the most potent derivatives were the clinically used sulfonamide CA inhibitor
acetazolamide, and 4-(3,4-dichlorophenylureidoethyl)benzenesulfonamide (114) (see Fig. 22).
P. falciparum (IC50¼ 2 mM), whereas acetazolamide achieved the same level of inhibition at only
20 mM. The enhanced efficacy of this compound as compared to acetazolamide may be explained
by the fact that 114 is a more liposoluble and thus have a better membrane penetration. Indeed, by
inhibiting pfCA, a critical enzyme for the life cycle of the parasite, the synthesis of pyrimidines
mediated by carbamoylphosphate synthase is impaired in P. falciparum but not in the human host,
thus sulfonamide CA inhibitors have the potential for the development of novel antimalarial drugs.
6. DHFR Inhibitors
P. falciparum dihydrofolate reductase (pfDHFR) is an essential enzyme in the folate pathway and
for malarial therapy. Pyrimethamine and cycloguanil, the active metabolite of proguanil, are potent
DHFR inhibitors and are clinically used for P. falciparum malaria treatment. Unfortunately,
resistance of the parasite to these drugs occurred rapidly and hence, their clinical utility has been
drastically affected. The mechanism of resistance has been shown to be due to the various point
mutations of DHFR, including those at positions 16, 50, 51, 59, 108, 140, and 164.210The P.
falciparum resistance to pyrimethamine arising from mutation at position 108 of pfDHFR from
atom of the 5-p-Cl aryl group, which consequently resulted in the reduction in binding affinity
such as trimethoprim (TMP) derivatives, could avoid this steric constraint and should be considered
as new, potentially effective compounds.210These studies showed stacking of the aromatic
substituent with the phenyl side chain of Phe116. Evidently, this interaction led to better binding
extension of the hydrophobic side chain on the 5-benzyl moiety of 5-benzyl-2,4-diaminopyrimidine
(e.g., compound 115) (see Fig. 22) led to better binding affinitythan that of trimethoprim, especially
with benzyloxy substituents that were about 5- to 30-fold and 60- to 200-fold more effective against
Figure 22. StructuresofsomeAdoHcyHydrolyase,CA,andDHFRinhibitors.
wild-type and mutant enzymes, respectively (IC50values at micromolar range).210In addition,
compounds with 6-alkyl substituents showed relatively good antimalarial activities against the
parasites bearing the mutant enzymes.
The 2,4-diaminopyrimidine analogs bearing a m-Cl and an unsubstituted 5-phenyl group
together with long 6-alkyl substituents show high binding affinity with the wild-type, S108N,
and C59RþS108N DHFRs.211These compounds also exhibit IC50values against the resistant
10–25 timesmoreeffectivethan their corresponding parentcompounds.Themostactivecompound
of this series 116 (see Fig. 22) has an IC50of 0.06 mM against thewild-type pfDHFR. These analogs
have low to no toxicity in mammalian cells. Further studies led to identification of two potent
inhibitors 117 and 118 (see Fig. 22), which are equally active against wild-type pfDHFR (117,
Ki¼ 1.4 nM; 118, Ki¼ 1.6 nM; cycloguanil, Ki¼ 1.5 nM), and are about 100-fold more effective
againsttheA16VþS108Tmutantascomparedtocycloguanil(117,Ki¼ 17.8nM;118,Ki¼ 11.0nM;
atom at 30position of N-1 aromatic ring and is believed to have an important role in enhancing the
pathway,inhibitors offatty acid synthesis and inhibitors of glycolysisand apicoplast were discussed
in details earlier.213,214
apotentinhibitorofP.falciparumandisrecently reviewed.195Chalcones werewidelythoughttoact
against malarial cysteine protease, an enzyme used by the parasite for hemoglobin degradation.
Dom?nguez et al.215have reported phenylurenyl chalcones to have excellent antimalarial activity
However, the results indicate that chalcones exert their activity via multiple mechanisms, but not by
heme detoxification. To investigate the role of ferrocene in antimalarial activity, Wu et al.216have
synthesized several ferrocenyl chalcones with varying electronic and lipophilic characteristics and
found that the physicochemical properties of the ferrocene ring do not contribute significantly to the
antimalarial activity. Only the 4-nitro substitution on the phenyl ring markedly enhanced activity
(120, IC50¼ 5.1 mM) (see Fig. 23).
Recently, Xue et al.217have carried out the 3D QSAR analyses of antimalarial alkoxylated and
hydroxylated chalcones by Comparative Molecular Field Analysis (CoMFA) and Comparative
Similarity Indices Analysis (CoMSIA) to determine the factors required for the activity of these
compounds. They obtained satisfactory results after performing a leave-one-out (LOO) cross-
validation study with cross-validation q2and conventional r2values of 0.740 and 0.972 by the
CoMFA model, 0.714 and 0.976 by the CoMSIA model, respectively. The results provided the tools
more potent antimalarial agents.
Figure 23. Chalconesantimalarialagents.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
J. Natural Product Based Antimalarial Agents
the study of the plants as potential source of antimalarial agents. Natural product-based antimalarial
are recently reviewed.195Saxena et al.218have also critically reviewed natural sources and their
secondary metabolites recently for their antimalarial activity, and present review covers advances
made during past three years.
showed potent activity againstP.falciparum.Takasu and group219have further exploredthis area by
increase in antimalarial activity compared to the lead MVC. Introduction of an ethyl moiety on the
pyridine nitrogen atom of MVC resulted in a 39-fold increased activity and 2- to 3-fold decreased
cytotoxicity by quaternization, for example, compound 121 (see Fig. 24). Transformation of MVC
into its carbolinium salts produced 67-fold increase in activity and these results indicate that b-
carbolinium compounds containing p-delocalized lipophilic cationic structure show higher
antimalarial potency. Uys et al.220isolated three diterpene lactones from the plant Parinari capensis
comparable with that of quinine, however their high toxicity prevents them from further
investigation. A new antimalarial quassinoid orinocinolide (123) (see Fig. 24) was isolated from
and W2 (IC503.27 and 8.53 ng/mL versus 3.0 and 3.67 ng/mL, respectively), but4- and 28-fold less
toxic against VERO and HL-60 cells, respectively.221Murakami et al.222have synthesized 3,15-
dialkyl carbonates of bruceolide and found that methyl, ethyl, and isopropyl carbonates have
pronounced in vitro and in vivo antimalarial activity and increased life span of mice as compared
totheparentcompoundbruceolideandchloroquine(ED50of3,15-O-diacetylbruceolide ¼ 0.46mg/
kg, chloroquine ¼ 2.0 mg/kg).
In vitro antimalarial and cytotoxic tests of synthetic febrifugines demonstrated that compound
124 (see Fig. 24) had antimalarial activity against P. falciparum, of similar potencyto that of natural
product febrifugine, with high selectivity.223The results also suggest that basicity of both the 1- and
the 100-nitrogen atoms of febrifugine is crucial in conferring powerful antimalarial activity.
effects (ED50¼ 0.6 mg/kg). Thus, the metabolite 124 appears to be a promising lead compound for
the development of new types of antimalarial drugs.
Figure 24. Naturalproductbasedantimalarialagents.
compounds found to have IC50values of <0.1 mM against P. falciparum (strain K1), 5- to 10-fold
lower than that of 125, and showed two to four times higher cytotoxicity.224Compounds with a
halogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhanced
antiplasmodial activity. In mice infected with P.berghei,the 7-bromo-2-chloro and 2-bromo-7-nitro
derivatives of 125 suppressed parasitemia by >90% at doses of 25 mg/kg/day with no apparent
toxicity. A dose-dependent suppression of parasitemia was observed for 2,7-dibromocryptolepine
that of chloroquine and involves the inhibition of hemozoin formation, however, the studies indicate
that antimalarial activity of the analogs of 125 also involves other mechanisms in addition to the
inhibition of hemozoin formation.
9 . C O N C L U S I O NS
The resistance of malaria parasites towidely used drugs prompted an upsurge in the development of
new drugs with novel mechanism of action, and re-evaluation of the existing drugs to overcome the
resistance problem. An international consortium has successfully sequenced the genome of
the human malaria parasite P. falciparum. For malaria researchers, sequencing of genome of
P. falciparum has provided an unprecedented opportunity. The analysis of the genome sequence
should provide valuable information to identify promising new leads for vaccine development. A
number of new potential target pathways have already been identified and efforts to develop lead
Among the endoperoxides; arteflene, non-acetal C-10 carba dimers and synthetic 1,2,4-
development of some bisquinolines, which are free of toxic side effect, 4-anilinoquinolines and
modified chloroquine analogs may be helpful to obtain drug candidates that inhibit the growth of
of chloroquine drug resistance reversal agents, new structural classes of antimalarial agents, target-
based antimalarial agents, iron chelators, and quaternary ammonium salts in the past several years.
These studies have made some interesting and promising lead molecules available for further
optimization to provide compounds for clinical development. The research conducted on 8-
aminoquinolines gave important information regarding the structure–activity relationship of this
class of compounds. Out of all 8-aminoquinoline analogs discussed herein, 4-alkyl-5-alkoxy, 4-
methyl-5-phenoxy, and 2-tert-butyl primaquine analogs with high order of radical curative activity,
reduced/no MetHb toxicity and added blood-schizontocidal activity hold the greatest promise. One
larger therapeutic index than primaquine, and much slower elimination. The former property might
make tafenoquine a safer drug, but its therapeutic role is yet to be established. Aablaquine has
excellent antimalarial activity against tissue-schizonts of P. vivax. It has overall better therapeutic
index than primaquine and should be given along with chloroquine for complete cure of malaria. At
the same time, development of 2-tert-butylprimaquine has provided first 8-aminoquinoline
completely free of MetHb toxicity and is currently under preclinical development.
10 years, which offers exciting opportunities for developing novel, efficacious and probably more
safer antimalarial drugs. However, issues related to ADMET for several of these lead compounds
needed to be resolved. It would become easier for the interested pharmaceutical companies and the
properties of these analogs are well established.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT
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Suryanarayana Vangapandu is currently a postdoctoral research associate in Whitehead Biomedical Download full-text
ResearchCenter, Emory University, USA. He received his Ph.D. in Medicinal Chemistry in 2002 from National
Institute of Pharmaceutical Education and Research (NIPER), India, on 8-aminoquinolines as broad-spectrum
antimalarial agents. He then moved to the University of Mississippi to pursue postdoctoral studies, focusing on
design and synthesis of partial analogs of bruceantin as potent antimalarial agents and stereoselective total
synthesis of salvinorin A. At Emory, he has developed two orally acting drug candidates, the iodonoscapine for
bioimaging studies in cancer patients to determine the trajectory and organ distribution, and the noscapine
folate to achieve targeted drug delivery to treat breast cancer tumors. His research interests include broad-
spectrum antimalarial agents, G-protein-coupled receptors, particularly kappa-opioid receptors, and micro-
tubule interfering anticancer agents.
Meenakshi Jain received her Ph.D. degree in organic chemistry from the University of Lucknow in 1997. She
joined Dr Jain’s research group at NIPER in 1999 as research associate and subsequently was promoted to
scientist in 2001. Her current research interests include development of broad-spectrum antimalarial agents,
peptides of biological importance, and antituberculosis drug discovery.
Kirandeep Kaur received her M.Sc. Degree in organic chemistry from the Panjab University, Chandigarh,
research on the development of 8-quinolinamines as potential broad-spectrum antimalarial agents.
Premanand Patil received his M.S. (Pharm.) degree from the Department of Medicinal Chemistry in 2005 as a
member of Dr Jain’s research group working on 8-quinolinamine class of antimalarial agents. He is currently
pursuing his Ph.D. degree under the direction of Dr R. Kartha in the area of glycopeptides working on GM-1
anchor cyclic peptide at NIPER.
Sanjay Patel received his M.S. (Pharm.) degree from the Department of Medicinal Chemistry in 2005 as a
memberof Dr Jain’s research group at NIPER working on 8-quinolinamine class of antimalarial agents. He is
currently working as a lecturer at the L. M. College of Pharmacy, Ahmedabad.
of Lucknow (1984). He then joined the division of medicinal chemistry, Central Drug Research Institute,
Lucknow, India and obtained his Ph.D. in 1990 under the direction of Dr Nitya Anand. He then moved to the
research assistant professor and worked on the discovery of samatostatin antagonists. He returned to India in
1997, and joined Department of Medicinal Chemistry at NIPER as assistant professor and subsequently was
promoted to associate professor in 2002. His research interests include antimalarial agents, new structural
include synthesis of TRH peptides which are specific to TRH receptors subtype 1 and 2, and new synthetic
methodologies for unnatural amino acids.
ADVANCES IN ANTIMALARIAL DRUG DEVELOPMENT