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Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Vishnoi et al
www.pharmasm.com IC Value – 4.01 377
PHARMA SCIENCE MONITOR
AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES
ANTIMALARIALS FROM SEMISYNTHETIC ORIGIN
Nishi Gupta, Garima Vishnoi*, Ankita Wal, Pranay Wal
Research Scholar, PSIT Kanpur.
ABSTRACT Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. So, there is an urgent need for the development of new treatments for malaria. Nature and particularly plants used in traditional medicine are a potential source of new antimalarial drugs as they contain molecules with a great variety of structures and pharmacological activities. A large number of antimalarial compounds with a wide variety of structures have been isolated from plants and can play a role in the development of new antimalarial drugs. Ethnopharmacological approaches appear to be a promising way to find plant metabolites that could be used as templates for designing new derivatives with improved properties. The literature from 1998 to October 2012 is reviewed.The review present literature compilation from plant and marine extracts, alkaloids (naphthylisoquinolines,bisbenzylisoquinolines, protoberberines and aporphines, indoles, manzamines, and miscellaneous alkaloids) terpenes (sesquiterpenes, triterpenes, diterpenes, and miscellaneous terpenes) quassinoids, flavonoids, limonoids, chalcones, peptides, xanthones, Quinones and coumarines, and miscellaneous antimalarials from nature. The review also provides an outlook to recent semisynthetic approaches to antimalarial Drugs discovered from natural sources. Keywords: antiplasmodial; malaria; plant compounds; Plasmodium falciparum; traditional medicine. INTRODUCTION
Among all parasitic agents causing disease in humans, malaria is undoubtedly the single
most destructive and dangerous infectious agent in the developing world [1,2]. This vector-
borne infectious disease is a classic example of one that affects the productivity of
individuals, families and the whole society, since it causes more energy loss, more
debilitation, more loss of work capacity and more economic damage than any other
human parasitic diseases [3].
According to the World Health Organization (WHO), malaria remains a major health
problem and affects more than 225 million individuals, causing approximately 700
thousand deaths each year. Plasmodium falciparum is the most common causative
agent[4].
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Malaria is commonly associated with poverty, but is also a cause of poverty and a major
hindrance to economic development. There were an estimated 247 million malaria cases
among 3.3 billion people at risk in 2006, causing nearly a million deaths, mostly of
children under 5Years of age. It is widespread in tropical and subtropical regions,
including parts of the Americas, Asia and Africa. A total of 109 countries were endemic
for malaria in 2008, 45 within the WHO African region [5].Although human malaria
transmitted by female Anopheles mosquitoes has four Plasmodium species as its
aetiological agents – P. falciparum, P. vivax, P. ovale and P. malariae, the most
widespread and severe disease is caused by P. falciparum, which transiently infects the
liver before invading red blood cells of the mammalian host (Figure 1). Clinical
manifestations occur at the erythrocytic stage and can include fever, chills, prostration
and anaemia, as well as delirium, metabolic acidosis, cerebral malaria and multi-organ
system failure, which may be followed by coma and death [6-8].Quinine (1), an
aminoquinoline alkaloid isolated from the bark of Cinchona species (Rubiaceae) in 1820
by Pelletier and Caventou, is one of the oldest and most important antimalarial drugs and
is still used today. For almost three centuries, this alkaloid was the sole active principle
effective against Plamodium falciparum, and it has been considered the responsible, after
the Second World War, for the development of synthetic antimalarial drugs belonging to
the classes of 4- and 8-aminoquinolines, such as chloroquine and primaquine , among
others. Until recently, chloroquine was the only drug used for the treatment of malaria
[9,10].
Sporozoites, injected by Anopheles mosquitoes as they bite into the skin of mammalian
hosts, rapidly enter the blood circulation to reach liver hepatocytes, where they mature in
an entirely asymptomatic phase that lasts for approximately two weeks. Sporozoites of P.
vivax and P. ovale remain dormant (hypnozoites) in the human hepatocyte, where they
mature months to years later. These forms cause late malaria relapses under conditions
that are not well understood and are related to host stress and low primaquine (PQ) doses
[11]; such relapses require new drug treatment. The ideal antimalarial should destroy
sporozoites soon after they are inoculated into the vertebrate host by the mosquitoes.
However, no effective prophylactic anti-sporozoite drug is currently in use. Medicinal
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plants that hamper sporozoite development in host cells have been reported and these
plants appear to act as prophylactics, as further discussed below.
Life cycle of plasmodium –
Merozoites are liberated as merosomes from liver cells and then bud off from the
hepatocytes to invade and develop in red blood cells (RBCs) [12]. In the RBCs, the
parasites undergo asexual multiplication by schizogony and release merozoites, which
invade other RBCs, thereby reinitiating the blood-stage cycle [13]. The infected RBCs
(iRBCs) are responsible for the disease symptoms, i.e., high and periodic fever
(paroxysms), headaches (common to all human malaria species) and anaemia. The
symptoms of P. falciparum include cerebral malaria and respiratory distress (life-
threatening manifestations that are related to iRBC cytoadherence on microvascular
endothelial cells), blockage of deep capillaries with neurological symptoms and death.
The pathogenesis of severe malaria is not completely understood, although
proinflammatory cytokines are known to be involved [14] and these cytokines contribute
to the suppression of erythropoiesis, particularly in infected children [15].Evidence
supports the role of type 1 pro-inflammatory cytokines that increase the expression of
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adhesion molecules on vascular endothelium and iRBC sequestration [16]. Experimental
data demonstrate that E6446, a synthetic antagonist of nucleic acid-sensing tool-like
receptors (TLRs), diminishes the activation of TLR9 and prevents the increased
production of cytokines in response to Plasmodium infections, consequently preventing
severe malaria symptoms[17].
Plasmodium ovale and Plasmodium vivax can produce a dormant form, a hypnozoite,
that can cause relapses of the disease months and even years after the original disease
(relapsing malaria) because it's dormant in the liver cells. This is why it's important after
these infections to be treated with primaquine to kill the liver stages. Primaquine cannot
be used by people with a condition called G6PD-deficiency.
Established natural product antimalarial drugs-
Cinchona species are well known for their antimalarial properties and the constituent
alkaloid quinine is still acknowledged as an effective drug. Perhaps the less widely
known stereoisomer quinidine (Figure 1) is at least as potent as, and possibly more potent
than quinine [18]. The Chinese traditional treatment of malaria includes the use of
Artemisia annua (Compositae) and its active compound, artemisinin, which are currently
under considerable interest. (Figure 1) [19]. Artemisinin has a higher chemotherapeutic
index than chloroquine and is effective in chloroquine-resistant strains of human malaria
[20]. Another species used as an antimalarial drug in Chinese traditional medicine is
Dichroea febrifuga (Saxifragaceae) [21]. The active principle, febrifugine (Fig. 1) has been
used clinically against P. vivax and P. ovalebut its liver toxicity makes it unacceptable as
a useful antimalarial drug [22]. The use of plants for the treatment of malaria extends to at
least three continents including several countries in Africa [23], Americas [24] and Asia [25].
The NAPRALERT natural product database lists species from 152 genera which have
folklore reputations for antimalarial properties. It is important that using modern
biological techniques plants with these traditional representations are investigated in
order to establish their safety and efficacy, and to determine their value as the source of
new antimalarial drug.
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Artemisinin Sergeolide
N
N
O
O HN
OH
FEBRIFUGINE
Figure 1 Some examples of antimalarial natural products
The discovery of the first antimalarial treatment almost 400 years ago resulted from
observations that acutely ill patients were cured of malaria after treatment with infusions
of bark obtained from plants growing in the Peruvian Amazon [26]. Such activity
in Cinchona calisaya and Cinchona succirubra plants was later attributed to the alkaloid
quinine (QN), which was characterized by French chemists in 1820. QN remains
important for treating complicated P. falciparum malaria despite its toxicity when used
for extended periods of time [27,28].
Several 4-aminoquinolines were later synthesised based on the QN ring (Table 1).
Among them, chloroquine (CQ) is the safest and least expensive drug and most
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frequently was used to treat malaria worldwide as an essential component of the Global
Malaria Eradication Campaign. This campaign, launched in 1955, was based on the
treatment of malaria patients using CQ in association with mosquito control measures. In
the late 1960s, P. falciparum CQ-resistant strains appeared in Latin America and South
East Asia and gradually spread to most endemic regions. This campaign was interrupted
in the 1970s. Malaria had been eradicated in a few countries [29]. Most importantly, multi-
drug and cross-drug resistance among existing antimalarials, mainly the aminoquinolines,
were reported. CQ is now used only in drug combinations against P. falciparum or as the
schizonticide of choice to treat P. vivax and other human plasmodia species.
ANTIMALARIAL DRUG RESISTANCE-
The appearance of drug-resistance P. falciparum strains since 1960, in particular to
chloroquine, has made the treatment of malaria increasingly problematic in virtually all
malarious regions of the world [2]. Several researchers have dedicated efforts to the
development of new active compounds, especially from artemisinin (4), as an alternative
to chloroquine (2). Currently no single drug is effective for treating multi-drug resistant
malaria, and effective combination therapy includes artemisinin derivatives such as
artesunate (5), or mixtures with older drugs such as the atovaquone (6) – proguanil (7)
combination Malarone® [2,30]. Unfortunately first reports on drug resistance to
artemisinin-derivatives [31] and to drug combination therapies [32] have already appeared.
So, in the absence of a functional, safe and widely available malaria vaccine, efforts to
develop new antimalarial drugs continue being urgently needed now.
There is a consensus among the scientific community that natural products have been
playing a dominant role in the discovery of leads for the development of drugs for the
treatment of human diseases [33]. Indeed, the vast majority of the existing antimalarial
chemotherapeutic agents are based on natural products, and this fact anticipates that new
leads may certainly emerge from thetropical plant sources, since biological chemo
diversity continues to be an important source of molecular templates in the search for
antimalarial drugs [34-36].
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THE PROMISE OF NATURAL PRODUCTS-
The most significant recent development in naturally occurring antimalarial drugs is
arguably the identification of artemisinin (Figure 1) as the active component of the plant
Artemisia annua,which is used in traditional medicine as an antimalarial agent [37]. This
unique sesquiterpene contains an endoperoxide group that appears to be an essential
requirement for its activity. It is particularly active in vivo against chloroquine resistant
P.falciparum and is reported to have relatively low toxicity. However, in the usual dose
of 0.6 mg/day for 3 days, the average recurrence rate is more than 10% [37]. Due to its
highly lipophilic nature, there are inherent problems with its administration as a drug and
several derivatives have been prepared, including arthemeter (methyl dihydroartemisinin)
and sodium artesunate (sodium dihyroartemisinin hemisuccinate). Artemisinin and its
two derivatives have been used clinically for the treatment of cerebral malaria in an area
where chloroquine resistance was endemic and the cure rate was greater than 90%[38].
The mode of action is not primarily at the level of nucleic acid synthesis but it appears to
inhibit protein synthesis [39].
The current review provides an overview of a great number of bioactive natural products
that have recently been described in the literature (from January 2009 to November 2010)
as showing antiplasmodial activity (in vitro), along with a few compounds that were
tested for antimalarial activity in animal models [40] using Plasmodium knowlesi (in
simians), Plasmodium yoelii, Plasmodiumberghei, Plasmodium chabaudi (in mice), and
Plasmodium gallinaceum (in birds). In most of these bioassays, antiplasmodial activities
were assessed using different P. falciparum strains, which include chloroquine-sensitive
(NF54, NF54/64, 3D7, D6, F32, D10, HB3, FCC1-HN, Ghana, MRC-02, TM4),
chloroquine-resistant (BHz26/86, Dd2, EN36, ENT30, FcB1, FCM29, FCR3, FCR-3/A2,
FCR3F86, S20,W2,), chloroquine-resistant and pyrimethamine-resistant (K1,
TM91C235), pyrimethamine-resistant (HB3), cycloguanil-resistant (CDC1), and
chloroquine- and antifolate-resistant (K1CB1). Most of evaluations used the [3H]-
hypoxanthine-incorporation assay to assess parasite inhibition of growth in the presence
of the test-drugs. Antimalarial activity of new compounds has also been determined by
using: i) the fluorometric method based on the intercalation of the fluorochrome
PicoGreen (SYBR) in the parasite DNA, [41]; ii) enzyme-linked immunosorbent assays
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(ELISAs) with monoclonal antibodies, which measure the P. falciparum-specific antigen
histidine-rich protein 2 (HRP2) or lactate dehydrogenase protein (pLDH). A chemical
reaction using ferriprotoporphyrine biocrystallization (FBTI Inhibition Test) has been
used to provide a possible action mechanism for presumed antimalarial compounds [42].
Protein farnesyltransferase (FTase) bioassays have also been used to provide insight into
their mode of action against P.falciparum [43]. The effects of natural products on
glutathione (GSH), which plays a key role in redox mechanisms, and on cysteine (Cys),
which is one of the substrates needed for the de novo synthesis of P. falciparum GSH, as
well as their impact on β-hematin formation have been investigated, since GSH
participates in heme detoxification [44].
Several criteria have been proposed for considering a compound as active. Generally, a
compound is considered to be inactive when it shows an IC50 > 200 μM, whereas those
with an IC50 of 100-200 μM have low activity; IC50 of 20-100 μM, moderate activity;
IC50 of 1-20 μM good activity; and IC50 < 1 μM excellent/potent antiplasmodial activity
[45].
A total of 360 antiplasmodial natural products comprised of terpenes, including
iridoids,sesquiterpenes, diterpenes, terpenoid benzoquinones, steroids, quassinoids,
limonoids, curcubitacins, and lanostanes; flavonoids; alkaloids; peptides;
phenylalkanoids; xanthones; naphthopyrones; polyketides, including halenaquinones,
peroxides, polyacetylenes, and resorcylic acids; depsidones; benzophenones; macrolides;
and miscellaneous compounds.
Classes of natural product with antimalarial activity-
Alkaloids -
Cassiarin A (2) from the leaves of Cassia siamea (Leguminosae) showed promising
antimalarial activities. Cassiarin A had inhibitory effects against P. falciparum (IC50 =
0.02 M).Antimalarial activity was assessed in vivo using the 4-day suppressive test
procedure. The ED50 value of cassiarin A was 0.17 [46].
Acridone alkaloids have been isolated from the fruits of Zanthoxylum leprieurii
(Rutaceae), and among them arborinine (3) and xanthoxoline (4) exhibited a good in
vitro antiplasmodial activity against the P. falciparum strain 3D7, with IC50 values of
15.8 and 17.0 μM, respectively [47].
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HO
N
O
2
N
O
R
OH
R
OMe
R R'
3 Me OMe
4H OMe
TERPENES-
SESQUITERPENES-
Antimalarial activity of sesquiterpene lactones from Neurolaena lobata has been
documented.[48]Bioasay-guided fractionation of the extract from the wood-decayed
fungus Xylaria sp. BCC 1067 led to the isolation of elemophilane sesquiterpenes (+)-
phaseolinone (5) and (+)-phomenone (6).[49] Sesquiterpenes 5 and 6 known as
phytotoxins exhibited promising antimalarial activity (EC50 = 0.50 and 0.32
lg/mL,respectively).
O
HO
O
OH
O
5. (+)Phaseolinone
O
HO
O
OH
6. (+)-Phomenone
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TRITERPENES-
Fanta et al. reported the antiplasmodial activity of two triterpenoid saponins, glinoside A
(7) and glinoside B (8) isolated from the aerial parts of Glinus oppositifolius.[50] The
crude extracts exhibited better antiplasmodial activity (IC50 = 31.8 lg/mL) than the pure
saponins (7, IC50 = 42.3 lg/mL). An antimalarial tirucalla- type triterpene, epi-oleanolic
acid (9, IC50 = 28.3 lM) has been reported from Celaenodendron mexicanum.[51 ]A bis
nortriterpene quinone methide, 20-epi-isoiguesterinol (10) isolated from the roots of
Salacia madagascariensis showed potent activity against P. falciparum(IC50 = 68
ng/mL).[52]
O
O
OH
OH
O
HO
HO
OH
7. GlinosideA, R=OH
8. GlinosideB, R=H
COOH
H
HO
9. epi- Oleanolicacid
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CH2OH
O
HO
10. 20- epi- Isoioguesterinol
DITERPENES-
Tilley et al. performed molecular modeling studies on a series of diterpene isonitriles and
isothiocyanates isolated from the tropical marine sponge Cymbastela hooperi, employing
3D-QSAR with receptor modeling methodologies.[53]These studies showed that the
modeled compounds like diisocyanoadociane (11) and axisonitrile- 3 (12) exert their
activities by: (i) inhibiting the decomposition of H2O2, (ii) inhibiting the peroxidative
destruction of FP, and the GSH-mediated breakdown of FP, and (iii) interfering with b–
hematin formation. Diisocyanoadociane (11) displayed IC50 of 14.48 nM against P.
falciparum D6 strain.
NC
H
H
H
H
H
NC
11. Diisocyanoadociane
CN
Axisonitrile-312.
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OH
R1
R2
13. R1 =OH,R2=iPr
14. R1=iPr,R2=H
CH2OH
H
15. Dehydroabieetinol
H
HO
16
Clarkson et al. studied the effect of two diterpenes 13 and 14 isolated from
Harpagophytum procumbens, on erythrocyte shape to determine the selectivity of their
antiplasmodial activity.[54]It was observed that 13 and 14 did not alter erythrocyte shape
at the concentrations which resulted in the inhibition of parasite growth (0.76 and 0.95
lg/mL, respectively) or at the highest test concentration (100 lg/mL). This suggested that
the mechanism of action of these compounds is different from dehydroabietinol (15)
despite of structural similarities. Ziegler et al. have reported that antiplasmodial activity
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of 15, an abietane-type diterpene from Hyptis suaveolens was due to erythrocyte
membrane modification.[55]Diterpene 15 inhibited parasite growth (IC50 = 25.6 lM) at
similar concentrations at which cytotoxicity was observed (IC50 = 28.0lM).
Miscellaneous terpenes –
Recently, Moein et al. isolated and characterized a terpene, 12,16-dideoxy aegyptinone B
(17) from the roots of Zhumeria majdae, which exhibited promising antiplasmodial
activity (IC50= 1.3 and 1.4 lg/mL against chloroquine sensitive and resistant strains,
respectively).[56]
17. 12,16-DideoxyaegyptinoneB
Flavonoid-
The exact mechanism of antimalarial action of flavonoids is unclear but some flavonoids
are shown to inhibit the influx of L-glutamine and myoinositol into infected
erythrocytes.[57]
Exiguaflavanone A (18a) and exiguaflavanone B (18b) from Artemisia indica exhibited
in vitro antiplasmodial activities (IC50= 4.6 and 7.0 lg/mL, respectively.[58]
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O
HO
OH
OH O
RO
18a. ExiguaflavanoneA,R=H
18b. exiguaflavanone B,R=CH3
O
OH
HO
O
OCOCH3
OH
19
O
OH
HO
O
OCH3
20. Acacetin
(_)-cis-3-Acetoxy-40,5,7-trihydroxyflavanone (19, IC50 = 24.3 lg/mL) was isolated from
the lipophilic extract of leaves of Siparuna andina which showed higher in vitro
antimalarial activity (IC50 = 3.0 lg/mL).[59]Although obtained from an active fraction,
19 was less active (IC50 = 24.3 mg/mL). 3.32 lM against K1 and NF54 strains, obtained
from Vriesea sanguinolenta,[59] acacetin (20, IC50 = 5.5 and 12.6 lg/mL against poW
and Dd2 strain, respectively), 7-methoxyacacetin, and genkwanin isolated from A.
afra,73possessed considerable antiplasmodial activity.
Quinones-
Quinone methides 21 and 22 were isolated from the roots of Salacia kraussii. The isolates
showed high antiplasmodial activity (IC50 = 94.0 and 27.6 ng/mL, respectively).[61] The
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mode of action of these furano and hydroxy-naphthoquinones appears to be the inhibition
of mitochondrial electron transport and respiratory chain by reduced oxygen consumption
similar to that of atovaquone.
HO
O
RH
21. R=CHO
22. R=COOMe
quinones
O
HO
HO
O OH
OR
COCH3HO
O
OHHO
HO
HO
23. R=
24. Knipholone, R=CH3
Phenylanthraquinones like (23) and knipholone (24) were isolated from Bulbine
frutescens.
The glycoside 23 displayed better activity than 24 (IC50 = 0.41and 0.67 lg/mL,
respectively), whose antiplasmodial activity appears to be associated intrinsically with
the complete molecular array of a phenylanthraquinone including the stereogenic axis.[62]
Xanthones-
The xanthone 1,5-dihydroxy-3,6-dimethoxy-2,7-diprenylxanthone (25) showed selective
activity against P. falciparum with an IC50 value of 7.25 μM. When screened for activity
against T. cruzi, T. brucei, L. infantum (Ghana strain), S. aureus, and E. coli, and for
cytotoxicity against MRC-5 cells, it showed IC50 values >64 μM [63]. Xanthones 26-27
and their analogues 28,29 have been isolated from Cratoxylum maingayi and Cratoxylum
cochinchinense (Clusiaceae) [64].These compounds showed antiplasmodial activity
against P. falciparum at concentrations of 11.0 to 1.9 μM. Most of these compounds also
showed cytotoxicity toward the NC1-H187 cancer cellline [64].
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O
O
OMeMeO
OH
25.
O
OH
OH
OH
HO
O
26.
O O
O OH
HO
OH
27
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OH OH
HO
O
OMe
28
HO
O OH OH
OMe
29
Coumarins-
Biologically guided fractionation of the methanolic extract of the roots of Zanthoxylum
flavum Vahl. (Rutaceae) led to the isolation of isoimperatorin (30) which displayed IC50
values of 5.5 and 2.7 mM against D6 and W2, respectively.[65] A new coumarinolignan
was isolated from a sample of Grewia bilamellata Gagnep. (Tiliaceae), grewin (31),
which displayed antimalarial activity against D6 and W2 (IC50 11.2 mM and 5.5 mM,
respectively) without significant sscytotoxicity.[66]shows coumarins with moderate or
promising activity in vitro against various strains of P. falciparum.
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O
OOO
30.
OO
O
OH
O
OCH3
HO
HO
31
Phenols-
The petroleum ether extract of Viola websteri Hemsl.(Violaceae) was investigated and
the main antiplasmodial compound was 6-(8’Z-pentadecenyl)-salicylic acid (32) with an
IC50 of 10.1 mM (D10).[47]
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OH
COOH
32.
Dictyochromenol (33) and a known compound, 2’E,6’ E 2-farnesyl hydroquinone (34)
obtained from the petroleum ether extract of the whole plant of Piper tricuspe C.DC.
(Piperaceae) showed antimalarial activity against FcB1 with IC50 values of 9.58 and
1.37 mM while the selectivity index suggests their high toxicity.[67]
O
HO
33
OH
HO
34
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Lignans-
From the hexane extract of holostylis reniformis duch(aristolochiaceae)three lignans were
isolated: (7’R,8S,8’R)-4,5 dimethoxy-3’,4’-methylene dioxy-2,7’ – cyclo lignan-7-
one(35)(IC50=0.20 (IC50 = 0.26 mM), (7’R,8S,8’R)-3’,4,4’,5-tetramethoxy-2,7’-
cyclolignan-7-one (36) (IC50 =0.32 mM), (7’R,8R,8’S)-3’,4,4’,5-tetramethoxy-2,7’-
cyclolignan-7-one (37) (IC50 =0.20 mM). Most compounds possessed high
antiplasmodial activity against BHz26/86 and low toxicity on hepatic cells. Therefore,
these compounds are potential candidates for the development of antimalarial drugs.[68]
O
H3CO
H3CO
OCH3
OCH3
36
O
H3CO
H3CO
OCH3
OCH3
37
CONCLUSIONS
Medicinal plants have provided valuable and clinically used antimalarials like quinine
and artemisinin. In past few years, not only plants but fungi, bacteria and marine
organisms have also been intensively investigated for obtaining new antimalarial agents.
As discussed in this review, several compounds containing unique structural composition
have been isolated and characterized from natural sources. These natural products have
exhibited promising antimalarial activities in vitro and in vivo. However, limitations such
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as toxicity, low bioavailability and/or poor solubility have restricted the scope of use for
several natural products in humans.
Nevertheless, nature provides novel leads, which can be developed into safe drugs by
synthetic strategies as exemplified by artemether, and quinoline class of antimalarials.
Therefore,compounds described herein provide useful bioactive synthons, which could be
modulated to obtain antimalarials active against not only drug-sensitive, but also drug-
resistant and multi-drug resistant strains of Plasmodium. In this direction, semisynthetic
approaches to newer and modified antimalarials have provided useful insights into their
applicability in antimalarial drug discovery.
To conclude, nature has been generous in providing several remedies for the treatment of
disease like malaria. However, still there is vast unexplored flora and fauna, which when
systematically explored will provide additional new leads and drugs for malaria
chemotherapy.
REFERENCES
1. Greenwood, B.M.; Bojang, K.; Whitty, C.J.; Targett, G.A. Malaria. Lancet 2005.
365: 1487-1498.
1. Winter, R.W.; Kelly, J.X.; Smilkstein, M.J.; Dodean, R.; Bagby, G.C.; Rathbun
R.K.; Levin, J.I.; Hinrichs, D.; Riscoe, M.K. Evaluation and lead optimization of
anti-malarial acridones. Exp Parasitol. 2006, 114, 47-56.
2. Sachs, J.; Malaney, P. The economic and social burden of malaria. Nature 2002,
415, 680-685.
3. WHO 2011. World Malaria Report 2011, WHO, Geneve, 3 pp.
4. WHO. World Malaria Report. World Health Organization: Geneva, Switzerland,
2008. http://apps.who.int/malaria/wmr2008/.
5. Fidock, D.A.; Rosenthal, P.J.; Croft, S.L.; Brun, R.; Nwaka, S. Antimalarial drug
discovery: efficacy models for compound screening. Nat. Rev. Drug Discov.
2004, 3, 509-520.
6. Deprez-Poulain, R.; Melnyk, P. 1,4-Bis(3-aminopropyl)piperazine libraries: from
the discovery of classical chloroquine-like antimalarials to the identification of
new targets. Comb. Chem. High Throughput Screen. 2005, 8, 39-48.
7. Jones, M.K.; Good, M.F. Malaria parasites up close. Nat. Med. 2006, 12, 170-171.
Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Vishnoi et al
www.pharmasm.com IC Value – 4.01 399
8. Saxena, S.; Pant, N.; Jain, D.C.; Bhakuni, R.S. Antimalarial agents from plant
sources. Curr. Sci. 2003, 85, 1314-1329.
9. Viegas Júnior, C.; Bolzani, V.S.; Barreiro, E.J. Os produtos naturais e a química
medicinal moderna. Quím. Nova 2006, 29:326-337.
10. Townell N, Looke D, McDougall D, McCarthy JS 2012. Relapse of imported
Plasmodium vivax malaria is related to primaquine dose: a retrospective study.
Malar J 11: 214
11. Sturm A, Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A, Krueger
A, Pollok JM, Menard R, Heussler VT 2006. Manipulation of host hepatocytes by
the malaria parasite for delivery into liver sinusoids. Science 313: 1287-1290.
12. Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL, Collins FH, Duffy
PE 2008. Malaria: progress, perils and prospects for eradication. J Clin Invest
118: 1266-1276.
13. Clark IA, Budd AC, Alleva LM, Cowden WB 2006. Human malarial disease: a
consequence of inflammatory cytokine release. Malar J 5: 85.
14. Perkins DJ, Were T, Davenport GC, Kempaiah P, Hittner JB, Ong’echa MJ 2011.
Severe malarial anemia: innate immunity and pathogenesis. Int J Biol Sci 7: 1427-
1442.
15. Schofield L, Grau GE 2005. Immunological processes in malaria pathogenesis.
Nat Rev Immunol 5: 722-735.
16. Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng
W, Ataíde MA, de Oliveira RB, Golenbock DT, Gazzinelli RT 2011.
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents
experimental cerebral malaria. Proc Natl Acad Sci 108: 3689-3694.
17. White NJ. 1985. Clinical pharmacokinetics of antimalarial drugs. Clin
Pharmacokinet 10: 187-215.
18. Phillipson JD, O’Neill MJ. 1987. Antimalarial and amoebicidal natural products.
In: Hostettmann K, Lea PJ (Eds.) Biologically Active Natural Products. pp. 49-64,
Oxford, Clarendon Press.
19. Warhurst DC. 1985. New drugs and their potential use against drug-resistant
malaria.
Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Vishnoi et al
www.pharmasm.com IC Value – 4.01 400
20. Anonymous. 1975. Herbal Pharmacology in the people republic of China.
Washington National Academy of Sciences.
21. Steck EA. 1972. The Chemotherapy of Protozoan Diseases. Washington, Walter
Reed Army Institute of Research 10. Taylor, W.R.; White, N.J. Antimalarial drug
toxicity: a review. Drug Saf. 2004, 27, 25-61.
22. Sofowora A. 1980. The present status of knowledge of the plants used in
traditional medicine in Western Africa: a medical approach and a chemical
evaluation. J Ethnopharmacol, 2: 109-118.
23. Lewis WH and Elwin-Lewis MPF. Medical Botany. Wiley, New York (1971).
24. Chopra RN, Nayar SL , Chpra IC. 1956. Glossary of Indian Medicinal Plants.
New Delhi, Council of Scientific and Industrial Research.
25. Graham PCC 1966. Historical summary of the discovery of the malaria parasites.
In Malaria parasites and other haemosporidia, Blackwell Scientific Publications,
Oxford, p. 3-16.
26. WHO 2010a. Guidelines for the treatment of malaria, 2nd ed., WHO, Geneve,
194 pp.
27. WHO 2010b. Global report on antimalarial drug efficacy and drug resistance:
2000-2010, WHO, Geneve, 121 pp.
28. Karunamoorthi K 2011. Vector control: a cornerstone in the malaria elimination
campaign. ClinMicrobiol Infec 17: 1608-1616.
29. Taylor, W.R.; White, N.J. Antimalarial drug toxicity: a review. Drug Saf. 2004,
27, 25-61.
30. Jambou, R.; Legrand, E.; Niang, M.; Khim, N.; Lim, P.; Volney, B.; Ekala, M.T.;
Bouchier, C.; Esterre, P.; Fandeur, T.; Mercereau-Puijalon, O. Resistance of
Plasmodium falciparum field isolates to in vitro artemether and point mutations of
the SERCA-type PfATPase6. Lancet 2005, 366, 1960-19s63.
31. Wichmann, O.; Muhlen, M.; Grub, H.; Mockenhaupt, F.P.; Suttorp, N.; Jelinek, T.
Malarone treatment failure not associated with previously described mutations in
the cytochrome b gene. Malaria J. 2004, 3, 1-3.
32. Newman, D.J.; Cragg, G.M.; Snader, K.M. Natural products as sources of new
drugs over the period 1981-2002. J. Nat. Prod. 2003, 66, 1022-1037.
Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Vishnoi et al
www.pharmasm.com IC Value – 4.01 401
33. Ziegler, H.L.; Staerk, D.; Christensen, J.; Hviid, L.; Hagerstrand, H.; Jaroszewski,
J.W. In vitro Plasmodium falciparum drug sensitivity assay: inhibition of parasite
growth by incorporation of stomatocytogenic amphiphiles into the erythrocyte
membrane. Antimicrob. Agents Chemother.2002, 46, 1441-1446.
34. Kalauni, S.K.; Awale, S.; Tezuka, Y.; Banskota, A.H.; Linn, T.Z.; Asih, P.B.;
Syafruddin,D.; Kadota, S. Antimalarial activity of cassane- and norcassane-type
diterpenes from Caesalpinia crista and their structure-activity relationship. Biol.
Pharm. Bull. 2006, 29, 1050-1052.
35. Portet, B.; Fabre, N.; Roumy, V.; Gornitzka, H.; Bourdy, G.; Chevalley, S.;
Sauvain, M.; Valentin, A.; Moulis, C. Activity-guided isolation of antiplasmodial
dihydrochalcones and flavanones from Piper hostmannianum var. berbicense.
Phytochemistry 2007, 68, 1312-1320.
36. Phillipson JD, O’Neill MJ. 1987. Antimalarial and amoebicidal natural products.
In: Hostettmann K, Lea PJ (Eds.) Biologically Active Natural Products. pp. 49-64,
Oxford, Clarendon Press.
37. Li GQ, Guo XB, Jin R, Wang ZC, Jian HX, Li ZY. 1982 Clinical studies on
treatment of cerebral malaria with qinghaosu and its derivatives. J Tradit Chin
Med, 2: 125-130.
38. Gu HM, Warhurst DC, Peters W. 1983. Rapid action of Qinghaosu and related
drugs on incorporation of [3H]isoleucine by Plasmodium falciparum in vitro.
Biochem Pharmacol, 32: 2463-2466.
39. Ikegami-Kawai, M.; Arai, C.; Ogawa, Y.; Yanoshita, R.; Ihara, M. Selective
accumulation of a novel antimalarial rhodacyanine derivative, SSJ-127, in an
organelle of Plasmodium berghei.Bioorg. Med. Chem. 2010, 18, 7804-7808.
40. Corbett, Y.; Herrera, L.; Gonzalez, J.; Cubilla, L.; Capson, T.L.; Coley, P.D.;
Kursar, T.A.; Romero, L.I.; Ortega-Barria, E. A novel DNA-based
microfluorimetric method to evaluate antimalarial drug activity. Am. J. Trop.
Med. Hyg. 2004, 70, 119-124.
41. Ibáñez-Calero, S.L.; Jullian, V.; Sauvain, M. A new anthraquinone isolated from
Rumex obtusifolius. Rev. Boliv. Quím. 2009, 26, 49-56.
Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Vishnoi et al
www.pharmasm.com IC Value – 4.01 402
42. Longeon, A.; Copp, B.R.; Roué, M.; Dubois, J.; Valentin, A.; Petek, S.; Debitus,
C.; Bourguet-Kondracki, M.L. New bioactive halenaquinone derivatives from
South Pacific marine sponges of the genus Xestospongia. Bioorg. Med. Chem.
2010, 18, 6006-6011.
43. Pabón, A.; Deharo, E.; Zuluaga, L.; Maya, J.D.; Saez, J.; Blair, S. Plasmodium
falciparum: Effect of Solanum nudum steroids on thiol contents and β-hematin
formation in parasitized erythrocytes. Exp. Parasitol. 2009, 122, 273-279.
44. Batista, R.; Silva, A.D.J.; de Oliveira, A.B. Plant-derived antimalarial agents: new
leads and efficient phytomedicines. Part II. Non-alkaloidal natural products.
Molecules 2009, 14,3037-3072.
45. Ekasari, W.; Widyawaruyanti, A.; Zaini, N.C.; Syafruddin, D.;Honda,T.;Morita,
H. Antimalarial activity of Cassiarin a from the leaves of Cassia siamea.
Heterocycles 2009, 78,1831-1836.
46. Tchinda, A.T.; Fuendjiep, V.; Sajjad, A.; Matchawe, C.; Wafo, P.; Khan,S.; Tane,
P.;Choudhary, M.I. Bioactive compounds from the fruits of Zanthoxylum
leprieurii.Pharmacologyonline 2009, 1, 406-415.
47. Francois, G.; Passreiter, C. M.; Woerdenbag, H. J.; Van Looveren, M. Planta
Med. 1996, 62, 126.
48. Isaka, M.; Jaturapat, A.; Kladwang, W.; Punya, J.; Lertwerawat, Y.; Tanticharoen,
M.; Thebtaranonth, Y. Planta Med. 2000, 66, 473.
49. Traore, F.; Faure, R.; Ollivier, E.; Gasquet, M.; Azas, N.; Debrauwer, L.; Keita,
A.; Timon-David, P.; Balansard, G. Planta Med. 2000, 66, 368.
50. Camacho, M. R.; Mata, R.; Castaneda, P.; Kirby, G. C.; Warhurst, D. C.; Croft, S.
L.; Phillipson, J. D. Planta Med. 2000, 66, 463.
51. Thiem, D. A.; Sneden, A. T.; Khan, S. I.; Tekwani, B. L. J. Nat. Prod. 2005, 68,
251.47. Chea, A.; Hout, S.; Buna, S. S.; Tabatadze, N.; Gasquet, M.; Azas, N.;
Elias, R.; Balansard, G. J. Ethnopharmacol. 2007, 112, 132.
52. Wright, A. D.; Wang, H.; Gurrath, M.; König, G. M.; Kocak, G.; Neumann, G.;
Loria, P.; Foley, M.; Tilley, L. J. Med. Chem. 2001, 44, 873.
53. Clarkson, C.; Campbell, W. E.; Smith, P. Planta Med. 2003, 69, 720.
Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Vishnoi et al
www.pharmasm.com IC Value – 4.01 403
54. Ziegler, H. L.; Jensen, T. H.; Christensen, J.; Staerk, D.; Hägerstrand, H.; Sittie,
A. A.; Olsen, C. E.; Staalsø, T.; Ekpe, P.; Jaroszewski, J. W. Planta Med. 2002,
68,547.
55. Moein, M. R.; Pawar, R. S.; Khan, S. I.; Tekwani, B. L.; Khan, I. A. Phytother.
Res. 2008, 22, 283.
56. Elford, B. C. Parasitol. Today 1986, 2, 309.
57. Chanphen, R.; Thebtaranonth, Y.; Wanauppathamkul, S.; Yuthavong, Y. J. Nat.
Prod. 1998, 61, 1146.
58. Jenett-Siems, K.; Siems, K.; Jakupovic, J.; Solis, P. N.; Gupta, M. P.;
Mockenhaupt, F. P.; Bienzle, U.; Eich, E. Planta Med. 2000, 66, 384.
59. Bringmann, G.; Ochse, M.; Zotz, G.; Peters, K.; Peters, E. M.; Brun, R.; Schlauer,
J. Phytochemistry 2000, 53, 965.
60. Figueiredo, J. N.; Räz, B.; Séquin, U. J. Nat. Prod. 1998, 61, 718.
61. Abegaz, B. M.; Bezabih, M.; Msuta, T.; Brun, R.; Menche, D.; Mühlbacher, J.;
Bringmann, G. J. Nat. Prod. 2002, 65, 1117.
62. Elfita, E.; Muharni, M.; Latief, M.; Darwati, D.; Widiyantoro, A.; Supriyatna, S.;
Bahti, H.H.;Dachriyanus, D.; Cos, P.; Maes, L.; Foubert, K.; Apers, S.; Pieters, L.
Antiplasmodial and other constituents from four Indonesian Garcinia spp.
Phytochemistry 2009, 70, 907-912.
63. Laphookhieo, S.; Maneerat, W.; Koysomboon, S. Antimalarial and cytotoxic
phenolic compounds from Cratoxylum maingayi and Cratoxylum cochinchinense.
Molecules 2009, 14,1389-1395.40. Lin, L. Z.; Hu, S. F.; Chu, M.; Chan, T. M.;
Chai, H.; Angerhofer, C. K.; Pezzuto, J. M.; Cordell, G. A. Phytochemistry 1999,
50, 829.
64. Ross SA et al. Constituents of Zanthoxylum flavum and their antioxidant and
antimalarial activities. Nat Prod Commun 2008; 3: 791–794.
65. Ma CY et al. Antimalarial compounds from Grewia bilamellata. J Nat Prod 2006;
69: 346–350.
66. Vega AS et al. Antimalarials and antioxidants compounds from Piper tricuspe
(Piperaceae). Pharmacologyonline 2008; 1: 1–8.
Vol - 4, Issue - 3, Apr-Jul 2013 ISSN: 0976-7908 Vishnoi et al
www.pharmasm.com IC Value – 4.01 404
67. Andrade-Neto VF et al. Antiplasmodial activity of aryltetralone lignans from
Holostylis reniformis. Antimicrob Agents Chemother 2007; 51: 2346–2350.
For Correspondence: Garima Vishnoi Email: [email protected]