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Chapter 27 1

Modulation oOf tThe Host-Parasite Redox Metabolism tTo Potentiate Antimalarial Drug 2

Efficiency 3

4

FedericaTurrini1*francesco.turrini@unito.it; 5

RaffaellaBoggia1; 6

PaolaZunin1; 7

Francesco MichelangeloTurrini2

8 9 1 Department of Pharmacy 10 University of Genoa 11

VialeCembrano, 4 I-16148 Genoa, Italy 12

13

2

Department of Genetics, Biology and Biochemistry 14 University of Turin 15 Turin, Italy 16 17 18

Abstract

19

Artemisinin-based combination therapy (ACT) is nowadays the most effective treatment 20

for P. falciparum malaria: artemisinin is the most active drug able to rapidly kill all 21

erythrocyte stages of the malaria parasite. However, due to its short half-life, it requires the 22

association with other long-acting drugs. Even if the exact mechanism of action of most 23

antimalarial drugs is still unknown, many of these compounds are able to interact directly 24

or indirectly with the redox metabolism of the parasite and / or the host, enhancing the 25

effectiveness of the antimalarial therapy. This review focuses on many natural compounds, 26

isolated mainly from plants, and used as traditional antimalarial treatments, known to 27

possess a potent antimalarial activity (IC50 lower than 1 ug/mL). These compounds belong 28

to some specific chemical family, mainly alkaloids, terpenoids, quassinoids, limonoids,

29

and polyphenols, sharing some common chemical features. These natural molecules could 30

offer new possibilities of combination therapies development as antimalarials when 31

associated with artemisinin. 32

33

Keywords

34

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Antimalarial drugs 35

Artemisinin-based combination therapy 36

Natural antimalarial compounds 37

Host-parasite redox metabolism; 38

39

27.1. Introduction

40

27.1.1.

Current Antimalarial

-

Therapy

41

The natural antimalarial product artemisinin and its semi-synthetic derivatives represent 42

the front-line treatment of P. falciparum malaria, as they are the most active antimalarials 43

available, rapidly killing all blood stages of the malaria parasite. Artemisinins contain an 44

endoperoxide bridge which plays a key role in the antimalarial activity with a mode of 45

action starting from radical transient species initiated by the cleavage of this bridge. Few 46

other natural compounds with such a peroxide bridge are known. On the other hand, the 47

oxygen-oxygen bridge, being chemically unstable, determines a very short plasma half-48

life, constituting a major limiting factor to the use of artemisinin as a single drug [1]. To 49

solve this problem, artemisinin was early used early on in combination with partner drugs 50

characterized by much longer half-life. Artemisinin-based combination therapy (ACT) is

51

the most effective treatment for P.falciparum malaria. Artemisinin derivatives such as: 52

dihydroartemisinin, artesunate, and artemether, are combined with a partner drug such

53

asincluding lumefantrine, mefloquine, amodiaquine, and piperaquine. Since the

54

introduction of artemisinin-combination therapies (ACTs), the overall number of malaria 55

cases displayed a marked decline, but, since the last few years, the rate of decline has 56

stalled or even reversed in some regions [2]. 57

The reasons of the recent increase of the number of malaria cases is are plausibly multi -58

factorial, including: insufficient investments for treatment and prevention, insecticide 59

resistance, and antimalarial drug resistance. The relative role of each factor is undefined. 60

In the Greater Mekong sSub-region, artemisinin resistance raised concern and it is 61

currently defined as “partial artemisinin resistance” in patients showing a delayed parasite 62

clearance following treatment with an ACT. Notably, in the same region, resistance to the 63

partner drugs is present. To rule out between artemisinin and partner drugs resistance in the 64

development, treatment failure is obviously very difficult. Currently, no evidence of 65

artemisinin resistance has been observed in African countries accounting for about 90% of 66

malaria cases and deaths worldwide. 67

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27.2. Interactions

oO

f Antimalarial Drugs

wW

ith Host-Parasite

69

Redox Homeostasis

70

27.2.1.

Antimalarial Drugs Showing Redox Activity

71

Although the precise mechanism of action of most of the antimalarial drugs is still 72

unknown, most of the antimalarial drugs have the potential of interacting directly or unin -73

directly with redox metabolism of the parasite and/or of the host. 74

A direct redox effect exerted by some antimalarial drugs on the host cells is clearly 75

evidenced as hemolysis (oxidative damage and rapid destruction of erythrocytes leading to 76

variable degrees of anemia) in G6PD- deficient individuals. Powerful antimalarial drugs 77

such as primaquine, methylene blue, and sulfphonamides cause acute and severe 78

haemolytic anemia in G6PD- deficient subjects [3, 4].In addition, popular antimalarial 79

drugs and their combinations such as halofantrine, quinine, chloroquine, and 80

chlorproguanil-dapsone have been associated withto variable degrees of haemolytic 81

anemia, generation of ROS, and depletion of erythrocyte GSH [5, 6].Artemisinin and its 82

derivatives also cause delayed hemolysis. The central role of the endoperoxide bridge of 83

artemisinin and the generation of free radicals following its cleavage has been clearly 84

established. Artemisinin activation needs iron provided by the host cells, resulting in the 85

rapid generation of free radicals and the formation of heme-artemisinin adducts. To explain 86

its high activity (IC50 ≈ 2 nM), specific molecular targets are expected to play a role in its 87

mechanism of action. 88

89

27.2.2.

Antimalarial Drugs Causing

t

T

he Accumulation

o

O

f

90

Free Heme

T

T

hrough

t

T

he Inhibition

o

O

f Hemozoin Synthesis

91

Many antimalarial drugs including chloroquine, lumefantrine, mefloquine, amodiaquine,

92

and piperaquine, show the capability to inhibit heme polymerization into form hemozoin, 93

an inert crystal, in a specialized digestive vacuole of P. falciparum [7, 8]. Heme 94

detoxification and its polymerization constitute a central step of the parasite metabolism,

95

and its inhibition leads to parasite death. On the other hand, free iron released during 96

haemoglobin digestion, and heme constitute a powerful source of free radicals needing to 97

be neutralized both by both parasite and erythrocyte enzymes [9, 10]. Although the 98

chemical and metabolic interactions occurring between artemisinin derivatives and heme 99

polymerization inhibitory drugs are scarcely understood, it is interestingly to notice that the 100

drugs that inhibit haemoglobin metabolism are the best candidates to be utilized in 101

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combination with artemisinin in ACTs [11] suggesting a combined mechanism of action 102

[12, 13]. 103

104

27.3. Response of the Host Cell

tT

o Redox Changes Exerted

105

bB

y Parasite Growth

aA

nd/

oO

r Antimalarial Drugs

106

Redox metabolism of the parasitized erythrocyte depends on the equilibrium between the 107

antioxidant defencesdefenses of both erythrocyte and parasite and, on the free radicals 108

produced by the parasite and by the erythrocyte [14]. Iron plays a central role in free 109

radical production in the parasite through hemoglobinaemoglobin digestion and in the 110

parasitized erythrocyte which accumulates large amounts of denatured 111

hemoglobinaemoglobin generated by the oxidative stress exerted by the parasite [15, 16]. 112

As an evidence of this unstable equilibrium, a large number of mutations have been 113

selected by malaria such as G6PD deficiency (defect of production of NADPH), sickle cell 114

anemia, thalassemias, HbC, HbE, and many other hemoglobinaemoglobin disorders 115

triggering oxidative stress through haemoglobin denaturation and plausibly amplifying the 116

redox stress exerted by the intracellular parasite. More than 500 million people living in 117

malaria endemic areas are affected by one or more of those mutations conferring variable 118

levels of protection to severe malaria [17, 18]. 119

It has been demonstrated that mild oxidative stress exerted by malaria parasite activates a 120

specific redox signalling pathway in the host erythrocyte inducing the Tyr phosphorylation 121

of some membrane proteins [19] which, in turn, appear to be essential for the remodelling 122

of the parasitized erythrocyte membrane needed to activate new functions essential for the 123

parasite growth such as import of nutrients and insertion of parasite proteins binding to 124

endothelium [20]. The activation of Syk kinase, constituting a key element of such 125

pathway, has been directly implicated both in the egress of merozoites and in the infection 126

of new erythrocytes occurring after the 48- hours life cycle of the parasite. A new class of 127

drugs has been developed to interfere with this pathway revealing good antiplasmodial 128

efficacy [21]. 129

Targeting the redox metabolism ofP. falciparumby antimalarial drugs is believed to create 130

an overload of oxidative stress leading to parasite death [22]. Anyway, much more 131

complex mechanism of action appears to be involved in the interactions occurring between 132

parasite and host cell metabolism and in the interference exerted by a large number of 133

redox active antimalarial drugs (Fig. 27.1). 134

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Fig. 27.1 Redox homeostasis perturbation between host and parasite

136 137

27.4. Natural Antimalarial Compounds

138

In addition to artemisinin, a large number of natural compounds present in plants, are

139

known to possess a potent antimalarial activity. In some cases, their clinical efficiency and

140

activity have been demonstrated by their use as traditional antimalarial treatments.

141

A comprehensive list of plant compounds with antimalarial activity, quantified as in vitro

142

IC50, is reported in Table 27.1. Only the compounds, whose IC50 is lower than 1 ug/mL, 143

have been selected.

144

It shall be noticed that most of these compounds belong to the families of alkaloids, in

145

particular, indole and naphthoisoquinoline alkaloids, with few exceptions including

146

sequipertenessequiterpenes, quassinoids, limonoids, and a polyphenolic compound (ellagic

147 acid). 148 149

27.4.1.

Alkaloids

150

Alkaloids are one of the most important antimalarial compound classes known from

151

ancient time. Quinine, which represents the first antimalarial natural drug used, belongs to

152

this group. It is a quinidine alkaloid isolated from the bark of Cinchona succirubra and it has

153

been used for more than three centuries for the treatment of malaria [23]. Numerous

154

studies reported in literature described the significant antimalarial activity of over 100

155

natural alkaloids, which have been considered more potent than chloroquine [24]. Some of

156

the active reported alkaloids can be also grouped according to their structural chemical

157

classes. In particular, indole alkaloids which from a chemical point of view contain an

158

important indole group in their structure and derive from the amino acid tryptophan,

159

represent one of the largest class of alkaloids grouping together many antimalarial

160

compounds [25]. The naphthoisoquinoline alkaloids represent as well potential antimalarial

161

compounds. These compounds are secondary metabolites naturally present mainly in some

162

plants of the Ancistrocladaceae and Dioncophyllaceae families. Structurally, they are chiral

163

molecules characterized by the presence of C,-C and C-, N bonds typical of the

164

naphthalene and isoquinoline structures contained in them. In addition to the antimalarial

165

activity, these alkaloids have shown many biological activities including anti-leishmanial,

166

anti-trypanosomal, fungicidal, insecticidal, and larvicidal [26].

167 168

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27.4.2.

Sesquiterpenes

169

An important medicinal plant used from ancient time because of its content in antimalarial

170

artemisinins is the Artemisia annua, an herb used in Chinese traditional medicine. As already

171

mentioned, artemisinin-combination therapies (ACTs) are nowadays the standard treatment

172

in the world against P. falciparum[1,;27]. Chemically, artemisinin belongs to sesquiterpenes,

173

namely, terpenes characterized by three isoprene units (C15H24), which represent a very

174

important class of secondary metabolites obtained from plants. In addition to artemisinin,

175

several other sesquiterpene compounds have shown a potentially antimalarial activity [25].

176

Structurally, as already mentioned, artemisinin presents a characteristic endoperoxidic 177

group which is considered responsible for its activity. However, the other sesquiterpene 178

compounds reported in Table 27.1, do not contain the typical peroxide group of artemisinin. 179

Interestingly, this chemical group is found in another antimalarial compound, named 180

Plakortin, recently isolated from a tropical sponge instead of from plants. It is a polyketide 181

endoperoxide isolated from the sponge Plak ortis simplex, and it has shown antiparasitic 182

activity against P. falciparum. It has been shown that the activity of this compound also

183

depends on the functionality of the peroxide [28]. 184

185

27.4.3.

Quassinoids

186

Quassinoids are related to terpenes group too. They are a class of degraded triterpenes, and

187

most of them are characterized by a C-20 and δ-lactone skeleton [22]. Concerning the

188

quassinoids, in particular, three compounds have reported significant antimalarial- malarial 189

activity with very low IC50 values as a result of our free research: Ailanthone and 6-

alpha-190

tTigloyloxychaparrinone isolated from Ailanthus altissimaand sSimalikalactone D obtained

191

from the roots of Simabaorinocensis. The presence of the ester function seems to be

192

important for in vitro antiplasmodial activity of these compounds [29].

193 194

27.4.4.

Limonoids

195

Limonoids present a similar structure to qQuassinoids. These compounds, classed as

196

tetranortriterpenes, present different variations of the furanolactone core structure.

197

Meliaceae, Cucurbitaceae, and Rutaceae are the plant families richer of these

198

phytochemical compounds, some of which have demonstrated different biological

199

properties such as antimalarial activity [23]. 200

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27.4.5.

Polyphenolic Compounds

202

As regards the polyphenolic compounds, only the ellagic acid (EA) has shown a very

203

interesting IC50 value. This is an antioxidant molecule which chemically belongs to the

204

hydrolysable tannins class, known for its antimalarial activity. EA is deriveds from the

205

hydrolysis of ellagitannins (ETs). ETs are hydrolyzsed, chemically by acids or bases or

206

enzymatically, into hexahydroxy diphenic acid, which spontaneously tends to EA [30]. EA

207

explains its antiplasmodial activity by interfering with haemoglobin metabolism and, in

208

particular, inhibiting the β-haematin formation [31]. For these reasons, ellagic acid could

209

be a potential candidate to be utilized in combination with artemisinin in ACTs.

210 211

Table 27.1 Summary of antimalarial- malarial natural compounds selected for their activity 212

“in vitro” (IC50 < 1 ug/mL) 213

Natural cCompound CAS

number IUPAC name

Chemical

sStructure Chemical group Botanical source

Anti-mMalarial activity IC50 (μg/mL) and strains used Potential mechanism of action Other aAntiparasitic -parasitic activities 10 -Hydroxyusambarine n.a (2S,3R,12bS)-3-ethenyl-2-[[(1S)-2-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]methyl]-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-9-ol

Indole aAlkaloids Strychnosusambarensis In vitro [32] 0.48 (FCA 20) 0.16 (W2) Not discussed Activities against Entamoeba histolytica In vitro [33] Akuammicine

639-43-0 2,16,19,20-tTetradehydrocuran-17-oic aAcid mMethyl eEster Indole aAlkaloids Picralimanitida

In vitro [34] 0.45 (D6) 0.73 (W2) Not discussed Akuammine 3512-87-6

M ethyl (1S,9S,14Z,15R)-14-ethylidene-6-hydroxy -2-methyl-18-oxa- 2,12-diazahexacyclo[13.3.2.01,9.03,8.09,16.012,19]icosa-3,5,7-triene-16-carboxylate

Indole alkaloids Picralimanitida In vitro [34] 0.95 (D6) 0.66 (W2) Not discussed Alstonine 642-18-2 (19α,20α)-16-(Methoxycarbonyl)-19-methyl-3,4,5,6,16,17-hexadehydro-18-oxayohimban-4-ium Indole aAlkaloids Picralimanitida; Alstonia scholaris In vitro [34] In vivo [35] 0.017 (D6) 0.038 (W2) Not discussed Berberine 633-66-9

5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium Indole aAlkaloids

Enantia Cchlorantha In vitro [36] In vitro and in vivo [37] 0.14 (D6) 0.15 (W2) Inhibitor of both nucleic acid and protein synthesis in human malarial parasite, P. falciparum, FCR-3 Antileishmanial activity [38, 39] Cryptolepine

480-26-2 5-methylindolo[3,2-b]quinoline Indole alkaloids Quassiaindica [23]

0.19 (K1)

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Fagaronine

52259-65-1

3,8,9-trimethoxy -5-methylbenzo[c]phenanthridin-5-ium-2-ol Indole alkaloids Fagara zanthoxyloides In vitro [40] 0.018 (3D7) Not discussed Jatrorrhizine 3621-38-3 2,9,10-tTrimethoxy-5,6-dihydroisoquinolino[2,1-b] isoquinolin-7-ium-3-ol Indole alkaloids Enantia Cchlorantha; Penianthuslongifolius In vitro [41] In vitro and in vivo [42] 0.42 (D6) 1.61 (W2) Not discussed Palmatine

3486-67-7 2,3,9,10-tetramethoxy -5,6-dihydroisoquinolino[2,1-b] isoquinolin-7-ium Indole alkaloids

Enantia Cchlorantha; Penianthuslongifolius In vitro [41;43] In vitro and in vivo [42] 0.28 (D6) 0.16 (W2) Not discussed Antibacterial activity against Clostridium perfringens [44] Antiflavivirus activity In vitro [43] Picraline 2671-32-1 M ethyl (1R,9S,11S,14Z,15S,17S,19S)-19-[(acetyloxy)methyl]-14- ethylidene-18-oxa-2,12- diazahexacyclo[9.6.1.1^{9,15}0.0^{1,9}0.0^{3,8}0.0^{12,17}]nonadeca-3,5,7-triene-19-carboxylate

Indole alkaloids PicralimanitidaPicralima

nitida [45] 0.44 (D6) 0.53 (W2) Not discussed Ψ-Akuammigine 642-17-1 (7aS,8S,11aS,12aR)-8-M

ethyl-5,6,7a,8,11a,12,12a,13-octahydro-7H-9-oxa-6a,13-diaza-indeno[2,1-a]anthracene-11-carboxylic acid methyl ester Indole alkaloids Picralimanitida [45]

0.42 (D6) 0.10 (W2) Not discussed 2,6-Dihydroxyfissinolide n.a M ethyl 2-[(1R,2S,5R,6R,13R,14S,16S)-14-(acetyloxy)-6-(furan-3-yl)-13- hydroxy-1,5,15,15-tetramethyl-8,17-dioxo-7- oxatetracyclo[11.3.1.0^{2,11}0.0^{5,10}]heptadec-10-en-16-yl]-2-hydroxyacetate

Limonoids Khayasenegalensis In vitro [46] 0.12 (chloroquine-sensitive (3D7) P. Falciparum strain) Not discussed IC50 > 0.20 mM against Leishmania major In vitro [46] Gedunin 2753-30-2 (4aR,6R,6aS,6bR,7aS,10S,10aS,12aR,12bR)-10-(3-Furyl)- 4,4,6a,10a,12b-pentamethyl-3,8-dioxo-3,4,4a,5,6,6a,7a,8,10,10a,11,12,12a,12b-tetradecahydronaphtho[2,1-f] oxireno [d]isochromen-6-yl acetate

Limonoids Azadirachta indica; Cedrela odorata; Khayagrandifoliola In vitro [47, 48] In vivo [49] 0.03 (D6) 0.02 (W2) 1.25 (W2-Indochina clone) Not discussed Insect antifeedant activity In vivo [50] Ancistrocladidine 52659-52-6

2-[(3S)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinolin-7-yl]-8-methoxy-3-methylnaphthalen-1-ol Naphthoisoquinolines Ancistrocladustanzaniensis

In vitro [51] 0.3 (K1) 1.9 (3D7) Not discussed Antileishmanial activity against Leishmania donovani (IC50 = 2.9 μg/mL) Antitrypanosomal activity against Trypanosoma brucei rhodesiense (IC50 = 2.0 μg/mL) aand T. cruzi (IC50 = 23.4 μg/mL) In vitro[51]

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31-0 1,2,3-trimethyl-3,4-dihydro-1H-isoquinolin-6-ol [51] 4.2 (3D7) activity against Trypanosoma brucei rhodesiense (IC50 = 1.3 μg/mL) aand T. cruzi (IC50 = 14 μg/mL) In vitro[51] Ancistrotectorine 98985-59-2

2-[(1R,3S)-6,8-dimethoxy-1,2,3-trimethyl-3,4-dihydro-1H-isoquinolin-7-yl]-8-methoxy-3-methylnaphthalen-1-ol Naphthoisoquinolines Ancistrocladustanzaniensis

In vitro [51] 0.7 (K1) 9.1 (3D7) Not discussed Antitrypanosomal activity against Trypanosoma brucei rhodesiense (IC50 = 4.3 μg/mL) Aand T. cruzi (IC50 = 4.3 μg/mL) In vitro[51]

Dioncopeltine A n.a (1R,3R)-7-[5-hydroxy -2-(hydroxymethyl)-4-methoxynaphthalen-1-yl]-1,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-8-ol Naphthoisoquinolines Triphyophyllumpeltatum In vitro and in vivo [52, 53] 0.0048 (K1) 0.0033 (NF54) Not discussed Antileishmanial activity against Leishmania major [54]

Dioncophylline C n.a (1R,3R)-5-(5-hydroxy

-4-methoxy-2-methylnaphthalen-1-yl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-8-ol Naphthoisoquinolines Triphyophyllumpeltatum

In vitro and in vivo [52, 53] 0.014 (blood form of P. falciparum) 0.015 (blood form of P. berghei) Not discussed Cytotoxicity against cloned virulent Leishmania major promastigotes [54]

Habropetaline A n.a

(1R,3R)-7-[2-(hydroxymethyl)-4,5-dimethoxynaphthalen-1-yl]-1,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-8-ol Naphthoisoquinolines Triphyophyllumpeltatum

In vitro [55] 0.005 (K1) 0.0023 (NF54) Not discussed Ellagic acid

476-66-4 2,3,7,8-Tetrahydroxychromeno[5,4,3-cde]chromene-5,10-dione Polyphenoliccompounds Alchorneacordifolia

In vitro [56] 0.10 (F32) 0.03(Dd2) 0.09 (FcB1) 0.10 (W2) 0.05(FcM 29) Inhibition of the β-hematin formation [31] Ailanthone 981-15-7

(1β,11β,12α)-1,11,12-Trihydroxy-11,20-epoxypicrasa-3,13(21)-diene-2,16-dione Quassinoids Ailanthus altissima

In vitro

[57] 0.003 Not discussed

6alpha-Tigloyloxychaparrinone n.a. Quassinoids Ailanthus altissima

In vitro [57] 0.061 Not discussed Simalikalactone D 35321-80-3 (1β,11β,12α,15βb)-1,11,12-trihydroxy-2,16-dioxo-13,20-epoxypicrasa

-3-en-15-yl (2R)-2-methylbutanoate Quassinoids Simabaorinocensis

In vitro [58] 0.003 (D6) 0.00367 (W2) Inhibitor of the protein biosynthesis in vitro in translation system from the Krebs cell

Antileishmanial activity against Leishmania donovani [58]

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56-5 dioxo-3a,4,5,11a-tetrahydrocyclodeca[b]furan-4-yl] 2-methylpropanoate [59] Cytoxicity IC50 = 0.71 (HTC-116) Urospermal A-15-O-acetate n.a [(3aR,4R,6E,10Z,11aR)-6-formyl-4-hydroxy

-3-methylidene-2-oxo-3a,4,5,8,9,11a-hexahydrocyclodeca[b]furan-10-yl]methyl acetate Sesquiterpenes Dicomatomentosa

In vitro [60] 0.92 (3D7) 0.77 (W2) Not discussed Artemisinin 63968-64-9

(4S,5R,8S,9R,12S,13R)-1,5,9-Trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one Sesquiterpenes Artemisia annua

In vitro [61] 0.006 (D6 e W2) Heme-mediated decomposition of the endoperoxide bridge to produce carbon-centered free radicals In vitro anti-promastigote activityin visceral leishmaniasis In vitro [62]

Plakortin n.a. Mmethyl 2-[(3R,4R,6S)-4-ethyl-6-[(E,2R)-2-ethylhex-3-enyl]-6-methyldioxan-3-yl]acetate

Endoperoxyketal

polyketides Plakortiscfr. Simplex

In vitro [63, 64] 0.12 (W2) 0.27 (D10) ROS generation, lipid peroxidation, and and generation of 4-HNE-protein conjugate with essential parasite proteins Anti-promastigote activity in Leishmania Chagasi (IC50 = 6.0 μg/mL) [65]

n.a not available 214

27.5. Conclusions

215

216

This work has revealed a wide range of natural products with potent antimalarial activity,

217

belonging to some specific chemical group, mainly alkaloids, terpenoids, quassinoids,

218

limonoids, and polyphenols. 219

Selected compounds from a physicochemical point of view are characterizsed for larger 220

molecular mass and higher hydrophobicity index (logP). These properties may be 221

considered necessary for the achievement of the intracellular target [66]. Furthermore, 222

most of these compounds are hydrogen bond acceptors. Structurally, there are recurrent 223

chemical groups that share these molecules. Most compounds present a rigid scaffold of at 224

least 3 cycles which confers high rigidity to the molecule. However, further structure-225

activity relationship studies are necessary for the possible identification of a pattern of 226

functional groups (pharmacophore) responsible for the antimalarial activity. 227

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Many of the selected compounds, including artemisinin, are likely expected to exert redox 228

activity in biological systems, but, in most instances, a direct evidence is missing. 229

At this regard, it should be considered that the erythrocyte-plasmodium system represents a 230

unique environment combining two interconnected oxidative defencedefense systems, 231

extremely high concentration of heme iron contained in the host compartment and intense 232

hemoglobinaemoglobin digestion and heme detoxification in the parasite [22]. 233

Experiments to test the interference with the host-parasite redox state of any potential 234

antimalarial- malarial compounds should be, therefore, tested in infected erythrocytes at 235

different development stages. 236

It should be also noticed that, the antimalarial mechanism of action of redox compounds is 237

complex involving very sensitive host targets [67]that could be considered for the 238

screening of antimalarial drug candidates. 239

240 241

References

242

1. Cui L, Su X (2007) Discovery, mechanisms of action and combination 243

therapy of artemisinin. Expert Rev Anti-infective Therapy 7(8):999–1013 244

2. World Health Organization (2017) World malaria report. WHO, Geneva 245

3. Gassner C (2012) Aging and cClearance of eErythrocytes. Transfus Med 246

Hemother 39(5):297–298 247

4. Luzzatto L, Arese P (2018) Favism and Glucose-6-pPhosphate 248

dDehydrogenase dDeficiency. N Engl J Med 378(1):1067–1069 249

5. AnabaF C, Ahiante BO, Pepple DJ (2012)In vitro hemolytic effect of 250

sulfadoxine/pyrimethamine and artemether/lumefantrine on malaria 251

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