p-issn: 2394-0514 antiplasmodial properties of plants ... · signaling symbiotic bacteria in the...

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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



Burkina Faso

Adama Hilou

Laboratoire de Biochimie &





Correspondence

Harouna Soré

(1) Laboratoire de

Pharmacognosie, Centre

National de Recherche et de

Formation sur le Paludisme



Burkina Faso

(2) Laboratoire de Biochimie &





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 ~


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 ~


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 ~


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 ~


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 ~


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


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 ~


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


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


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 ~


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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