Professional Documents
Culture Documents
Universite catholique de Louvain, Louvain Drug Research Institute, Analytical Chemistry, Drug Analysis and
Pharmacognosy Unit, Brussels and bUniversity of Lie`ge, Natural and Synthetic Drugs Research Center,
Laboratory of Pharmacognosy, Lie`ge, Belgium
Abstract
Objectives This review covers the compounds with antiplasmodial activity isolated from
plants published from 2005 to the end of 2008, organized according to their phytochemical
classes. Details are given for substances with IC50 values 11 mM.
Key findings Malaria is a major parasitic disease in many tropical and subtropical
regions and is responsible for more than 1 million deaths each year in Africa. The rapid
spread of resistance encourages the search for new active compounds. 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.
Summary 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.
Keywords antiplasmodial; malaria; plant compounds; Plasmodium falciparum;
traditional medicine
Introduction
Correspondence: J. Bero,
Catholic University of Louvain,
Analytical Chemistry, Drug
Analysis and Pharmacognosy
Unit, Avenue E. Mounier,
72, B-1200 Brussels, Belgium.
E-mail: joanne.bero@uclouvain.be
Malaria is a parasitic disease caused by Plasmodium species transmitted from the blood of
an infected person and passed to a healthy human by a female Anopheles mosquito. There
are four types of human malaria and Plasmodium falciparum is responsible for the most
severe cases, and so most studies have evaluated the activity of compounds on this species.
Malaria affects 350500 million people per year worldwide and is responsible for
1.1 million deaths per year. In many parts of the world the parasites have developed
resistance to a number of antimalarials such as chloroquine and derivatives, the most
widely used treatment for malaria, and so there is an urgent need to discover new
compounds with an original mode of action. Plants commonly used in traditional medicine
are a source of active new compounds. For example, artemisinin isolated from Artemisia
annua and used in China to treat malaria is a sesquiterpene lactone prescribed in
combination therapies to fight chloroquino-resistant P. falciparum. In this review, all new
active metabolites isolated from plants used in traditional medicine to treat malaria are
described and organised according to their phytochemical classes. All the activities
described were determined in vitro on P. falciparum strains, unless otherwise specified, and
bio-guided fractionation was also based on this antimalarial test. Activities were assessed
on different strains, among which are chloroquine sensitive (NF54, NF54/64, 3D7, D6, F32,
D10, HB3, FCC1-HN, Ghana), chloroquine resistant (FcB1, W2, FCM29, BHz26/86, Dd2,
EN36, ENT30, FCR3, FCR-3/A2) and/or multidrug resistant (K1, TM91C235) strains, to
find effective compounds against resistant malaria. We considered that those having an
IC50 11 mM may have some interest for further development, while those with lower
activity were less interesting. We only give structures for promising compounds, the others
are cited in tables. As reviews already exist for compounds published before 2005,[17]
we focused on those published from 2005 to the end of 2008. Some examples of recent
natural antiplasmodial compounds are also cited in Mambu and Grellier[8] and, more
recently, in Kaur et al.[9]
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1401
1402
Phenolic derivatives
Flavonoid derivatives
Bioassay-guided fractionation of the ethyl acetate extract of
the leaves of Piptadenia pervillei Vatke (Leguminosae) led
to the isolation of two phenolic compounds: (+)-catechin 5gallate (1) and (+)-catechin 3-gallate (2). Compounds 1 and 2
displayed high activity, with IC50 values of 1.2 mM and
1.0 mM (FcB1), respectively, and no significant cytotoxicity.[10] New secondary metabolites were isolated from the
root extract of Bauhinia purpurea L. (Leguminosae). Among
the isolated metabolites, a flavanone exhibited moderate
antimalarial activity, demethoxymatteucinol (3) (IC50 =
9.5 mM against K1).[11] Phytochemical investigation of the
stem bark and root bark of Friesodielsia obovata (Benth.)
Verdc. (Annonaceae) also afforded demethoxymatteucinol
(3), which possessed weak antiplasmodial activity, with
IC50 = 34.1 and 29.9 mM against K1 and NF54, respectively.[12] Investigation of the chemical constituents of the
root bark of Artocarpus rigidus Blume subsp. rigidus
(Moraceae) led to the isolation of two known flavonoids,
artonin F (4) and cycloartobiloxanthone (5), which exhibited
antiplasmodial activity against K1 (4.8 mM and 8.5 mM,
respectively).[13] Two new prenylated flavones, artocarpones
A (6) and B (7) (IC50 = 0.12 and 0.18 mM, respectively), and
seven known prenylated flavonoids, including artonin A (8)
(IC50 = 0.55 mM), cycloheterophyllin (9) (IC50 = 0.02 mM),
artoindonesianin R (10) (IC50 = 0.66 mM), heterophyllin
(11) (IC50 = 1.04 mM), heteroflavanone C (12) and artoindonesianin A-2 (13) (IC50 = 1.31 mM) were isolated from the
stem bark of Artocarpus champeden Spreng. (Moraceae).
The isolated compounds were tested for their inhibitory
activity against 3D7. All possessed interesting activity with
inhibitory concentrations from 0.001 to 1.31 mM. Compound
12 was the most potent with an IC50 of 1 nM. The inhibitory
activity of these flavonoid derivatives supports the traditional
use of the dried stem bark of A. campeden as an antimalarial
drug.[14] Antitubercular and antimalarial activity-guided
study of the dichloromethane extract of the roots of
Artocarpus altilis (Parkinson) Fosberg (Moraceae) led to
the isolation of nine prenylated flavones, including cycloartocarpin (14), artocarpin (15), chaplashin (16), morusin (17),
cudraflavone B (18), artonin E (19) and artobiloxanthone
(20). All compounds exhibited antiplasmodial activity
against K1 with IC50 values of 9.9, 6.9, 7.7, 4.5, 5.2, 6.4
and 6.9 mM, respectively.[15] Ethyl acetate extract from the
stem bark of Erythrina fusca Lour. (Leguminosae) showed
antimalarial activity against K1, and lonchocarpol A (21)
isolated from that extract showed notable antimalarial
activity (IC50 = 3.9 mM). However, two others flavonoids
isolated from the same sample did not show any activity,
even though these compounds possessed prenylated substitution.[16] Isoflavonoids and flavonoids were isolated from the
root bark and the stem bark of Erythrina sacleuxii Hua
(Leguminosae). The two most active against D6 and W2
were 50-prenylpratensein (22, IC50 on D6 = 6.3 mM and IC50
on W2 = 8.7 m M ) and shinpterocarpin (23, IC50 on
D6 = 6.6 mM and IC50 on W2 = 8.3 mM).[17] Phytochemical
investigation of the hexane and CH2Cl2 extracts of Erythrina
stricta Roxb. (Leguminosae) roots and Erythrina subumbrans Merr. (Leguminosae) stems led to the isolation of two
pterocarpans, erybraedin A (24) and erystagallin A (25), and
one flavanone, 5-hydroxysophoranone (26). All of them
exhibited reasonable antiplasmodial activity against K1 with
IC50 = 8.7, 9.0 and 5.3 mM, respectively.[18] Vogelin C (27)
and lespedezaflavanone B (28) were isolated from the bark of
Erythrina subumbrans Merr. (Leguminosae) and possessed
antiplasmodial activity against K1 with IC50 values of 6.6
and 9.1 mM, respectively.[19] A known compound, 6-prenylapigenin (29), was isolated from Cannabis sativa L.
(Cannabaceae) and displayed notable antimalarial activity
against D6 and W2 with IC50 values of 6.7 and 4.8 mM,
respectively.[20] The 80% ethanol extract from the outer bark
of Ochna integerrima Lour. (Merr.) (Ochnaceae) led to
isolation of a biflavanone (30) that had not been found
previously from a natural plant source and is a potent
antimalarial ingredient against K1 (IC50 = 157 nM). The
stereoisomer of 30 (31) was also isolated from this plant but
its activity was significantly lower than that of 30 (IC50 =
10.2 mM).[21] The antiplasmodial activity of five natural
biflavonoids was estimated on K1. Lanaroflavone (32)
isolated from the aerial parts of Campnosperma panamensis
Standl. (Anacardiaceae) showed the highest antiplasmodial
activity (IC50 = 0.48 mM) and exhibited a high selectivity
index value (SI = 159), indicating selective antiplasmodial
activity. Ginkgetin (33), isoginkgetin (34), bilobetin (35)
and sciadopitysin (36) isolated from the leaves of Ginkgo
biloba L. (Ginkgoaceae) showed antiplasmodial activity
(IC50 = 2.0, 3.5, 6.7 and 1.4 mM with SI = 4.1, 3.2, 4.0 and
49, respectively).[22,23] A new biflavanone, ent-naringeninyl(I-3a,II-8)-40-O-methylnaringenin (37) was isolated from the
root bark of Garcinia livingstonei T.Anderson (Clusiaceae)
collected in Tanzania. This compound showed reasonable
activity against Ghana strain (IC50 = 6.7 mM).[24] Phytochemical re-examination of the aerial exudates of Polygonum
senegalense Meisn. (Polygonaceae) forma senegalense
resulted in the isolation of two chalcones (38 and 39) active,
respectively, with an IC50 of 3.1 mM on D6 and 2.4 mM on
W2, and 14.0 mM on D6 and 9.5 mM on W2.[25] The bioassayguided purification of an n-hexane extract from the leaves of
Piper hostmannianum C.DC. var. berbicense (Piperaceae)
led to the isolation of four monoterpenes or prenylsubstituted dihydrochalcones as well as known compounds.
()-Methyllinderatin (40) and linderatone (41) exhibited
moderate antiplasmodial activity with IC50 values of 5.6
and 5.3 mM (40) and 10.3 and 15.1 mM (41), respectively,
against F32 and FcB1. The activity of 40 was confirmed in
vivo against Plasmodium vinckei petteri in mice (80%
reduction of parasitemia) at a dose of 20 mg/kg per day
intraperitonally.[26] A prenylated chalcone, medicagenin
(42), was isolated from Crotalaria medicagenia Lam.
(Leguminosae). Antimalarial activity was evaluated against
NF-54 and medicagenin exhibited 100% inhibition of
schizont maturation at a concentration of 2 mg/ml.[27] A
prenylated chalcone, bartericin A (43), and three known
natural products, stipulin (44), 4-hydroxylonchocarpin (45)
and kanzonol B (46) were isolated from the twigs of
Dorstenia barteri var. subtriangularis (Engl.) Hijman & C.C.
Berg (Moraceae). These compounds were evaluated against
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Xanthones
The methanol extract of the stem bark of Allanblackia
monticola Mildbr. (Clusiaceae) resulted in the isolation of a
new prenylated xanthenedione, designated as allanxanthone C
(47), together with the known compounds norcowanin (48),
mangostin (49) and tovophyllin A (50). Compounds were
assayed for their antiplasmodial activity and for their
cytotoxicity. Three of these compounds (4749) were found
to be active against Plasmodium: 47, IC50 on FcM29 =
1.3 mM and IC50 on F32 = 6.9 mM; 48, not tested on FcM29
and IC50 on F32 = 6.3 mM; 49, IC50 on FcM29 = 4.1 mM and
IC50 on F32 = 7.8 mM, and also showed weak cytotoxicity
against human melanoma A375 cells.[30] Tovophyllin A (50)
was the most interesting with promising antimalarial activity
(IC50 on FcM29 = 0.7 mM and IC50 on F32 = 20.3 mM) and
relatively low cytoxicity.[31] A new prenylated xanthone, 5-Omethylcelebixanthone (51), together with a known compound,
cochinchinone C (52), were isolated from roots of Cratoxylum
cochinchinense Blume (Clusiaceae). Compounds 51 and
52 exhibited antimalarial activity against K1 with IC50 values
of 8.9 and 6.3 mM, respectively. IC50 values for cytotoxicity
were within the range of 5.6 mM for 52. No cytotoxicity was
observed with 51.[32] A xanthone derivative, gaboxanthone
(53), was isolated from the seed shells of Symphonia
globulifera L.f. (Clusiaceae), together with known compounds, symphonin (54) and globuliferin (55). The antiplasmodial activity of the phenolic compounds was evaluated
against W2. Compounds 5355 gave IC50 values of 3.5, 1.3
and 3.9 mM, respectively.[33] The whole plant of Swertia alata
Royle ex D.Don (Gentianaceae) was investigated and three
xanthones, swertiaperennine, swertianin and decussatin, were
isolated and tested for antimalarial activity. The results
indicated that all xanthones possessed superior IC50 values
at 50 mM. However, swertiaperennine was tested in vivo in the
P. berghei test model and reduced parasitemia by 17.60% at a
dose of 10 mg/kg.[34] A new compound, garciniaxanthone
(56), was isolated from the roots of Garcinia polyantha Oliv.
(Clusiaceae), in addition to three known compounds, smeathxanthone A (57), smeathxanthone B (58) and chefouxanthone
(59). They exhibited antimalarial activity against NF54 with
IC50 values ranging from 2.5 to 4.1 mM.[35]
Figure 2 shows xanthones with moderate or promising
activity in vitro against various strains of P. falciparum.
1403
Stilbenes
A new stilbene glycoside, piceid-(1!6)-b-D-glucopyranoside (60), was isolated from the MeOH extract of the leaves
of Parthenocissus tricuspidata Planch. (Vitaceae) together
with three known compounds, piceid (IC50 = 13.2 mM),
longistylin A (IC50 = 34.3 mM) and longistylin C (IC50 =
19.2 mM). The antiplasmodial activity of isolated compounds
was determined in vitro against D10. Among the compounds
isolated, 60 was the best inhibitor with an IC50 value
of 5.3 mM.[36] Compound 60 was tested in vivo against
P. berghei in mice intraperitoneally and exhibited significant
blood schizontocidal activity in 4-day early infection, in
preventive and curative treatment, with chemosuppression
of 59 and 44% at 5 mg/kg per day, respectively, and an
LD50 > 500 mg/kg.[37] A stilbene glycoside was isolated
from an n-butanol-soluble fraction of the root of Pleuropterus ciliinervis Nakai (Polygonaceae). The compound
was identified as (E)-resveratrol-3-O-a-L-rhamnopyranosyl(1-2)-b-D-xylopyranoside (61). It showed only moderate
cytotoxicity and antimalarial activity against D10 with an
IC50 of 3.9 mM.[38] Compound 61 was also found to have
moderate antimalarial activity in vivo when tested against
P. berghei in mice intraperitoneally. It possessed useful
blood schizontocidal effects when used at doses that cause
no marked toxicity in mice.[39]
Figure 3 shows stilbenes with moderate or promising
activity in vitro against various strains of P. falciparum.
Coumarins
Biologically guided fractionation of the methanolic extract of
the roots of Zanthoxylum flavum Vahl. (Rutaceae) led to the
isolation of isoimperatorin (62) which displayed IC50 values
of 5.5 and 2.7 mM against D6 and W2, respectively.[40] A new
coumarinolignan was isolated from a sample of Grewia
bilamellata Gagnep. (Tiliaceae), grewin (63), which displayed antimalarial activity against D6 and W2 (IC50
11.2 mM and 5.5 mM, respectively) without significant
cytotoxicity.[41] The compound 1-O-galloyl-6-O-luteoyl-aD-glucose (64) with an IC50 value of 2.21 mM (FCR3) was
isolated from the boiled aqueous extract of the whole plant of
Phyllanthus niruri L. (Euphorbiaceae).[42]
Figure 4 shows coumarins with moderate or promising
activity in vitro against various strains of P. falciparum.
Lignans
From the hexane extract of Holostylis reniformis Duch.
(Aristolochiaceae), five lignans were isolated: (70R,8S,80R)4,5-dimethoxy-30,40-methylenodioxy-2,70-cyclolignan-7-one
(65) (IC50 = 0.26 mM), (70R,8S,80R)-30,4,40,5-tetramethoxy2,70-cyclolignan-7-one (66) (IC50 = 0.32 mM), (70R,8R,80S)30,4,40,5-tetramethoxy-2,70-cyclolignan-7-one (67) (IC50 =
0.20 m M ), (7 0R,8S,8 0S)-3 0,4,4 0,5-tetramethoxy-2,7 0-cyclolignan-7-one (68) (IC50 = 0.63 mM) and (70R,8S,80S)-30,40dimethoxy-4,5-methylenodioxy-2,70-cyclolignan-7-one (69)
(IC50 = 8.00 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.[43] Seven tetrahydrofuran lignans isolated from Nectandra megapotamica Mez
(Lauraceae) were evaluated for their antimalarial activity.
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1404
OH
O
HO
OH
HO
O
HO
OH
OR2
OR1
OH
OH
OH
3
OH
Ga 5
HO
O
OH
1. R1 5 Ga, R2 5 H
2. R1 5 H, R2 5 Ga
HO
OCH3
OH
OH
OH
O
O
7
OH
H3CO
OH
5
HO
OH
OH
OH
HO
HO
HO
O
OCH3
OH
O
HO
OH
OH
OH
O
9
10
OH
OH
H3CO
HO
HO
OCH3
OCH3
OCH3
HO
O
OH
OH
OH
OH
O
12
OH
13
OH
OH
O
O
H3CO
H3CO
11
OH
OH
OH
OH
H3CO
15
16
HO
O
14
HO
OH
O
17
HO
OH
HO
O
OH
OH
HO
OH
OH
OH
O
18
OH
OH
OH
OH
O
20
OH
OH
OH
21
O
19
Figure 1 Flavonoid derivatives with moderate or promising activity in vitro against various strains of P. falciparum
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to distribute this material for personal or professional (non-commercial) use only, subject to the terms and conditions
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HO
OH
OCH3
HO
OH
OH O
O
OH
HO
H O
22
H O
23
OCH3
25
OH
24
OH
HO
HO
OH
OH
OH O
OH O
26
HO
OH
27
OH O
OH
OH
HO
OH
28
O
HO
H
O
H
OH O
OH
29
H
H
OH
OH
31
OH
32
R2
OH
OR2
HO
OH OHO
O
O
R3
R1
OH O
OR4
R3O
OH
30
HO
OH O
H
O
H
OH
O
O
HO
H
H
HO
O
R1O
OH
37
OH O
OH O
OH
HO
OH O
H
OH
42
OH O
OH O
HO
HO
41
40
OH
OH O
OH
43
HO
OH
OH O
HO
45
OH O
OH O
44
46
Figure 1 (Continued)
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1405
1406
OH
OH
OH
H3CO
HO
HO
HO
OH
HO
47
OH
OH
49
48
OH
OH
H3CO
O
O
HO
OH
OH
H3CO
O
O
50
HO
O
OCH3
51
52
OH
O
H3CO
OH
H3CO
H3CO
H3CO
OH
OH
H3CO
OH
53
OH
OH
OH
OH
OCH3
OH
55
OH
OH
OH
OH
OH
OH
O
58
57
56
O
OH
54
OH
OH
H3CO
OH
OH
59
Figure 2 Xanthones with moderate or promising activity in vitro against various strains of P. falciparum
OH
HO
OH
HO
O HO
O
OH
OH
O
O
O OH
OH
OH
O
60
OH
OH
OH
O
OH
OH
OH
61
Tannins
Partitioning of extracts of Punica granatum L. (Lythraceae)
led to the isolation of ellagic acid, gallagic acid (72),
punicalin and punicalagin (73). Gallagic acid and punicalagin exhibited moderate antiplasmodial activity against D6
(IC50 of 10.9 and 10.6 mM) and W2 clones (IC50 of 7.5 and
8.8 mM).[46]
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1407
OH
O
OH
HO
O
HO
OH
HO
HO
OCH3
62
HO
63
OH
OH
OH
HO
HO
OH
64
Figure 4 Coumarins with moderate or promising activity in vitro against various strains of P. falciparum
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
65
66
68
67
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OH
OCH3
O
O
H3CO
OCH3
70
OCH3
O
HO
OH
OGlu
OCH3
69
H3CO
OCH3
71
Figure 5 Lignans with moderate or promising activity in vitro against various strains of P. falciparum
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1408
HO
HO
OH
HO
OH
OH
HO
OH
OH
OH
HO
OH
HO
OH
OH
OH
HO
HO
O
OH
HO
OH
OH
O
72
O
O
O
O
HO
73
OH
HO
OH HO
Figure 6 Tannins with moderate or promising activity in vitro against various strains of P. falciparum
HO
O
74
COOH
75
OH
HO
OH
76
77
OH
OH
HO
OH
O
78
OH
O
79
HO
OH
HO
O
HO
O
OH
80
OH
81
Figure 7 Other phenolic derivatives with moderate or promising activity in vitro against various strains of P. falciparum
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OH
1409
Table 1 Phenolic derivatives presenting low or no activity in vitro against various strains of P. falciparum
Compound
Plant
Family
IC50 (mM)
Reference no.
27.5 (K1)
119.1 (NF54)
18.9 (K1)
12
Lawinal
Annonaceae
Ellipeiopsis cherrevensis
(Pierre ex Finet & Gagnep.) R.E.Fr.
Commiphora opobalsamum Engl.
Annonaceae
Cannabichromanone A
Cannabis sativa L.
Cannabaceae
Celebixanthone
b-Mangostin
1,5-Dihydroxy-3-methoxy-4isoprenylxanthone
1,3,7-Trihydroxy-2,4diisoprenylaxnthone
Toxyloxanthone A
Combretastatin D-3
Combretastatin D-4
3,5-Di-O-galloylquinic acid
Burseraceae
52
53
Clusiaceae
Clusiaceae
Clusiaceae
17.7 (D6)
16.2 (W2)
11.1 (D6)
11.4 (W2)
14.3 (K1)
16.9 (K1)
31 (W2)
Clusiaceae
20 (W2)
54
Clusiaceae
Combretaceae
Combretaceae
Elaeocarpaceae
51
32
32
54
54
55
55
56
Euphorbiaceae
16 (W2)
31.7 (HB3)
23.6 (FcM29)
35.5 (HB3)
15.7 (FcM29)
35.3 (HB3)
23.1 (FcM29)
20.2 (HB3)
20.6 (FcM29)
18.5 (FCR3)
Phyllanthus niruri L.
Croton lobatus L.
Euphorbiaceae
Euphorbiaceae
14.6 (FCR3)
19.1 (K1)
42
57
Gentianaceae
Gentianaceae
Gentianaceae
Lamiaceae
Leguminosae
Leguminosae
Leguminosae
Leguminosae
34
34
34
58
16
16
16
17
Corylin
Leguminosae
Erysubin F
Leguminosae
30-Prenylbiochanin A
Leguminosae
7-Demethylrobustigenin
Leguminosae
50-Formylpratensein
Leguminosae
2,3-Dehydrokeivetone
Leguminosae
Prostratol C
Leguminosae
Saclenone
Leguminosae
2,3-Dihydro-7-demethylrobustigenin
Leguminosae
(3R)-7-Hydroxy-30,40-dimethoxyisoflavan-20,50-quinone
6,3 0-Dihydroxy-7,4 0dimethoxyisoflavone
Leguminosae
>50
>50
>50
22.3 (K1)
30.8 (K1)
14.8 (K1)
12.1 (K1)
17.6 (D6)
22.5 (W2)
16.6 (D6)
19.7 (W2)
12.0 (D6)
12.8 (W2)
23.7 (D6)
28.4 (W2)
27.2 (D6)
31.7 (W2)
21.7 (D6)
27.9 (W2)
15.1 (D6)
12.7 (W2)
17.6 (D6)
19.8 (W2)
24.2 (D6)
22.6 (W2)
28.0 (D6)
31.8 (W2)
>50 (D6, W2)
Leguminosae
59
1,6-Di-O-galloyl glucopyranoside
3,4,5-Tri-O-galloylquinic acid
1,2,3,6-Tetra-O-galloyl glucopyranoside
3-O-b-D-Glucopyranosyl-(2!1)-Ob-D-xylopyranoside
b-Glucogallin
(E)-3-(4-Methoxy-phenyl)-2-phenylacrylic acid
Swertiaperennine
Swertianin
Decussatin
Luteolin
Lupinifolin
Citflavanone
8-Prenyldaidzein
5-Deoxy-30-prenylbiochanin
Elaeocarpaceae
Elaeocarpaceae
Elaeocarpaceae
56
56
56
42
17
17
17
17
17
17
17
17
17
59
(Continued)
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1410
Table 1
(Continued)
Compound
20-Methoxy-40,50-methylenedioxy-7,8-[2(1-methylethenyl)furo]isoflavone
()-Maackiain
6,7-Dimethoxy-3 0,4 0methylenedioxyisoflavone
7,2 0-Dimethoxy-4 0,5 0methylenedioxyisoflavone
5-Acetonyl-7-hydroxy-2methylchromone
Anhydrobarakol
7-Demethylartonol E
Bartericin B
Isobavachalcone
Talaumidin
5-Galloylquercetin-3-O-R-Larabinofuranoside
2 0,6 0-Dihydroxy-4 0methoxydihydrochalcone
3-Farnesyl-p-hydroxybenzoic acid
Polygohomoisoflavanone
2-Propen-1-one,1-(2,4-dihydroxy-3,
6-dimethoxyphenyl)-3-phenyl2-Propen-1-one, 1-(2-hydroxy-4,
6-dimethoxyphenyl)-3-phenyl1-Propanone, 1-(2,6-dihydroxy-4-methoxyphenyl)-3-phenyl1-Propanone, 1-(2,6-dihydroxy-3,
4-dimethoxyphenyl)-3-phenyl4H-1-Benzopyran-4-one,2,3-dihydro5-hydroxy-7-methoxy-2-phenyl2-Propen-1-one,1-(2,4-dihydroxy6-methoxyphenyl)-3-phenylQuercetin
5-O-b- D -Glucopyranosyl-7,4 0dimethoxy-3 0-hydroxy-4phenylcoumarin
5-O-b- D -Glucopyranosyl-7-methoxy30,40-dihydroxy-4-phenylcoumarin
Bipinnatones A
Bipinnatones B
Bergapten
Syringaldehyde
Plant
Family
IC50 (mM)
Reference no.
Leguminosae
>50
60
Leguminosae
Leguminosae
>50
>50
60
60
Leguminosae
>50
60
Leguminosae
19.4 (3D7)
50
Leguminosae
Moraceae
Moraceae
36.4 (3D7)
18.0 (K1)
19.3 (W2)
50
13
28
Moraceae
19.0 (W2)
28
Myristicaceae
Myrtaceae
60.5 (Dd2)
14.5 (W2)
61
62
Piperaceae
26
Rubiaceae
12.7 (F32)
16.9 (FcB1)
29.78 (FcB1)
19.2 (D6)
18.2 (W2)
16.6 (D6)
17.8 (W2)
15.7 (D6)
11.3 (W2)
23.5 (D6)
22.8 (W2)
11.8 (D6)
12.9 (W2)
16.3 (D6)
21.8 (W2)
14.0 (D6)
9.5 (W2)
18.2 (K1)
Rubiaceae
29
Piper hostmannianum
C.DC. var. berbicense
Piper tricuspe C.DC.
Polygonum senegalense
Meisn. forma senegalense
Polygonum senegalense
Meisn. forma senegalense
Polygonum senegalense
Meisn. forma senegalense
Polygonum senegalense
Meisn. forma senegalense
Polygonum senegalense
Meisn. forma senegalense
Polygonum senegalense
Meisn. forma senegalense
Polygonum senegalense
Meisn. forma senegalense
Morinda morindoides (Baker)
Milne-Redh.
Hintonia latiflora
(Sesse & Moc. ex DC.) Bullock
Piperaceae
Polygonaceae
Polygonaceae
Polygonaceae
Polygonaceae
Polygonaceae
Polygonaceae
Polygonaceae
48
25
25
25
25
25
25
25
63
Hintonia latiflora
(Sesse & Moc. ex DC.) Bullock
Boronia bipinnata Lindl.
Boronia bipinnata Lindl.
Zanthoxylum flavum Vahl.
Vepris uguenensis Engl.
Rubiaceae
29
Rutaceae
Rutaceae
Rutaceae
Rutaceae
64
64
40
65
Greveichromenol
Nitidanin
Simaroubaceae
Tiliaceae
6-(80Z,110Z,140Z-Heptadecatrienyl)salicylic acid
Piceid
Longistylin A
Longistylin C
Violaceae
64 (Hbase II assay)
51 (Hbase II assay)
21.8 (W2)
71.4 (3D7)
117.6 (FcM29)
38.3 (K1)
21.2 (D6)
18.4 (W2)
13.3 (D10)
Vitaceae
Vitaceae
Vitaceae
13.2 (D10)
34.3 (D10)
19.2 (D10)
37
37
37
Quinones
Primin (82), a natural benzoquinone occurring in Primula
obconica Hance. (Primulaceae), was investigated for its
antiprotozoal potential. Compound 82 showed moderate
activity against K1 with an IC50 of 10.9 mM.[67] A new
66
41
47
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Terpenoid compounds
Sesquiterpenes
Two sesquiterpenes, corymbolone (104) and mustakone
(105), isolated from the chloroform extract of the rhizomes
1411
of Cyperus articulatus L. (Cyperaceae), exhibited antiplasmodial properties (IC50 = 4.53 and 0.64 mM against NF54
and IC50 = 8.14 and 1.15 mM against EN36, respectively).[77]
Oncosiphon piluliferum (L.f.) Kallersjo (Asteraceae) is used
traditionally to treat a variety of ailments, mainly fevers.
Sesquiterpene lactones of the germacranolide and eudesmanolide types displaying antiplasmodial activity against D10
were isolated and identified: sivasinolide (106, IC50 =
9.8 mM), tatridin A or tavulin (107, IC50 = 1.5 mM) and
tanachin (108, IC50 = 1.5 mM). In addition, the cytotoxic
effects of the active compounds against Chinese Hamster
Ovarian cells were evaluated and the compounds were found to
be toxic to mammalian cells at similar concentrations.[78] Two
new helenanolide sesquiterpene lactones, helenalin-[2-(1hydroxyethyl)acrylate] (109) and helenalin-[2-hydroxyethyl3-methyl)acrylate] (110), as well as one known related
structure, 11a,13-dihydrohelenalin-[2-(1-hydroxyethyl)acrylate] (111), were isolated from an ethyl acetate extract of
leaves of Vernoniopsis caudate (Drake) Humbert (Asteraceae).
The three lactones displayed strong antiplasmodial activity
against FcB1, with IC50 values of 1, 0.19 and 0.41 mM,
respectively. However, these compounds also exhibited considerable cytotoxicity on KB cells (IC50 < 1 mM in each
case).[79] Leaves and flowers of Artemisia gorgonum Webb
(Asteraceae) collected in Fogo, Cape Verde, were phytochemically investigated and resulted in the isolation of a known
germacranolide, hanphyllin (112), which exhibited antiplasmodial activity with an IC50 of 9.7 mM against FcB1 and was
weakly cytotoxic to the Vero cell line (IC50 = 111.9 mM).[80]
Two new sesquiterpene lactones, wedelolides A (113) and B
(114), were isolated from the leaves of Wedelia trilobata Hitchc.
(Asteraceae). The two compounds displayed antimalarial
activity with IC50 values of 4.2 and 9.1 mM, respectively.[81]
A new sesquiterpene lactone as well as two known ones were
isolated from the dichloromethane fraction of an aqueous extract
from Vernonia cinerea Less. (Asteraceae). Three compounds,
8a-tigloyloxy-hirsutinolide-13-O-acetate (115), 8a-(4-hydroxyethacryloyloxy)-hirsutinolide-13-O-acetate (116) and vernolide D (117), were active against W2 with IC50 values of
3.9, 3.7 and 3.5 mM, respectively.[82] Fractionation of the
dichloromethane extract of the leaves of Vernonia staehelinoides
Mart. ex Baker (Asteraceae) allowed the isolation of two
structurally related hirsutinolides. These compounds displayed
strong antiplasmodial activity against D10 and were less effective
against K1, compound 118, 8a-(2-methylacryloyloxy)-3-oxo1-desoxy-1,2-dehydrohirsutinolide-13-O-acetate had an
IC50 = 0.6 mM on D10 and IC50 = 4.5 mM on K1 and compound
119, 8a-(50-acetoxysenecioyloxy)-3-oxo-1-desoxy-1,2-dehydrohirsutinolide-13-O-acetate had an IC50/D10 = 0.5 mM and
IC50/K1 = 5.5 mM. These two compounds were found to be
cytotoxic to mammalian Chinese Hamster Ovarian cells at
similar concentrations.[83] Chemical exploration of Camchaya
calcarea Kitam. (Asteraceae) led to the isolation of eight known
sesquiterpene lactones, which exhibited moderate antiplasmodial
activity against K1, including goyazensolide (120) (IC50 =
3.3 mM), lychnophorolide B (122) (IC50 = 7.2 mM), isogoyazensolide (123) (IC50 = 4.4 mM), isocentratherin (124)
(IC50 = 5.6 mM), 5-epi-isogoyazensolide (125) (IC50 = 4.4 mM)
and 5-epi-isocentratherin (126) (IC50 = 8.0 mM). The most
promising was lychnophorolide A (121) with an IC50 of
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1412
O
O
O
H3CO
83
O
O
82
HO
84
O
O
85
HO
O
OH
OH
OH
HO
OH
H
HO
O
OCH3
HO
O
86
OH
O
HO
OH
OCH3
HO
O
NaO3SO
OH
OH
OH
88
HO
OH
R1
OH
OH
OR2
OH
OH
R3
OH O
OH
93. R15 Geranyl,R25 Prenyl, R35 H
94. R15 Geranyl, R25 H, R35 Geranyl
OH
H
HO
HO
O
OCH3
OR
90
HO
95. R5 Geranyl
96. R5 Prenyl
HO
OH
HO
OH
OCH3
HO
R
OH
OH
R3
HO
OH
R1
H3C
HO
OH
R4
OCH3
HO
OH
91. R5 H
92. R5 OH
O
HO
87
OH
89
R2
98. R15 Prenyl, R25 Prenyl, R35 OH, R45 H
99. R15 H, R25 Prenyl, R35 H, R45 Prenyl
100. R15 H, R25 Prenyl, R35 Prenyl, R45 H
101. R15 H, R25 H, R35 Prenyl, R45 Prenyl
102. R15 H, R25 H, R35 Prenyl, R45 H
H
N
97. R5 Geranyl
O
103
Figure 8 Quinones and derivatives with moderate or promising activity in vitro against various strains of P. falciparum
Table 2 Quinones presenting low or no activity in vitro against various strains of P. falciparum
Compound
Newbouldiaquinone A
Bauhinoxepin H
Rubiadin-1-methyl ether
Nordamnacanthal
Damnacanthal
Chrysarin
Alizarin
2,6-Dimethoxy-1-acetonylquinol
Plant
Newbouldia laevis Seem.
Bauhinia purpurea L.
Prismatomeris malayana Ridl.
Prismatomeris malayana Ridl.
Prismatomeris malayana Ridl.
Morinda morindoides (Baker) Milne-Redh.
Morinda morindoides (Baker) Milne-Redh.
Grewia bilamellata Gagnep.
Family
Bignogniaceae
Leguminosae
Rubiaceae
Rubiaceae
Rubiaceae
Rubiaceae
Rubiaceae
Tiliaceae
IC50 (mM)
Reference no.
78% at 20 mM (NF54)
11.2 (K1)
105.4 (NF54/64)
60.4 (NF54/64)
42.2 (D6)
23.0 (W2)
75
11
76
76
76
63
63
41
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Diterpenes
Geranylgeraniol (129) was isolated from the stems and
leaves of Croton lobatus L. (Euphorbiaceae), a medicinal
plant used in western Africa in traditional folk medicine to cure
malaria, pregnancy troubles and dysentery. The compound
showed reasonable antiplasmodial activity against K1 with an
IC50 value of 3.7 mM and good selectivity (SI value > 25).[57]
A new diterpenoid, steenkrotin A (130), was isolated from
an ethanol extract of the leaves of Croton steenkampianus
OH
OH
OH
O
105
H
H
106
H
109. R25
H
HO
O
R2O
O
H
OR
HO
108
HO
O
HO H
H
115. R 5
H
HO
HO
O
OR
O 116. R 5
O
O
O
H
HO
H OR1
H3C
118. R 5
OR
O
OAc
O
O
120. R 5
O
O
127
OH
OH
O
117. R 5
OR
112
H
HO
107
O
R2O
OH
O 111. R25
110. R25
OH
OH
104
OH
1413
HO
119. R 5
121. R 5
O
O
122. R 5
O
OR
123. R 5
HO
O
OR
HO
H
O
124. R 5
125. R 5
126. R 5
OH
128
Figure 9 Sesquiterpenes with moderate or promising activity in vitro against various strains of P. falciparum
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1414
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OH
HO
129
OH
HO
132
O
HO
130
HO
131
OH
OH
133
HO
HH
EZ
H
O
134
O
O
OH
137
O
R2
OH
135
O O
1415
O
O
136.
138.
139.
140.
O O
OR1
O
O
R1 5 H, R2 5 CH3
R1 5 CH3, R2 5 CH3
R1 5 COPh, R2 5 H
R1 5 COPh, R2 5 CH3
141
145
142
O
H H O
HO
O
O
OCH3
OO
O
O
H
O
O
H
144
OO
O
OH
OO
O
OH
O
O
OCH3
146
OO
OH
O
143
147
H
148
O
R1
H
H
R5
R6
R4
OH
R3
R1
OH
O
H
H
O
HO
OH
R2
O
O
OO
OO
O
R2
H
R6
R3
R5
OH
R4
155. R15 -OAc, -H, R25 R35 R45 H, R55 OAc, R65 CH2
157. R15 -OAc, -H, R25 R35 H, R45 R55 OAc, R65 O
158. R15 R65 O, R25 R35 H, R45 R55 OAc
159. R15 -OAc, -H, R25 R45 R55 H, R35 OAc, R65 CH2
162. R15 O, R25 R35 R55 H, R45 OAc, R65 -H, -COOCH3
163. R15 O, R25 R35 H, R45 R55 OAc, R65 -H, -COOCH3
166. R15 -OAc, -H, R25 OAc, R35 R45 R55 H, R65 CH2
167. R15 -OAc, -H, R25 OAc, R35 R45 R55 H, R65 O
168. R15 -OAc, -H, R25 R45 R55 H, R35 OAc, R65 O
170. R15 -OAc, -H, R25 R35 R45 H, R55 OH, R65 O
171. R15 -OAc, -H, R25 R45 R55 H, R35 OAc, R65 O
172. R15 R65 O, R25 R35 H, R45 OAc, R55 OH
174. R15 -OAc, -H, R25 R35 H, R45 R55 OAc, R65 CH2
178. R15 -OAc, -H, R25 R35 OAc, R45 R55 H, R65 CH2
179. R15 O, R25 R35 H, R45 OAc, R55 OH, R65 -H, -COOCH3
182. R15 O, R25 R35 H, R45 R55 OAc, R65 CH2
Figure 10 Diterpenes with moderate or promising activity in vitro against various strains of P. falciparum
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1416
156
150
H
AcO
HO
OH
OAc
OH
O
O
187
189
OH
OAc 184
OH
O
188
OH
OH
OAc
186
185
OH
OAc
OH
H
H
H
H
O
OAc
O
H
OH
O
O
OH
R3
O
183
OAc
R2
OH
R2
R1
H
OAc
OH
OAc
AcO
OH
169
R1
H
H
OH
H
CH2OH
OAc
OAc
190
HO
HO
HO
191
HO
192
OH O
O
HO
O
O
193
O
HO
O
O
OH
HO
O
OH
OH
HO HO
HO AcO
O
H
194
195
OAc
O H
O
OAc
197
196
AcO
RO AcO
AcO
AcO AcO
OAc
O H
OAc
O H
HO
OAc
OAc
198. R 5 H
199. R 5 Ac
Figure 10 (Continued)
Triterpenes
From the stem bark of Ekebergia capensis Sparrm. (Meliaceae), a triterpenoid derivative was isolated and screened
against FCR-3 and K1 strains. 2,3,22,23-Tetrahydroxy2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene
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1417
Steroids
Four new pregnane glycosides, 12-O-benzoyl-20-O-acetyl
3b,12b,14b,20b-tetrahydroxy-(20S)-pregn-5-ene-6-deoxy3-O-methyl-b-D-allopyranosyl(1!4)-b-D-cymaropyranosyl
(1!4)-b-D-cymaropyranoside (232), 12-O-benzoyl-20-Oacetyl 3b,7a,12b,14b,20b-tetrahydroxy-(20S)-pregn-5-ene6-deoxy-3-O-methyl-b-D-allopyranosyl-(1!4)-b-D-cymaropyranosyl-(1!4)-b-D-cymaropyranoside (233), 12-O-benzoyl-20-O-acetyl 3b,5a,12b,14b,20b-pentahydroxy-(20S)pregn-6-ene-b- D -glucopyranosyl-(1!4)-6-deoxy-3-Omethyl-b- D -allopyranosyl-(1!4)-b- D -cymaropyranosyl(1!4)-b-D-cymaropyranoside (234) and 12,20-dibenzoyl3b,12b,14b,20b-tetrahydroxy-(20S)-pregn-5-ene-b-D-glucopyranosyl-(1!4)-6-deoxy-3-O-methyl-b-D-allopyranosyl(1!4)-b-D-cymaropyranosyl-(1!4)-b-D-cymaropyranoside
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1418
201. R1 5 R2 5 O, R3 5 CHO
202. R1 5 OH, R2 5 H, R3 5 CHO
OH
HO
HO
R3
H
OH
OH
200
HOOC
HO
COOH
R2
R1
205
COOH
O
O
203
206
OH
O
HO
207
HO
HO
H
O
HO
HO
COOH
H
O
209
HO
OH
HO
O
204
COOH
208
H
OH
COOH
HO
212
HO
213
HO
211
HO
210
COOH
HO
OH O
H
O
216
OH
OH O
OH
215
HO
H
H
HO
214
HO
COOH
COOH
OH
OH
H
H
HO
OH
OH
O
OH
OH
217
O
H
218
CO2CH3
HO
O
OCOCH3
O
HO
219
220
Figure 11 Triterpenes with moderate or promising activity in vitro against various strains of P. falciparum
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HO
221
O
223
224
OH
OAc
H
O
O
O
222
1419
H
O
OCH3
OAc
OAc
H
O
OCH3
OAc
OCH3
O
225
O
226
O
O
O
O
AcO
228
227
O
OH
OH
O
O
O
OH
O
O
O
O
O
231
O
O
230
229
O
OAc
O
O
O
OH
O
Figure 11 (Continued)
OR2
OR3
OR1
OH
Sugar
O
HO
OCH3
OH
O
O
OCH3
OH
Sugar
R1
OR2
5I
OH
O
OCH3
O
O
HO
OH
OH
O
H3CO
O
O
OH
OCH3
5 II
O
OCH3
Figure 12 Steroids with moderate or promising activity in vitro against various strains of P. falciparum
Alkaloids
Ornithine and lysine derivatives
The methanolic extract of Albizia gummifera C.A.Sm. (Leguminosae) was fractionated to isolate five known spermine alkaloids
from the alkaloidal fraction, budmunchiamine K (237), 6hydroxybudmunchiamine K (238), 5-normethylbudmunchiamine K (239), 6-hydroxy-5-normethylbudmunchiamine K
(240) and 9-normethylbudmunchiamine K (241). These alkaloids
exhibited good activity with IC50 values of 0.18, 0.29, 0.20, 0.33
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1420
Table 3 Terpenoid compounds presenting low or no activity in vitro against various strains of P. falciparum
Compound
16-Hydroxycleroda-3,13(14)Z-dien-15,16-olide
Lupeol
3-O-(30-Hydroxyeicosanoyl)lupeol
3-O-[(20-(Tetracosyloxy)acetyl]lupeol
3-O-[(100-Hydroxyoctadecyloxy)-20hydroxypropanoyl]lupeol
Uzarigenin
Calactin
Calotropin
Taraxasteryl acetate
Esacetyl-a-cyclopyrethrosin
1,10-Dioxo-1,10-deoxy-1,10-secogorgonolide
3b,4b-Epoxy-1b,10b-epiarborescin
Arborescin
1b,10b-Epoxy-2a-hydroxykauniolide
1a,4a,10a-Trihydroxy-5a,11bH-guaia2-en-12,6a-olide
Ridentin
Anthecularin
Anthecotulide
4-Acetoxyanthecotulide
Methyl populnoate
Populnoic acid
Stigmast-5-en-3-O-b-(D-glucopyranoside)
Endodesmiadiol
Canophyllal
Cerin
Morelloflavone
3b-Acetoxyoleanolic acid
Sutherlandioside A
Sutherlandioside B
Sutherlandioside C
Sutherlandioside D
Laetianolide A
Plant
Family
IC50 (mM)
Reference no.
Annonaceae
Apocynaceae
Apocynaceae
Apocynaceae
Apocynaceae
Asclepiadaceae
Asclepiadaceae
Asclepiadaceae
Asclepiadaceae
Asteraceae
Asteraceae
Asteraceae
Asteraceae
Asteraceae
Asteraceae
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
16.7 (D10)
50.0 (FcB1)
50.4 (FcB1)
15.3 (FcB1)
22.1 (FcB1)
32.1 (FcB1)
122
122
122
122
78
80
80
80
80
80
Asteraceae
Asteraceae
Asteraceae
Asteraceae
Celastraceae
Celastraceae
Celastraceae
Clusiaceae
Clusiaceae
Clusiaceae
Clusiaceae
Clusiaceae
Fabaceae
Fabaceae
Fabaceae
Fabaceae
Flacourtiaceae
21.4 (FcB1)
>50 (K1)
16.1 (K1)
16.7 (K1)
>50 (D6)
>50 (D6)
>50 (D6)
13.0 (W2)
18.2 (W2)
14.1 (W2)
23.6 (W2)
13.1 (W2)
>50 (D6/W2)
>50 (D6/W2)
>50 (D6/W2)
>50 (D6/W2)
57.6 (F32)
27.5 (FCb1)
>50 (D6/W2)
>50 (D6/W2)
>50 (D6/W2)
22.14 (MRC-02)
80
123
87
87
124
124
124
125
125
125
125
125
126
126
126
126
92
127
127
127
128
>50 (W2)
12.7
76 (3D7)
83.1 (F32)
>50 (F32)
129
130
131
132
133
105
115
115
134
135
>50
>50
>50
>50
11.3 (K1)
(FCR-3/3D7)
(FCR-3/3D7)
(FCR-3/3D7)
(FCR-3/3D7)
15-O-Ethylleopersin C
15-O-Methylleopersin C
15-Epi-O-methylleopersin C
12,17-Diacetoxy,15-hydroxy,2-oxo,3,13
E(14)-diene clerodane
Fagraldehyde
Geranylfarnesol
Kurubasch aldehyde
16-Oxolabda-8(17),12(E)-dien-15-oic acid
Methyl 14,15-epoxylabda-8(17),12Ediene-16-oate
Ekeberin D4
Domesticulide D
6-Acetoxymexicanolide
Walsuronoid
Leonurus cardiaca L.
Leonurus cardiaca L.
Leonurus cardiaca L.
Gomphostemma crinitum Wall.
Lamiaceae
Lamiaceae
Lamiaceae
Lamiaceae
Loganiaceae
Marantaceae
Meliaceae
Meliaceae
Meliaceae
Meliaceae
Meliaceae
Meliaceae
Meliaceae
Walsuronoid B
Meliaceae
24-Methylene cycloartenol
7a-Acetoxydihydronomilin
Methylangolensate
6a-Acetoxyepoxyazadiradione
Kotschyin A
Methyl 3,4-dihydroxy-5-(3-methyl-2butenyl)benzoate
Methyl 4-hydroxy-3-(3-methyl-2butenyl)benzoate
Meliaceae
Meliaceae
Meliaceae
Meliaceae
Meliaceae
Piperaceae
40 (FCR-3)
11.8 (K1)
18.4 (K1)
40% at 40 mM
(3D7)
40% at 40 mM
(3D7)
12.3 (W2)
34.9 (W2)
48.7 (W2)
12.0 (K1)
> 5 (K1)
17.4 (F32)
Piperaceae
12.7 (F32)
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74
121
121
121
121
134
117
117
117
118
119
135
(Continued)
1421
(Continued)
Compound
Plant
Family
Piperaceae
b-Acetylolean-12-en-28-olic acid
Methyl uguenenoate
Rhizophoraceae
Rubiaceae
Lamiaceae
Rubiaceae
Rutaceae
3,4-Dihydro-methylcatalpol
Scrolepidoside
Catalpol
6-O-Methylcatalpol
Sinuatol
aucubin
6-O-b-D-Xylopyranosylaucubin
Ajugol
Ajugoside
Iridoid-related aglycone
3-O-b-D-glucopyranosylpseudojujubogenin
Bacoside A3
Bacoside A6
Bacopaside II
Bacopaside IV
Bacopaside V
Bacopaside X
Bacopaside N2
Bacopasaponin C
Bacopasaponin G
Buddlejasaponin
3a,20-Lupandiol
Aulacocarpin A
Zambesiacolactone A
Zambesiacolactone B
(1R,2S,5S,9S,10S,11R,13R)-1,2,11trihydroxypimara-8(14),15-diene
and 0.24 mM, respectively, on NF54, and 1.43, 1.73, 1.88, 1.72
and 1.79, respectively, on ENT30. Four of these alkaloids were
further evaluated intraperitoneally for activity against P. berghei
in vivo. The alkaloids showed chemosuppression percentages of
parasitaemia in mice ranging from 43 to 72% at 20 mg/kg per day
The use of the extracts of A. gummifera for the treatment of
malaria in traditional medicine seems to have a scientific
basis.[141] Vertine (242) and epi-lyfoline (243) were isolated
from Heimia salicifolia Link & Otto (Lythraceae) and showed
antimalarial activity with IC50 values of 10.9 and 6.7 mM,
respectively.[142] A new lycorine derivative LT1 (244), 1-O(30S)-hydroxybutanoyllycorine was isolated from the aerial part
and bulbs of Lycoris traubii Hayward (Amaryllidaceae). It
showed significant activity against FCR-3 and K1 strains
(IC50 = 1.2 and 1.6 mM, respectively).[143]
Figure 13 shows alkaloids derived from ornithine and
lysine with moderate or promising activity in vitro against
various strains of P. falciparum.
Zingiberaceae
Zingiberaceae
Zingiberaceae
Zingiberaceae
IC50 (mM)
Reference no.
34.0 (F32)
135
14.6 (K1)
32.3 (CQs)
19.8 (3D7)
11.9 (K1)
20.7 (3D7)
27.5 (FCM29)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
24.5 (K1)
19.8 (D6)
19.1 (W2)
13.7 (FcB1)
17.2 (FcB1)
15.5 (FcB1)
27.5 (K1)
136
110
58
137
65
138
138
138
138
138
138
138
138
138
138
139
139
139
139
139
139
139
139
139
139
140
41
89
89
89
94
siamea Lam. (Leguminosae). It showed promising antiplasmodial activity (IC50 23.5 nM).[144] Zanthoxylum rhoifolium
Lam. (Rutaceae) bark is a medicinal plant traditionally used
in French Guiana to treat and prevent malaria. Bioassayguided fractionation of the alkaloid extract yielded three
benzophenanthridine alkaloids. Dihydronitidine (246) was
evaluated against FcB1 (IC50 = 4.9 mM).[145] Biologically
guided fractionation of the methanolic extract of the roots of
Zanthoxylum flavum Vahl (Rutaceae) led to the isolation of
two alkaloids, dihydrochelerythrin (247) and chelerythrine
acetonate (248). Compound 247 was only moderately active
with an IC50 of 10.6 mM on D6. Compound 248 displayed
greater activity with IC50 values of 5.7 and 3.4 mM on D6
and W2 strains, respectively.[40] Decoction of Strychnopsis
thouarsii Baill. (Menispermaceae) is used in Malagasy
traditional medicine to fight malaria. It has been shown
that this traditional remedy prevents malaria infection by
targeting Plasmodium at its early liver stage. Bioassayguided fractionation of S. thouarsii stem barks extracts,
using a rodent Plasmodium yoelii liver stage parasites
inhibition assay, led to the isolation the new morphinan
alkaloid tazopsine (249) together with sinococuline (250).
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1422
R3
R2
R1
H
OH
244
O
OH
H
HO
HO
N
H O
242
OH
243
O
H
O
H
O
Figure 13 Alkaloids derived from ornithine and lysine with moderate or promising activity in vitro against various strains of P. falciparum
and 1,2-dehydrotelobine (266). They demonstrated antiplasmodial activity with IC50 values of 1.72, 0.93, 1.39 and
12.4 mM, respectively, on 3D7, and 0.35, 1.10, 1.63 and
1.52 mM, respectively, on W2.[154] Three new fully dehydrogenated naphthylisoquinoline alkaloids, the 7,10-coupled
ent-dioncophylleine A (267), the 7,1 0-coupled 5 0-Odemethyl-ent-dioncophylleine A (268), and the 7,80-linked
dioncophylleine D (269), were isolated from the leaves of the
liana Ancistrocladus benomensis Rischer & G.Bringmann
(Ancistrocladaceae). Compounds 267 and 268 exhibited
moderate antiplasmodial activity against K1 with IC50
values of 10.5 and 8.6 mM, respectively. Compound 269
showed better activity with a low IC50 (1.3 mM).[155] From the
roots of a recently discovered Ancistrocladus taxon with close
affinity to Ancistrocladus congolensis J. Leonard (Ancistrocladaceae), six new naphthylisoquinoline alkaloids, 50-Odemethylhamatine (270), 50-O-demethylhamatinine (271),
6-O-demethylancistroealaine A (272), 6,50-O,O-didemethylancistroealaine A (273), 5-epi-6-O-methylancistrobertsonine A
(274), and 5-epi-40-O-demethylancistrobertsonine C (275),
and also the known 6-O-demethylancistrobrevine A (276),
were isolated. All of the naphthylisoquinoline alkaloids tested
were found to exhibit antiplasmodial activity against K1 strain:
IC50 = 2.5, 7.2, 4.4, 5.4, 4.4, 6.2 and 5.0 mM, respectively.[156]
Figure 14 shows alkaloids derived from phenylalanine
and tyrosine with moderate or promising activity in vitro
against various strains of P. falciparum.
Tryptophane derivatives
Bioassay-guided fractionation of the antimalarial CHCl3
extract of the dried stem of Nauclea orientalis (L.) L.
(Rubiaceae) resulted in the isolation of a novel tetrahydro-bcarboline monoterpene alkaloid glucoside, naucleaorine
(277), which showed activity with an IC50 of 6.9 mM on
D6 and 8.0 on W2.[112] An indole alkaloid, naucleofficine A
(278), was isolated from the stems (with bark) of Nauclea
officinalis Pierre ex Pitard (Rubiaceae). Compound 278
exhibited moderate antimalarial activity against FCC1-HN
with an IC50 value of 9.7 mM and no cytotoxic effect was
observed.[157] A dimeric indoloquinoline alkaloid, biscryptolepine (279), originally obtained from the plant Cryptolepis
sanguinolenta (Lindl.) Schltr. (Asclepiadaceae), showed
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HO
H3CO
N
H3CO
245
246
OH
HO
R1
R2
HO
NH
H
OCH3
O
HO
O
H
O
O
H
NH
H3CO
O
252
251
OCH3
OCH3
OCH3
OCH3
OCH
HO
HO
H3CO
OCH3
NH
H3CO
N
HO
H3CO
253
OH
249. R1 5 OH, R2 5 H
250. R1 5 R2 5 H
248
OCH3
H3CO
247
1423
255
OCH3
OCH3
254
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
OH
HO
O
O
258
HN
256
N
H
260
OH
OH
OCH3
H3CO
OH
HO
O
N
H
257
N
H
OCH3
261
OH
OH
OCH3 H3CO
H3CO
N
H3CO
OCH3
N
H
OCH3
OCH3
OCH3
O
259
H3CO
263
HO
OCH3
262
H3CO
H3CO
O
OH
H3CO
O
OH
264
O
O
265
OCH3
266
H3CO
HO
OH
H3CO
OH OCH3
OH
H3CO
H3CO
268
267
H3C
OH OCH3
H3CO
HO
269
O OR 1
272. R15 CH
273. R15 H
H3C
NH
OCH3
OH OCH3
274
275
H3CO
271
OCH3
OCH3
270
O OCH3
HO
HO
OH
H3CO
N
OCH3
OCH3
HO
276
H3CO
H3CO
N
OCH3
Figure 14 Alkaloids derived from phenylalanine and tyrosine with moderate or promising activity in vitro against various strains of P. falciparum
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1424
Steroidal alkaloids
Bioguided phytochemical investigation of Sarcococca hookeriana Baill. (Buxaceae) yielded two new pregnane-type
steroidal alkaloids hookerianamide H (281) and hookerianamide I (282), along with three known alkaloids, Namethylepipachysamine D (283), sarcovagine C (284) and
dictyophlebine (285). These compounds showed reasonable
antiplasmodial activity with IC50 values of 3.5, 6.6, 10.3, 3.4
N
O
N
H
N
H
O
HO
NH
OH
O
OH
OCH3
279
OH
277
278
HO
N
H
OH
OH
OH
280
OH
Figure 15 Alkaloids derived from tryptophane with moderate or promising activity in vitro against various strains of P. falciparum
R1
282. R1 5 H
283. R1 5 CH3
H
N
H
H
N
281
R1
H
N
H
R2
Tig 5
H
H
H
H
H
N
R1
N
R1
286. R1 5 CH3
288. R1 5 H
287. R1 5 CH3
289. R1 5 H
Figure 16 Steroidal alkaloids with moderate or promising activity in vitro against various strains of P. falciparum
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1425
OR1
H
O
O
H
R3
HN
H
N
HN
H
N
O O
O
H
N
O
H3CO
OCH3
292
R2
290. R1 5 R2 5 CH3, R3 5 CH2CH(CH3)2
291. R1 5 R2 5 CH3, R3 = CH(CH3)2
Figure 17 Other N-containing compounds with moderate or promising activity in vitro against various strains of P. falciparum
Table 4 Alkaloids presenting low or no activity in vitro against various strains of P. falciparum
Compound
Plant
Family
IC50 (mM)
Reference no.
Annonaceae
Annonaceae
Annonaceae
Annonaceae
Annonaceae
Annonaceae
Apocynaceae
27.8 (FcB1)
>37 (FcB1)
18.4 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
>50 (K1)
149
149
150
164
164
164
49
Apocynaceae
19 (K1)
49
165
165
166
166
166
166
144
147
148
148
167
112
Naucleofficine B
Naucleofficine C
Naucleofficine D
Naucleofficine E
Uncarine D
Maculosidine
Flindersiamine
r-Fagarine
Rutaevine
Tegerrardin A
Dihydroavicine
Fagaridine
7,9-Dimethoxy-2,3methylenedioxybenzophenanthridine
Bis[6-(5,6-dihydrochelerythrinyl)] ether
Rubiaceae
Rubiaceae
Rubiaceae
Rubiaceae
Rubiaceae
Rutaceae
Rutaceae
Rutaceae
Rutaceae
Rutaceae
Rutaceae
Rutaceae
Rutaceae
>50 (K1)
>50 (K1)
Nt
Alkaloidal extract =
6.11 g/ml (Gombak A)
0.69 g/ml (D10)
22.0
16.1 (P. yoelii)
32.6 (W2)
>50 (W2)
13.5 (FcB1)
12.4 (D6)
13.2 (W2)
42.1 (FCC1-HN)
40.5 (FCC1-HN)
39.8 (FCC1-HN)
38.3 (FCC1-HN)
46.2 (W2)
>50 (3D7/FCM29)
>50 (3D7/W2)
>50 (3D7/W2)
>50 (3D7/W2)
12.3 (D10)
33.0 (FcB1)
38.0 (FcB1)
>50 (3D7/FCM29)
Rutaceae
Zanthomamide
Lemairamide
Harmine
Harmaline
Rutaceae
Rutaceae
Zygophyllaceae
Zygophyllaceae
Predicentrine
Aristolactam
Octadeca-9,11,13-triynoic acid
N-methylouregidione
Ouregidione
Oxostephanine
Ellipticine
Aspidocarpine
Integerrimide A
Integerrimide A
(-)-Phoebescortechiniine
Phoebegrandine A
Phoebegrandine B
Tetrahydropronuciferine
Cassiarin B
10-Epi-tazopsine
Tetrahydropalmatine
Xylopinine
Cycleanine N-oxide
Epimethoxynaucleaorine
Euphorbiaceae
Euphorbiaceae
Lauraceae
Lauraceae
Lauraceae
Lauraceae
Leguminosae
Menispermaceae
Menispermaceae
Menispermaceae
Menispermaceae
Rubiaceae
15.3 (3D7)
14.9 (FCM29)
>50 (3D7/FCM29)
>50 (3D7/FCM29)
37.7
>50
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157
157
157
157
168
65
169
169
169
170
145
145
171
171
171
171
172
172
1426
Other metabolites
Two compounds were isolated from the stems and leaves of
Croton lobatus L. (Euphorbiaceae), a medicinal plant used
in western Africa in traditional folk medicine to cure
malaria, pregnancy troubles and dysentery. (Z,Z,Z)-9,12,15Octadecatrienoic acid methyl ester (293) and 8,11,17,21tetramethyl-(E,E,E,E)-8,10,17,21-tetraentetracosanoic acid
(294) showed some antiplasmodial activity on K1 strain,
with IC50 values of 10.9 and 9.1 mM, respectively, and SI
values of 18.4 and over 20, respectively.[57] Bioassaydirected fractionation of the CHCl3 extract of the dried
stems of Rourea minor (Gaertn.) Aubl. (Connoraceae) liana
led to the isolation of rouremin (295), as well as a known
COOCH3
293
294
COOCH3
O
O
OH
HO
O
O O
O
297
O
NH2
O
HO
OH
OH
OH
OH
O
O
296
HO
O
HO
OH
O
OH
OH
O
R3
O
O
R1O
R2O
HO
HO
O
O
HO
HO
295
301
O
OH
COOH
OH
OH
O
O
O
O
O
302
O
303
O
Figure 18 Other metabolites with moderate or promising activity in vitro against various strains of P. falciparum
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1427
Table 5 Other metabolites presenting low or no activity in vitro against various strains of P. falciparum
Plant
Family
IC50 (mM)
Reference no.
Annonaceae
Arialaceae
Santalaceae
Sapindaceae
>50 (K1)
19
27.3 (K1)
11.7 (FcB1)
176
175
177
173
Compound
19-(2-Furyl)nonadeca-5,7-diynoic acid
8-Hydroxyheptadeca-4,6-diyn-3-yl ethanoate
Scleropyric acid
Matayoside C
anoate (303). They were active with IC50 values of 1.4 and
2.2 mM, respectively.[175]
Figure 18 shows other metabolites with moderate or
promising activity in vitro against various strains of
P. falciparum.
Table 5 gives the tested other metabolites presenting
low or no activity in vitro against various strains of
P. falciparum.[173,175177]
Discussion
Several plants are used in traditional medicine in many
countries for the treatment of malaria or symptoms of the
50
High activity
45
Moderate activity
40
Number of compounds
35
30
25
20
15
10
Xanthones
Triterpenes
Tannins
Stilbenes
Steroids
Sesquiterpenes
Quinones
Other phenolic
derivatives
Other metabolites
Lignans
Flavonoids
Diterpenes
Coumarins
Alkaloids
Chemical class
Figure 19 Number of compounds with high (IC50 2 mM) or moderate (2 < IC50 11 mM) activity in vitro against various strains of
P. falciparum, classified according to their chemical classes
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1428
25
High activity
Moderate activity
Number of compounds
20
15
10
Amaryllidaceae
Anacardiaceae
Ancistrocladaceae
Annonaceae
Apocynaceae
Arialaceae
Aristolochiaceae
Asclepiadaceae
Asphodelaceae
Asteraceae
Buddlejaceae
Buxaceae
Caesalpiniaceae
Cannabaceae
Celastraceae
Clusiaceae
Combretaceae
Connaraceae
Cucurbitaceae
Cupressaceae
Cyperaceae
Ebenaceae
Euphorbiaceae
Flacourtiaceae
Ginkgoaceae
Lamiaceae
Lauraceae
Leguminosae
Lythraceae
Magnioliaceae
Meliaceae
Menispermaceae
Moraceae
Ochnaceae
Piperaceae
Polygonaceae
Primulaceae
Rhamnaceae
Rubiaceae
Rutaceae
Sapindaceae
Scrophulariaceae
Simaroubaceae
Tiliaceae
Violaceae
Vitaceae
Zingiberaceae
Plant family
Figure 20 Number of compounds with high (IC50 2 mM) or moderate (2 < IC50 11 mM) activity in vitro against various strains of
P. falciparum, classified according to the plant family from which they were isolated
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Conclusions
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 approach appears to be a promising
1429
Declarations
Conflict of interest
Michel Frederich is a senior research associate from the
FNRS.
Funding
This review received no specific grant from any funding
agency in the public, commercial or not-for-profit sectors.
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