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~ 43 ~
International Journal of Herbal Medicine 2018; 6(5): 43-56
E-ISSN: 2321-2187
P-ISSN: 2394-0514
IJHM 2018; 6(5): 43-56
Received: 18-07-2018 Accepted: 20-08-2018
Harouna Soré
(1) Laboratoire de
Pharmacognosie, Centre
National de Recherche et de
Formation sur le Paludisme
(CNRFP), Ouagadoudou, 01
BP : 2208 Ouagadougou 01,
Burkina Faso
(2) Laboratoire de Biochimie &
Chimie Appliquée (LABIOCA),
Université Ouaga I Pr Joseph
Ki-Zerbo, 09 BP : 984
Ouagadougou 09, Burkina Faso
Souleymane Sanon
Laboratoire de Pharmacognosie,
Centre National de Recherche et
de Formation sur le Paludisme
(CNRFP), Ouagadoudou, 01
BP : 2208 Ouagadougou 01,
Burkina Faso
Adama Hilou
Laboratoire de Biochimie &
Chimie Appliquée (LABIOCA),
Université Ouaga I Pr Joseph
Ki-Zerbo, 09 BP : 984
Ouagadougou 09, Burkina Faso
Correspondence
Harouna Soré
(1) Laboratoire de
Pharmacognosie, Centre
National de Recherche et de
Formation sur le Paludisme
(CNRFP), Ouagadoudou, 01
BP : 2208 Ouagadougou 01,
Burkina Faso
(2) Laboratoire de Biochimie &
Chimie Appliquée (LABIOCA),
Université Ouaga I Pr Joseph
Ki-Zerbo, 09 BP : 984
Ouagadougou 09, Burkina Faso
Antiplasmodial properties of plants isolated flavonoids
and their derivatives
Harouna Soré, Souleymane Sanon and Adama Hilou
Abstract Flavonoids are one of the major groups of plant secondary metabolites and have long been used as
traditional medicines with scientifically proven pharmacological profits. They are commonly found in
fruit, vegetables, nuts, tea, wine, propolis, seeds, stems, flowers and honey. Among the multiple roles of
flavonoids in plants, we can cite the important roles in transport of auxin, root and shoot development,
pollination, modulation of reactive oxygen species. Flavonoids have received considerable attention
because of their anti-infective and many groups have isolated and identified the structures of flavonoids
possessing antifungal, antiviral, antiplasmodial and antibacterial activity. The antioxidant effects of that
group of natural product in the prevention of human diseases such as cancer and cardiovascular diseases
have also been proven. This review enlightens the prospective antiplasmodial role of flavonoids.
Keywords: Plants, flavonoids, malaria
1. Introduction Malaria, a parasitic disease caused by Plasmodium sp. and transmitted by Anopheles
mosquitoes, remains one of the most common infectious diseases with high mortality and
morbidity, especially in the sub-Saharan Africa, Asia and Latin America. According to WHO
estimation, 216 million new malaria cases and 445000 deaths have occurred worldwide in
2016. Of all, more than 90% were recorded in sub-Saharan Africa, the remaining occurring in
South-East Asia and South America [1]. Morbidity and mortality due to malaria have fallen in
recent years with the advent of artemisinin-based combination therapy (ACT) and widespread
use of impregnated bed nets. However, ACT treatment failures have been reported in some
countries [2], justifying the search for new antimalarial drugs.
The World's poorest people are the most affected with malaria and many of them get treatment
from traditional medicines because they are readily available and cheap compared to
conventional medicine. Some local communities perceive traditional medicine as more
effective than conventional medicine and Traditional Medical Practitioners (TMPs) use herbal
remedies for treatment of malaria in Uganda [3]. A remarkable feature about malaria therapy is
that the two herbal treatments viz. cinchona bark and qinghao leaves were used to treat malaria
effectively for hundreds of years even prior to our basic understanding of malaria. With
advances in analytical techniques, the active antimalarial molecules viz. quinine in the bark of
cinchona trees and Artemsinin in the leaves of qinghao (Artemisia annua) were identified and
used as the magic bullets against Malaria [4]. Chemotherapeutic prophylactics sourced from
plant species are the core of malaria treatment [5]. Over 1200 plant species are reportedly used
for the treatment of malaria and fevers worldwide, and are potentially important sources of
new anti-malarial treatments [6].
Flavonoids comprise a large group of low-molecular-weight polyphenolic plant metabolites
that are found in fruits, vegetables, nuts, seeds, stems, flowers, roots, bark, dark chocolate, tea,
wine and coffee and, thus, are common substances in the daily diet [7]. Flavonoids are plant
pigments that are synthesized from phenylalanine and generally display marvelous colors in
the flowering parts of plants [8]. Besides their relevance in plants, flavonoids are important for
human health because of their high pharmacological activities as radical scavengers [9]. Recent
interest in these substances has been stimulated by the potential health benefits arising from
the antioxidant activities of these polyphenolic compounds. As a dietary component,
flavonoids are thought to have health-promoting properties due to their high antioxidant
capacity in both in vivo and in vitro systems [9, 10]. The functionality in human health is
supported by the ability of the flavonoids to induce human epidemiological studies suggesting
protective effects against cardiovascular diseases, cancers, and other age-related diseases [9].
Although flavonoids have many roles in plants, including their influence on the transport of
auxin [11], they also play important roles in modulating the levels of reactive oxygen species
~ 44 ~
International Journal of Herbal Medicine (ROS) in plant tissues [12], and provide coloring to various
tissues including flowers [13]. In addition, they are required for
signaling symbiotic bacteria in the legume rhizobium
symbiosis and are important in root and shoot development [14].
This review gives a critical account of isolated active
flavonoids from plants possessing significant antimalarial
activity, reported during last ten years. We have reported
compounds exhibiting inhibition activity either IC50 ≤ 10
µg/ml or IC50 ≤ 10 µM
2. Biosynthesis of flavonoids
The biosynthesis of flavonoid is important for understanding
their diversity arid to the design of sound analytical
procedures. The flavonoid molecule are biosynthesized by
their precursor i.e. three molecules of acetic acid and phenyl
propane moiety.
The basic pathways to the core (iso) flavonoid skeleton shave
been established both enzymatically and genetically. It
involves the interaction of at least five different pathways,
namely the glycolytic pathway, the pentose phosphate
pathway, the shikimate pathway that synthesizes
phenylalanine, the general phenylpropanoid metabolism that
produces activated cinnamic acid derivatives (4-coumaroyl-
CoA) and also the plant structural component lignin and
finally the diverse specific flavonoid pathways. The entry
point enzymes are the polyketide synthase chalcone synthase
(CHS) and isoflavone synthase (IFS), more correctly termed
2-hydroxyisoflavanonesynthase, a cytochrome P450 that
catalyzes the aryl migration reaction that converts a 2-
phenylchromanto a 3-phenylchroman. The structural diversity
of (iso) flavonoids is derived by substitution of these basic
carbon skeletons through further hydroxylation,
glycosylation, methylation, acylation and prenylation as well
as, in the case of the proanthocyanidins and phlobaphenes, by
polymerization. The enzymes that catalyze the substitution
reactions are often encoded by large gene families, which can
be recognized in EST and genome data sets through family-
specific conserved sequence motifs [15].
In the pivotal step of flavonoid biosynthesis, ordinarily 4-
coumaroyl-coenzyme A, derived from L-phenylalanine in the
general phenylpropanoid metabolism [16], enters a stepwise
condensation reaction with three molecules of malonyl
coenzyme A to form the C15 chalcone intermediate, the
tetrahydroxychalcone (naringenin chalcone). Chalcone
synthase (CHS) and chalcone isomerase (CHI) are the
enzymes involved in the production of the flavonoid
naringenin. In the following well known flavonoidal
metabolism, the 3,4-cis-diol (leucoanthocyanidin), is formed,
which then appears to be converted to the anthocyanidin
flavyliu cation by a hydroxylation at C-2 followed by two
dehydrations. The enzymic conversion of
leucoanthocyanidins to anthocyanidins, however, has not yet
been demonstrated, and nor has it been for the analogous
reaction with the flavan-4-ol leading to 3-
desoxyanthocyanidins [17]. The oxidation of the flavonoid
naringenin by flavanone 3-hydroxylase (F3H) yields the
dihydrokaempferol (colour less dihydroflavonol) that
subsequently can be hydroxylated on the 3' or 5' position of
the B-ring, by flavonoid 3'-hydroxylase (F3'H) or flavonoid
3',5'-hydroxylase (F3'5'H), producing, respectively,
dihydroquercetin or dihydromyricetin [18]. Figure 1 highlights
the contribution of phenyalanine on flavonoids biosynthesis.
Fig 1: The succinct flavonoid biosynthetic Pathway. Enzymatic Abbreviations: PAL, phenylalanine ammonia lyase; CHS, chalcone synthase;
CHI, chalcone isomerase; IFS, isoflavone synthase; FNSI, flavone synthase I; FNSII, flavone synthase II; F3H, flavonone 3-hydroxylase; F3’H,
flavonoid 3’-hydroxylase ; DFR, dihydroflavonol 4-reductase ; ANS, anthocyanidin synthase.
~ 45 ~
International Journal of Herbal Medicine 3. Classification of flavonoids
From a chemical viewpoint, flavonoids are phenolic
compounds that consist of two benzene rings (A and B)
combined with an oxygen-containing heterocyclic benzopyran
ring (C). Flavonoids can be divided into different classes
based on their molecular structure. The number of these
classes varies according to the classification criteria. For
instance, according to the position of the phenyl ring (B)
relative to the benzopyran moiety, they can be classified as
flavonoids (2-phenyl-benzopyrans), isoflavonoids (3-phenyl-
benzopyrans) and neoflavonoids (4-phenyl-benzopyrans) [19].
Oxidation and saturation status in the heterocyclic ring also
enables division of flavonoids into flavan-3-ols (catéchines,
épicatéchines, théaflavines et théarubigines), flavanones
(naringenin, naringin, silybin, eriodictyol, hesperidin),
flavonols (rutin, quercetin, kaempferol, myricetin, resveratol),
flavones (tangeritin, luteoli, apigenin), and isoflavone
(génistéine, glycitéine, daidzéine), while, depending upon the
type, number and arrangement of substituents, flavonoids can
be further divided into other groups, such as anthocyanidins
(delphinidin, peonidin, maldivin, pelarggonidin), aurone and
chalcones (catéchines, épicatéchines, théaflavines et
théarubigines) [20]. Figure 2 shows the big chemical flavonoid
groups.
Fig 2: Basic structure of flavonoid subclasses
4. Antiplasmodial properties
The antimalarial activity of flavonoids has not been described
earlier, although it constitutes one of the most characteristic
classes of compounds in higher plants. Some recent reports of
antimalarial activity from these classes of compounds are
presented in the table 1. Have been reported here, compounds
that exhibited in vitro an IC50 less than 10 µg/ml or 10 µM
against any Plasmodium.
Table 1: Flavonoids and derivatives presenting high activity in vitro against various strains of P. falciparum
Plant Family Especies Collected
part Molecular structure Name IC50 values
Parasite
strain Authors
Asteraceae Artemisia indica
Willd
Stem bark
exiguaflavanone B
7.05x10-6
g/mL
(1.60x10-5
M)
K1 [21]
~ 46 ~
International Journal of Herbal Medicine
exiguaflavanone A
4.6x10-6
g/mL
(1.08x10-5
M)
K1
Fabaceae Erythrina fusca Stem Bark
Lupinifolin 12.5 µg/mL
K1 [22]
Citflavanone 5.0 µg/mL
Erythrisenegalone ˃12.5
µg/mL
Lonchocarpol A 1.6 µg/mL
Liquiritigenin ˃12.5
µg/mL
8-Prenyldaidzein 3.9 µg/mL
Leguminosae Piptadeniapervillei
Vatke Leaves
(+)-catechin 5-
gallate 1.2 µM
(FcB1)
[23]
(+)-catechin 3-gallate 1.0 µM
Leguminosae Bauhinia
purpurea L. Root
desmethoxymatteucinol 9.5 µM K1 [24]
Annonaceae
Friesodielsia
obovata (Benth.)
Verdc.
Stem bark
and root demethoxymatteucinol
34.1/29.9
µM K1/NF54 [25]
~ 47 ~
International Journal of Herbal Medicine
Moraceae
Artocarpus
rigidus Blume
subsp. rigidus
Rootbark
artonin F 4.8 µM
K1 [26]
cycloartobiloxanthone 8.5 µM
Moraceae
Artocarpus
champeden
Spreng.
Stem bark
artocarpone
A 0.12 µM
3D7 [27]
artocarpone B 0.18 µM
artonin A 0.55 µM
cycloheterophyllin 0.02 µM
artoindonesianin R 0.66 µM
heterophyllin 1.04 µM
heteroflavanone C 1 nM
~ 48 ~
International Journal of Herbal Medicine
artoindonesianin
A2 1.31 µM
Moraceae
Artocarpus
altilis
(Parkinson)
Fosberg
Root
cycloartocarpin 9.9 µM
K1 [28]
artocarpin
6.9 µM
chaplashin 7.7 µM
morusin 4.5 µM
cudraflavone B 5.2 µM
artonin E 6.4 µM
artobiloxanthone 6.9 µM
Leguminosae Erythrina
sacleuxii Hua
Root
bark/Stem
bark
5’
-prenylpratensein
6.3 / 8.7
µM
D6 / W2 [29]
shinpterocarpin 6.6 / 8.3
µM
~ 49 ~
International Journal of Herbal Medicine
Leguminosae
Erythrina stricta
Roxb./ Erythrina
subumbrans
Merr.
Root/
Stem
erybraedin A 8.7 µM
K1 [30]
erystagallin A 9.0 µM
hydroxysophoranone 5.3 µM
Erythrina
subumbrans
Merr.
Bark
Vogelin C 6.6 µM
K1 [31]
lespedezaflavanone B 9.1 µM
Cannabaceae Cannabis
sativa L.
6-prenylapigenin
6.7/4.8 µM D6/W2 [32]
Ochna
integerrima
Lour. (Merr.)
biflavanone 1 157 nM
K1 [33]
Biflavanone 2 10.2 µM
~ 50 ~
International Journal of Herbal Medicine
Anacardiaceae
Campnosperma
panamensis
Standl.
aerial parts
Lanaroflavone 0.48 µM
[34]
Ginkgoaceae Ginkgo
biloba L. Leaves
Ginkgetin 2.0 µM
isoginkgetin 3.5 µM
bilobetin 6.7 µM
sciadopitysin 1.4 µM
Clusiaceae
Garcinia
livingstonei T.
Anderson
Rootbark
ent-naringeninyl-
(I-3a,II-8)-4’
-O-methylnaringenin
6.7 µM [35]
Polygonaceae
Polygonum
senegalense
Meisn.
Aerial
exudates
R1=R2= OCH3, R3= OH
chalcone A 3.1 / 2.4
µM D6 / W2 [36]
R1= H, R2= OH, R3= OCH3 chalcone B 14 / 9.5 µM
Piperaceae
Piper
hostmannianum
C.DC. var.
berbicense
Leaves
Methyllinderatin 5.6 / 5.3
µM
F32 / FcB1 [37]
linderatone 10.3 / 15.1
µM
Moraceae
Dorstenia
barteri var.
subtriangularis
(Engl.) Hijman
& C.C.
twigs
bartericin A 2.2 µM
W2 [38]
~ 51 ~
International Journal of Herbal Medicine Berg
stipulin 5.1 µM
4-hydroxylonchocarpin
3.4 µM
kanzonol B 9.6 µM
Bromeliaceae
Vriesea
sanguinolenta
(L)
Rh= rhamnose
6-Hydroxyluteolin-7-O-(1' '-
α-rhamnoside)
2.1 3 / 3.32
µM K1 / F-54 [39]
Fabaceae
Andira inermis
(W. Wright)
Kunth ex DC.
Calycosin 4.2 / 9.8
µg/ml
poW / Dd2 [40]
Genistein 2 / 4.1
µg/ml
Guttiferaceae Allanblackia
floribunda Root bark
morelloflavone
3.36±2.00 /
4.8±2.2
µg/ml
F32/FcM29 [41]
volkensiflavone
1.18±1.25 /
0.95±0.27
µg/ml
Morelloflavone -7”-O-
glucoside
8.38±10.87
/
25.82±7.58
µg/ml
Fabacea
Albizia zygia
(DC.) J.F.Macbr.
Barks
3',4',7-trihydroxyflavone 0.078
μg/ml K1 [42]
Asteraceae Artemisia afra
Jacq. ex Willd. Leaves
7-methoxyacacetin 4.3 / 7.0
µg/ml
PoW / Dd2 [43]
Acacetin 5.5 / 12.6
µg/ml
~ 52 ~
International Journal of Herbal Medicine
Genkwanin 5.5 / 8.1
µg/ml
Plumbaginaceae
Limonium
caspium
(Willd)
Arial parts
myricetin
1.82 / 1.51
μg/mL
W2 / D6 [44]
Platanaceae
Platanus
occidentalis L.*
Leaves
and stem
R1 = R2 =
trans-p-coumaroyl
kaempferol 3-O-α-L-(2″,3″-
di-E-p-coumaroyl)
rhamnoside
0.6±0.2 /
7±1 µM
HB3/NHP1337 [45]
R1= trans-p-coumaroyl
R2= cis-p-coumaroyl
kaempferol 3-O-α-L-(2″-E-
p-coumaroyl-3″-Z-p-
coumaroyl) rhamnoside
2.0±0.6 /
4.1±0.5 µM
R1= cis-p-coumaroyl
R2= trans-p-coumaroyl
kaempferol 3-O-α-L-(2″-Z-
p-coumaroyl-3″-E-p-
coumaroyl) rhamnoside
0.50±0.03 /
4.1±0.5 µM
R1= R2= cis-p-coumaroyl
kaempferol 3-O-α-L-(2″,3″-
di-Z-p-coumaroyl)
rhamnoside
1.8±0.4 /
7±1 µM
~ 53 ~
International Journal of Herbal Medicine
Fagaceae
Quercus laceyi
Small*
R1 = R2 =
trans-p-coumaroyl
kaempferol-3-O-(3″,4″-
diacetyl-2″,6″-di-E-p-
coumaroyl)-glucoside
0.6±0.1 /
2.1±0.6 µM
R1= trans-p-coumaroyl
R2= cis-p-coumaroyl
kaempferol 3-O-(2″-cis-p-
coumaroyl-3″,4″-diacetyl-
6″-trans-p-coumaroyl)-β-D-
glucopyranoside
0.9±0.2 /
5±5.1 µM
R1= cis-p-coumaroyl
R2= trans-p-coumaroyl
kaempferol 3-O-(2″-trans-p-
coumaroyl-3″, 4″-diacetyl-
6″-cis-p-coumaroyl)-β-D-
glucopyranoside
0.8±0.1 /
4±1 µM
R1 = R2 =
trans-p-coumaroyl
kaempferol-3-O-(3″,4″-
diacetyl-2″,6″-di-Z-p-
coumaroyl)-glucoside
2.1±0.9 /
3.8±0.6 µM
Euphorbiaceae
Mallotus
philippensis
(Lam.) Müll. Arg.
stem wood
bergenin 6.92 ± 0.43
µM
D10 [46]
11-O-galloylbergenin 7.85 ± 0.61
µM
~ 54 ~
International Journal of Herbal Medicine
Theaceae
Schima
wallichii Choisy
leaves
kaempferol-3-O-rhamnoside
106 μM K1 [47]
Burseraceae
Dacryodes
edulis (G.Don)
H.J. Lam
Stem
barks
Quercitrin
5.96 ± 0.51
/ 2.26±0.28
µg/ml
3D7 / Dd2 [48]
Afzelin
4.59±0.21 /
19.34±1.56
µg/ml
Quercetin
6.0±0.34 /
5.91±0.97
µg/ml
*
5. Conclusion
Flavonoids are ubiquitous in plant foods and drinks and,
therefore, a significant quantity is consumed in our daily diet.
The toxicity of flavonoids is very low in animals. For rats, the
LD50 is 2-10 g per animal for most flavonoids. Flavonoids
are abundantly present in the human diet, e.g. in fruits,
vegetables, and beverages such as tea and red wine.
Numerous in vitro and in vivo studies enable a variety of
potential beneficial effects of flavonoids to be elucidated.
With regard to natural products, it is generally accepted that
phytochemicals are less potent anti-infectives than courant
antimalarial agent origin, but new classes of antiplasmodial
drug are urgently required because of the resistance increasing
and the flavonoids represent a novel set of leads. Future
optimization of these compounds through structural alteration
may allow the development of a pharmacologically
acceptable antimalarial agent or group of agents. Synthesis
and screening of structural analogues of active flavonoids
through genetic manipulation might lead to the identification
of compounds that are sufficiently potent to be useful as
antiparasitic, antifungal, antiviral or antibacterial
chemotherapeutics.
6. Conflict of Interests
The authors declare that they do not have any conflict of
interests.
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