Antimalarial activity of plant metabolites†

Sianne Schwikkard and Fanie R. van Heerden*

Department of Chemistry and Biochemistry, Rand Afrikaans University, P.O. Box 524,Auckland Park, 2006, South Africa

Received (in Cambridge, UK) 4th July 2002First published as an Advance Article on the web 25th September 2002

Covering: 1990 to the end of 2000

This review covers the structures of compounds with antiplasmodial activity isolated from plants and is organizedaccording to plant family. A total of 170 structures has been reviewed from 186 references found in the literature upto December 2000.

1 Introduction2 Alliaceae–Asphodelaceae2.1 Alliaceae, Amaryllidaceae and Anacardiaceae2.2 Ancistrocladaceae and Dioncophyllaceae2.3 Annonaceae2.4 Apocynaceae2.5 Araceae, Asparagaceae and Asphodelaceae3 Berberidaceae–Cyperaceae3.1 Berberidaceae and Bignoniaceae3.2 Celastraceae, Chenopodiaceae, Clusiaceae

(Guttiferae) and Combretaceae3.3 Compositae (Asteraceae)3.4 Cyperaceae4 Dracaenaceae–Hernandiaceae4.1 Dracaenaceae and Ebenaceae

† Electronic Supplementary Information (ESI) available: IC50 values ofplant metabolites. See http://www.rsc.org/suppdata/np/b0/b008980j/

4.2 Euphorbiaceae4.3 Fabaceae (Leguminosae)4.4 Hernandiaceae5 Lamiaceae–Nepenthaceae5.1 Lamiaceae (Labiatae), Lauraceae and Malvaceae5.2 Meliaceae5.3 Menispermaceae5.4 Molluginaceae, Monimiaceae, Moraceae,

Myristaceae and Myrtaceae5.5 Nepenthaceae6 Olacaceae–Rutaceae6.1 Olacaceae, Periplocaceae and Piperaceae6.2 Ranunculaceae6.3 Rubiaceae6.4 Rutaceae7 Saxifragaceae–Zingiberaceae7.1 Saxifragaceae7.2 Simaroubaceae

Sianne Schwikkard

Sianne Schwikkard was born in Sasolburg, South Africa in 1970 and completed her PhD in 1998 atthe University of Natal, Durban, South Africa. Her research at the University of Natal wasconducted under the supervision of Professor Dulcie Mulholland and involved a phytochemicalinvestigation of various members of the Meliaceae, Rutaceae and Dichapetalaceae. This wasfollowed by a post-doctoral research fellowship (1998) at Virginia Polytechnic Institute and StateUniversity, where she joined Professor Kingston’s group and investigated the anticancer properties ofvarious South African plants. A further post-doctoral study was carried out at the Rand AfrikaansUniversity under the supervision of Professor van Heerden involving the antibacterial and anti-HIVproperties of South African plants. She is currently employed by Sasol Technology in their Researchand Development Division.

Fanie van Heerden

Fanie van Heerden was born in Murraysburg, South Africa in 1954 and obtained a PhD at theUniversity of the Orange Free State, Bloemfontein, South Africa in 1980 after studying flavonoidchemistry with Professor D. G. Roux. She joined the National Chemical Research Laboratory,CSIR, Pretoria in 1980 and performed research on mycotoxins and toxic plants. In 1989 she joinedthe Rand Afrikaans University in Johannesburg and is currently associate Professor in Chemistry.Her main research interest is the chemistry and biological activity of South African medicinalplants.

DOI: 10.1039/b008980j Nat. Prod. Rep., 2002, 19, 675–692 675

This journal is © The Royal Society of Chemistry 2002

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7.3 Solanaceae and Strychnaceae7.4 Taccaceae, Taxaceae, Valerianaceae and

Zingiberaceae8 Conclusion9 References

1 Introduction

Malaria is a life-threatening parasitic disease transmitted bymosquitoes. There are four types of human malaria—Plasmodium vivax, P. falciparum, P. malariae, and P. ovale ofwhich the first two are the most common, and P. falciparumthe most deadly type of malaria infection. Today it is foundthroughout the tropical regions of the world and causes morethan 300 million acute illnesses and at least one million deathsannually. Most of the deaths are among young children insub-Saharan Africa. Commercial antimalarial drugs such aschloroquine (1), when used as monotherapies, are rapidly losingtheir effectiveness, and there is an increasing demand for activecompounds with a new mode of action to replace the currentineffective drugs.1 For thousands of years, plants have formedthe basis of sophisticated traditional medicine systems andmore recently, natural products have been a good source oflead compounds, especially against infective diseases. Themost important lead compound against malaria is quinine(2), isolated from Cinchona bark, which was used as a templatefor chloroquine and mefloquine. More recently, artemisinin(3),2 isolated from the Chinese plant Artemisia annua, has beenused successfully against malaria that has become resistant tochloroquine. In this review we want to discuss plant-derivedcompounds with antimalarial activity. With plant metabolites,a specific structural class of compounds is often isolated froma specific family only, and, therefore, the review is organisedaccording to investigations on specific plant families. Tocompare the activity of the different compounds, the IC50

values are collated in the Supplementary Information. †

2 Alliaceae–Asphodelaceae

2.1 Alliaceae, Amaryllidaceae and Anacardiaceae

Ajoene (4), a metabolite of Allium sativum (Alliaceae, garlic),was tested by Perez et al.3 for activity against P. berghei in mice.This compound was nontoxic and reduced the severity of the

infection in mice. When used in combination with chloroquine,at a dose that is usually not effective, the malaria was com-pletely cleared.

Three members of the Amaryllidaceae have been investigatedfor antimalarial activity, Brunsvigia littoralis,4 B. radulosa 5 andCrinum amabile.6 All of them contained alkaloids characteristicof the Amaryllidaceae that, in addition to antimalarial activity,also exhibit cytotoxicity. Campbell et al.4 isolated four alkaloidsfrom B. littoralis, two of which showed antimalarial andcytotoxic activity, lycorine (5) and 1,2-di-O-acetyllycorine (6).The most active compounds of B. radulosa were identified aslycorine (5) and crinamine (7). Likhitwitayawuid et al.6 isolatedfive alkaloids from C. amabile, three of which showed anti-malarial and cytotoxic activity, (�)-lycorine (5), (�)-crinamine(7) and (�)-augustine (8).

A biflavanone, 7,7�-di-O-methyltetrahydromentoflavone (9),with moderate antiplasmodial activity but no cytotoxicity, wasisolated from Rhus retinorrhoea (Anacardiaceae), a tree grow-ing in the southern parts of Saudi Arabia.7 An extract of a leafand twig sample from Swintonia foxworthyi, a large tree grow-ing in the Philippines, showed activity against two clones ofP. falciparum (W-2 and D-6). The active compounds werefound to be methyl gallate and methyl digallate (methyl 3-O-galloylgallate).8

2.2 Ancistrocladaceae and Dioncophyllaceae

Ancistrocladaceae and Dioncophyllaceae are two small familiesof tropical vines found in the rain forests of West Africa andin South-East Asia. The Ancistrocladaceae consists of asingle genus Ancistrocladus containing 20 species whereas theDioncophyllaceae consists of three monotypic genera only.Both families contain a variety of naphthylisoquinolinealkaloids that exhibit a remarkable range of biologicalactivities, including HIV-inhibitory, antimalarial, fungicidal,larvacidal and moluscicidal activities.

One species of the Dioncophyllaceae, Triphyophyllumpeltatum,9–12 and several species of Ancistrocladaceae, viz. A.abbreviatus,9,10 A. barteri,9,10 A. heyneanus,13,14 A. korupensis,15–18

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A. likoko 19 and A. robertsoniorum 20 were investigated for theirantiplasmodial activity. In agreement with the results on thecrude extracts, the compounds from the Dioncophyllaceae weremore active than those isolated from the Ancistrocladaceae.Among the most active compounds isolated from T. peltatumare dioncophylline C (10) (IC50 0.014 µg ml�1), dioncopeltine A(11) (IC50 0.021 µg ml�1), 7-epidioncophylline A (12) (IC50 0.190µg ml�1), and dioncophylline B (13) (IC50 0.224 µg ml�1). TheIC50 values obtained for these compounds are much lower thanthose observed for most other plant-derived compounds, andcompare well with the IC50 values for antiplasmodial drugs thatare currently in use (chloroquine, IC50 0.005 µg ml�1). The goodactivity exhibited by dioncophylline C (10) and dioncopeltineA (11) in vitro led to its being tested in vivo against P. berghei inmice.21,22 It showed good activity without any obvious signs oftoxicity. Apart from testing the activity of these alkaloids onthe asexual erythrocytic P. falciparum and P. berghei in vitro,François et al.23 have also investigated the activity of a seriesnaphthylisoquinoline alkaloids on exoerythrocytic malariaparasites. They used P. berghei infected human hepatoma cells(Hhep G2) that were incubated with culture medium containing10 µg ml�1 of the test alkaloid. The most active were found to bedioncophylline A (14), dioncophyllacine A and ancistrobarter-ine A. It is clear that the naphthylisoquinoline alkaloids can beregarded as lead compounds for novel drugs acting againstboth erythrocytic and exoerythrocytic stages of Plasmodium.23

Hallock et al.15–18 did extensive research on Ancistrocladuskorupensis. Two classes of naphthylisoquinoline alkaloids wereidentified, the dimeric alkaloids that have good anti-HIVactivity and the monomeric alkaloids that exhibited goodantimalarial activity. The exception is korundamine A (15)(IC50 1.1 µg ml�1), a dimeric naphthylisoquinoline alkaloidthat showed both anti-HIV and antimalarial activity.18 Mono-meric naphthylisoquinoline alkaloids from A. korupensis can bedivided into two classes, the korupensamines 15 [e.g. korupens-amine B (16), IC50 0.41 µg ml�1] and yaoundamines 17 [e.g.yaoundamine A (17), IC50 2.2 µg ml�1], both with good in vitroantiplasmodial activity.

Bringmann et al.24 isolated betulinic acid, a lupane-typetriterpene that is widespread in nature and has been isolatedfrom numerous higher plants, from T. peltatum and A. heynea-nus, and showed that this compound has moderate activityagainst P. falciparum in vitro, with an IC50 of 10.46 µg ml�1.Steele et al.25 confirmed the in vitro activity of betulinic acid,but found that it was ineffective in in vivo experiments.

2.3 Annonaceae

In 1979 Liang et al.26 isolated yingzhaosu A (18), a sesquiter-pene peroxide, from the roots of Artabotrys uncinatus, a plant

that has been used in a Chinese traditional herbal medicinefor the treatment of malaria. Yingzhaosu A has exceptionallygood antimalarial activity, but sufficient amounts were notavailable for full evaluation. Consequently, a synthetic analoguearteflene (RO 42–1611) (19) with enhanced activity andpotential for commercialization as an antimalarial drug, wasdeveloped.27 The structure of yingzhaosu A is related to thatof the promising compound artemisinin (qinghaosu) (seeCompositae).

Two known alkaloids, sampangine (20) and 3-methoxy-sampangine (21), were isolated as the antimalarial principles ofthe South American plant Duguetia hadrantha.28 Bisbenzyl-isoquinolines, a class of compounds that is known to havevarious pharmacological activities including antiparasiticactivity, were isolated as the active compounds in two plants inthis family, i.e. Guatteria boliviana 29 (funiferine) and Isolonaghesquiereina 30 (curine, chondrofoline and isochondodendrine).The activity of this class of compounds will be discussed underMenispermaceae. Nkunya and his coworkers 31 have investi-gated nine Tanzanian species of the genus Uvaria, U. dependens,U. faulknerae, U. kirkii, U. leptocladon, U. lucida, U. pandensis,U. scheffleri and U. tanzaniae. The most active extracts weresubjected to further fractionation and several active com-pounds were isolated. They were mainly C-benzylated dihydro-chalcones (the uvaretins) and indolosesquiterpenes.31 The mostactive components were uvaretin (22) and 3-(8,9-dihydroxy-farnesyl)indole, although neither was as active as chloroquinediphosphate.

2.4 Apocynaceae

There are 43 species of the genus Alstonia distributed through-out Africa, Central America, China, SE Asia, and the Pacific. Anumber of species have been reported to be used by traditionalhealers in the treatment of malaria though there are conflicting

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reports in the literature 32 as to the activity of various species.More than 130 alkaloids have been isolated from Alstoniaspecies, only a few of which have been assessed for antimalarialactivity. Wright et al.33 investigated Alstonia angustifolia, a plantthat is used in South-East Asia to treat malaria and dysentery.Nine alkaloids were isolated and tested and the most active oneagainst P. falciparum was villalstonine (23). Thirteen indolealkaloids were isolated from the active extract of A. macro-phylla,34 and again villalstonine was the most active compon-ent. A related dimeric indole alkaloid, voacamine (24), wasthe most active alkaloid isolated from Peschiera (= Tabernae-montana 35) fuchsiaefolia.36

Two groups investigated Picralima nitida.37,38 François et al.37

looked at the organic and aqueous extracts of the roots, stembark, fruit rind, seeds and leaves. A wide range of activitieswere noted with the highest activities being found in the rootdichloromethane extract, the stem bark dichloromethaneextract and the fruit rind aqueous extract (IC50 values of 0.188,0.545 and 1.581 µg ml�1 respectively). Kapadia et al.38 found anactive alkaloid, akuammine (25), in the seeds of P. nitida.

2.5 Araceae, Asparagaceae and Asphodelaceae

Leave and stem extract extracts of Rhaphidophora decursiva(Araceae), a vine growing in Vietnam, were shown to be activeagainst both the D6 and W2 clones of P. falciparum with noapparent toxicity.39 The two most active compounds wereidentified as polysyphorin (26) and rhaphidecurperoxin (27).

Asparagus africanus (Asparagaceae) is used by the Akambatribe in Kenya to treat malaria. A bioassay-guided fractionationof the root extract led to the isolation of two active compounds,the sapogenin muzanzagenin (28) and the lignan nyasol (29).40

Knipholone (30), a compound first isolated from Kniphophiafoliosa (Asphodelaceae),41 three of its natural derivatives andseven structurally related compounds were assayed for anti-plasmodial activity.42 All the phenylanthraquinones showedconsiderable activity with only little cytotoxicity, whereas theindividual anthraquinone and phenyl moieties were completely

inactive. Apart from knipholone, the anthrone 31 was foundto have good activity. A number of isofuranonaphthoquinonesisolated from Bulbine capitata showed only weak antiplas-modial activity.43

3 Berberidaceae–Cyperaceae

3.1 Berberidaceae and Bignoniaceae

Berbamine (32) has been isolated from several Berberis(Berberidaceae) species. Ye et al.44 tested berbamine in vitroagainst both a chloroquine-resistant and a chloroquine-sensitive strain of P. falciparum and its effect when usedin combination with chloroquine and artemisinin. It wasactive against both the resistant and the sensitive strains ofP. falciparum. When administered with chloroquine,berbamine had an antagonistic effect to chloroquine on thechloroquine-sensitive strain and a potentiating effect on thechloroquine-resistant strain. Administration in combinationwith artemisinin had an additive effect on the chloroquine-sensitive strain of P. falciparum and a potentiating effect on thechloroquine-resistant strain.44 The monomer berberine (33)also has an antiplasmodial IC50 of less than 1 µM 45 (see alsodiscussion under the Menispermaceae).

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Lapachol (34), a hydroxynaphthoquinone with antimalarial,antifungal, antibacterial and anticancer activity, which ispresent in many members of the Bignoniaceae, was used astemplate for the synthetic antimalarial atovaquone (35). Theaqueous, chloroform and hexane extracts of the stem bark ofSpathodea campanulata (Bignoniaceae) were investigated.46

Each extract was tested against P. berghei berghei in mice usingchloroquine as the control. The hexane and chloroform extractsshowed good activity while the aqueous extract showed little tono activity. Amusan et al.47 isolated ursolic acid and two deriv-atives, tomentosolic acid and 3β,20β-dihydroxyurs-12-en-28-oicacid from the stem bark of this plant. These three compoundswere found to suppress the disease and to prolong the survivaltimes of mice infected with P. berghei berghei. 47 An investiga-tion of Tabebuia ochracea ssp. neochrysantha (Bignoniaceae),used traditionally in the Amazon to treat malaria, resulted inthe isolation of five furanonaphthoquinones.48 The bioactivityof these compounds was tested against P. falciparum andP. berghei in vitro and the most active fraction was a mixtureof two compounds that could not be separated, 5- and8-hydroxy-2-(1�-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione.An African tree, Kigelia pinnata (Bignoniaceae), contains fourcompounds with antimalarial activity, the most active onesbeing 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione (36)and isopinnatal (37).49

3.2 Celastraceae, Chenopodiaceae, Clusiaceae (Guttiferae) andCombretaceae

Salacia kraussii (Celastraceae) is a small shrub growing on thedunes, bushy steppes and open woods of Mozambique andKwaZulu-Natal Province, South Africa. In Mozambique, thisplant is used to treat bilharzia and dysentery. Bioassay-guidedfractionation of the roots resulted in the isolation of six quino-methanes, 28-norisoiguesterin-17-carbaldehyde (38), 17-methoxycarbonyl-28-norisoiguesterin (39), 28-hydroxyiso-iguesterin (40), celastrol (41), pristimerin (42) and isoiguesterol

(43).50 Each of these compounds was tested against two strainsof P. falciparum and against HT-29 cells to determine thecytotoxicity. Compounds 39 and 43 showed greater activitythan chloroquine on the chloroquine-resistant K1 strain ofP. falciparum. Each compound showed a 10–100 fold higheractivity against P. falciparum than against the HT-29 cells,thus indicating that there was some selectivity in their actionand that their antimalarial activity was not just due to generaltoxicity. Compound 39 was tested in vivo against P. berghei inmice, but was inactive against blood stages of the parasite andwas toxic.50

In Thailand the root bark of the Celastrus paniculatus(Celastraceae), known locally as Kra-Thong-Lai, is sold in theform of pressed pills for the treatment of malaria. In vitrotesting showed a chloroform extract of the root bark to beactive and the active constituent to be pristimerin (42).51

Ascaridole (44), a terpene isolated from Chenopodium ambro-sioides (Chenopodiaceae), is one of the few naturally occurringendoperoxides and exhibits some antiplasmodial activity.52

Several members of the Clusiaceae are associated withbiological activity, the most well-known being Hypericumperforatum (Saint John’s wort). A number of compounds withantibacterial, antifungal, antiviral and antitumour activity arepresent in this family. Two species of Garcinia (Clusiaceae), G.dulcis and G. cowa,53,54 have been investigated for antimalarialactivity. In both cases the active compounds were xanthoneswith moderate in vitro activity. Five xanthones were isolatedfrom G. dulcis, the most active one being garciniaxanthone(45).53 Likewise, five xanthones were isolated from G. cowa,and the two most active compounds were cowanol (46) andcowaxanthone (47).54 Investigation of the Chinese speciesHypericum japonicum resulted in the isolation of four newacylphloroglucinol derivatives, two of which were active againstP. berghei in mice, japonicins A (48) and B (49).55 The Europeanspecies H. calycinum, also used as a horticultural plant, yieldedthe phloroglucinol derivative 50 as an antimalarial.56 A highlyactive preanthraquinone, vismione H (51), was isolated fromVismia guineensis.57

Terminalia bellerica (Combretaceae) is extensively used in theIndian system of traditional medicine for the treatment offever, cough, diarrhea, dysentery and skin conditions. Earlierwork has demonstrated the antiviral, antibacterial and anti-fungal activity of this plant.58 Valsaraj et al.,58 using a bioassay-guided fractionation, succeeded in isolating four compoundsfrom the fruit rind, two of which showed antimalarial activity,termilignan (52) and anolignan B (53).58 Antimalarial activitywas also observed for extracts of the stem bark of Combretum

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molle (Combretaceae) 59 and the activity is associated with twohydrolysable tannins of which one was identified as theellagitannin punicalagin.60

3.3 Compositae (Asteraceae)

The most well-known member of the Asteraceae withantiplasmodial activity is Artemisia annua. This Chinese herbhas been used for centuries as a remedy for malaria, the activeconstituent being artemisinin (quinghaosu) (3). Several totalsyntheses of artemisinin have been reported, but the costinvolved makes the A. annua plant still the best source of artem-

isinin. Artemisinin, first isolated in pure form in 1972, and someof its more lipophilic (injectable) and hydrophilic syntheticderivatives are used in China to treat tens of thousands ofpatients without any adverse side effects, making this by far themost useful group of compounds, discovered thus far, to treatchloroquine-resistant malaria.2 The functional group associ-ated with the activity, an endoperoxide, is also present in thestructure of another potent natural antimalarial, yingzhaosuA (18) (see Annonaceae). An extensive amount of work hasbeen done on the antimalarial activity of artemisinin and itssynthetic derivatives,2 none of which will be included in thisreview. Rücker et al.61 tested a number of other naturally occur-ring peroxides, not only from Artemisia but also from othermembers of the Asteraceae (Artemisia sp., Achillea millefolium,Anthemis nobilis, Heterothalamus psiadioides), and found thatalthough all of them show some activity, none was as active asartemisinin (3).

Some flavonoids, with reduced activities, are also present inA. annua. 62 Artemisia indica,63 found in Thailand, has beenreported to have been used to treat malaria and bioassay-guided fractionation resulted in the isolation four antimalarialcompounds of which the most active were exiguaflavanone A(54) and exiguaflavanone B (55).63 Artemisia abrotanum iswidely cultivated in Europe for its aromatic properties. Twocompounds with antimalarial activity, isofraxidin (56) and(1S )-1-hydroxy-α-bisabolol oxide A acetate (57) were isolatedfrom this plant.64

Two Brazilian species have been investigated for their anti-malarial potential, Eupatorium rufescens and Senecio selloi,65

and in both cases, the active principles were the bisaboleneendoperoxides, viz. zingiberene 3,6-β-endoperoxide (58) andzingiberene 3,6-α-endoperoxide (59). A eudesmane sesquiter-penoid 60, isolated from Jasonia glutinosa, is also active againstP. falciparum.66

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Neurolaena lobata is an important medicinal plant in CentralAmerica and the Caribbean region, where it has been usedfor a variety of ailments including stomach pains, nervousweakness, anemia, diabetes, hypertension, hepatic ailments,cancer and skin diseases. Near the coast, around Lake Izabal inGuatemala, it is used to treat malaria.67 The aqueous extractwas tested in vivo in mice and found to be active. Bioassay-guided fractionation resulted in the isolation of seven sesquit-erpene lactones.67 These compounds were concentrated in thedichloromethane extract, which showed the highest activity, buttraces were also found in the aqueous extract, which wouldexplain the in vivo activity. The most active components wereneurolenin A (61), B (62) and C (63). All the compounds werealso found to be cytotoxic, though their IC50 values on bothtumor cell lines tested were considerably higher than their IC50

values for activity against P. falciparum.

Two species of the Vernonia genus have been investigated.68–70

This is a large genus of the Asteraceae comprising more than athousand species worldwide. Vernonia brachycalyx is a herb,reaching about 4 m in height, growing in East Africa in dryforest edges or semideciduous bushveld and is reportedly usedby the Maasai, the Kipsigis and other East African tribes as atreatment for parasitic diseases.68 Both the leaves and the rootsof this plant have been investigated. The roots yielded two5-methylcoumarins, 2�-epicycloisobrachycoumarinone epoxide(64) and cycloisobrachycoumarinone epoxide (65), both ofwhich showed antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum invitro.68 The leaves of V. brachycalyx yielded an active sesquiter-pene dilactone, 16,17-dihydrobrachycalyxolide (66). 69 Thesecond Vernonia species investigated, V. brasiliana, is used inBrazil as an aromatic and as a stimulant.70 Bioassay-guidedfractionation of the leaves of this plant found lupeol to be theactive constituent in vitro. However, no in vivo activity wasobserved for this compound when tested in mice against P.berghei.70 Centipeda minima is used by the Chinese to treatcolds, nasal allergies, asthma, malaria and amoebiasis.71 Asesquiterpene lactone, brevilin A (67) was isolated from thisplant and found to have activity against P. falciparum.71

3.4 Cyperaceae

Cyperus rotundus, a Tanzanian plant used traditionally to treatmalaria, was investigated by Weenen et al.72,73 as part of theirinvestigation into Tanzanian medicinal plants. The dichloro-methane extract had in vitro activity against P. falciparum, andthe active components was identified as α-cyperone (68) andβ-selinene (69).73 However, the activity of β-selinene fluctuated,and it was suggested that the parent compound is not active,but that it forms peroxides readily by autoxidation, and thatthese decomposition products are active.73 The same species(C. rotundus), obtained from Thailand, was investigated byThebtaranonth et al.74 This plant grows as a common weed inThailand and the hexane extract of the tubers showed goodactivity against P. falciparum. Bioassay-guided fractionationresulted in the isolation of four active compounds, of whichthe most active one was 10,12-peroxycalamenene (70), asesquiterpene with an endoperoxide group similar in structureto artemisinin (3).

4 Dracaenaceae–Hernandiaceae

4.1 Dracaenaceae and Ebenaceae

Two species of the West African ‘soap tree’ were investigated,Dracaena mannii (Dracaenaceae) and Dracaena arborea,75 andthe active component in both trees was the saponin spiro-conazole A (71).

Hazra et al.76 found that the compound diospyrin (72),isolated from Diospyros montana (Ebenaceae), showed someactivity against P. falciparum in vitro (IC50 626 µM), andprepared two hydroquinone derivatives from diospyrin withenhanced activity (IC50 of 2.391 and 5.796 µM).

4.2 Euphorbiaceae

Phyllanthus fraternus is used in Ghana during the rainy seasonto treat skin infections and malaria. Sittie et al.77 isolated twoalkamides, (E,E )-octa-2,4-dienamide (73) and (E,Z)-deca-2,4-dienamide (74) with moderate in vitro plasmodial activity fromthis plant.

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A Benedictine mission at Peramiho in Tanzania has used anaqueous decoction of the root bark of Uapaca nitida to treatmalaria. Kirby et al.78 investigated various extracts of thisroot bark for in vitro activity against the chloroquine andpyrimethamine-resistant P. falciparum K1 strain. Their resultsindicated good activity in the ethanolic and hexane extracts butnot in the aqueous extract. Some in vivo activity was also noted,using P. berghei in mice, but the toxicity was quite high. Steeleet al.25 found that the in vitro activity could be attributed tobetulinic acid, a triterpene, but that the compound did notexhibit any in vivo activity.

Weenen et al.73 included Margaritaria discoidea of theEuphorbiaceae in their study on medicinal plants of Tanzania.The root bark of this plant was active, with the active con-stituent being securinine (75).

4.3 Fabaceae (Leguminosae)

Andira inermis is a tree native to Mexico and northern SouthAmerica. Bioassay-guided fractionation resulted in the isol-ation of andidermals A (76) and C (77) 79 and the isoflavonescalycosin (78) and genistein (79) 80 as antimalarial compounds.Two tetracyclic compounds, racemosol (80) and demethylrace-mosol (81), were identified as the most active compounds fromBauhinia malabarica, a tree growing in Thailand.81 Liquoriceroots, under the name Gan Cao, are used in China to treatgastric and duodenal ulcers, bronchial asthma, Addison’sdisease, food and drug poisoning and skin diseases likeeczema.82 The Chinese pharmacopoeia accepts three species ofGlycyrrhiza, G. glabra, G. uralensis and G. inflata, as sources ofGan Cao.82 The chalcone licochalcone A (82) can be isolatedfrom all Glycyrrhiza species in different amounts and has beenshown to exhibit good antimalarial activity.83 In in vivo testsagainst P. yoelii in mice, oral doses of 1000 mg kg�1 resulted inthe complete eradication of the malaria parasite and no toxicitywas noted.

4.4 Hernandiaceae

The stem bark of Hernandia voyronii is used by the Madagas-can people in combination with chloroquine to treat mal-aria.84,85 An investigation of the stem bark by Rasoanaivoet al.84,85 resulted in the isolation of hervelines A–D (83–86),and all four compounds showed moderate activity againstP. falciparum. Hervelines B and C acted as enhancers ofchloroquine activity in a dose dependent manner whileherveline D was a chloroquine antagonist. Laudanosine (87)also displayed in vitro chloroquine-potentiating action. Theseresults showed that the methylation of the hydroxy group atC-12 was vital for the potentiating action and that the bio-activity probably resulted mainly from the benzyltetrahydro-isoquinoline moiety. Roemrefidine (88), an aporphine alkaloidisolated from a Bolivian vine Sparattanthelium amazonumand also several members of the Papavaraceae, was also foundto be active against both resistant and sensitive P. falciparumstrains.86 It has also been shown that 88 acts on the parasitematuration, but has no effect on the erythrocytic reinvasion andthat there is no cumulative influence of the compound on themetabolic pathways of the parasite.

5 Lamiaceae–Nepenthaceae

5.1 Lamiaceae (Labiatae), Lauraceae and Malvaceae

Hoslundia opposita (Lamiaceae) is used in East and West Africato treat malaria.87 The hexane extract of the root bark showedgood activity in vitro against P. falciparum, with an IC50 of 5.6µg ml�1.72,87 Bioassay-directed fractionation led to the isolationof an active ester of an abietane-type quinomethane alcohol,

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3-O-benzoylhosloppone (89).87 The activity was attributed tothe presence of an α,β-unsaturated carbonyl moiety in thiscompound.

In South Africa, Tetradenia riparia (Lamiaceae) has trad-itionally been used in the treatment of malaria, fevers, coughs,dropsy, diarrhea, headaches and toothaches.88 Campbell et al.88

investigated the essential oil of the leaves. Thirty-five com-ponents were identified and the oil gave moderate antimalarialactivity against two strains of P. falciparum. The main con-stituents of the oil were α-terpineol, fenchone, and β-fenchylalcohol.

Three species of the Lauraceae were investigated for theirantimalarial activity, Dehaasia incrassata from Malaysia,89

D. tiandra from the Phillipines 90 and Nectandra salicifolia fromthe rain forests in Costa Rica.91 Eight bisbenzylisoquinolinealkaloids were isolated from D. triandra, but none of them wastested for antimalarial activity.90 However, the three alkaloidsisolated from the leaves and bark of D. incrassata were testedagainst the K1 strain of P. falciparum, and one of them,oxyacanthine, a bisbenzylisoquinoline, was active (IC50

0.31 µg ml�1).89 Work on Nectandra salicifolia by Böhlke et al.91

resulted in the isolation of sixteen alkaloids, of which only one,costaricine (90), was found to show appreciable activity againstP. falciparum.

Gossypol (91) is an abundant component of cottonseed oil(cotton = Gossypium sp., Malvaceae) and exhibits a variety ofbiological activities, including antispermatogenic, anticancer,antiparasitic and antiviral activity. Deck et al.92 demonstratedthat this compound also showed antimalarial activity againstboth chloroquine-sensitive and chloroquine-resistant strainsof P. falciparum, with IC50 values in the order of 10 µM. Thepresence of aldehyde functional groups renders gossypol toxicand in the light of this fact, Deck et al.92 investigated syntheticanalogs of gossypol for biological activity. It was found that thebiological activity was retained, including the antimalarialactivity.

5.2 Meliaceae

Members of the Meliaceae have been used for generations inAfrica, India and tropical America to treat malaria. In tropical

America Cedrela odorata, Carapa quianensis and Swieteniamahagoni have been used while in Africa and India the ‘Neem’tree or Azadirachta indica is used.93 MacKinnon et al.93 testeda series of sixty extracts of twenty-two Meliaceae for activityagainst P. falciparum, using both chloroquine-sensitive andchloroquine-resistant strains. The extracts showing the highestactivity against the chloroquine-sensitive strain were the leavesof Azadirachta indica, Cedrela salvadorensis and Chukrasiatabularis, the bark of Trichilia glabra and the wood of bothCedrela odorata and Dysoxylum fraseranum. The leaves ofA. indica, C. tabularis and C. salvadorensis and the wood ofC. odorata and Guarea pyriformis showed the most activityagainst the chloroquine-resistant strain. The common denom-inator in the Meliaceae was the presence of limonoids, inparticular the limonoid gedunin (92). In a study of A. indicawood extracts from different locations, the activity increasedas the percentage of gedunin increased.93 MacKinnon et al.93

prepared a series of nine derivatives of gedunin (92) in anattempt to establish some sort of structure–activity relation-ship. None of the derivatives was as active as gedunin but anumber of important characteristics were identified. It wasfound that the presence of an α,β-unsaturated ketone in ringA was vital for activity and that the presence of a 7α-acetategroup as well as the furan ring also contributed to the activity.In a survey of twenty-one compounds isolated from medicinalplants, Khalid et al.94 found particular activity in geduninisolated from Melia azedarach. This study found gedunin to beroughly as active as quinine. However, despite the promisingin vitro activity of gedunin, Bray et al.95 found that it did notinhibit Plasmodium berghei in mice. Work on the leaves ofAzadirachta indica collected in India resulted in the isolation offour limonoids, of which meldenin (93) was the most activeagainst the chloroquine-resistant K1 strain of P. falciparum.96

Further investigation on A. indica has been carried out byJones et al.97 and Dhar et al.98 Jones and his co-workers lookedat azadirachtin (94) and a series of seventeen semisyntheticderivatives and their affect in vitro on male gamete productionfrom malarial microgametocytes. Azadirachtin (94) and threeof the semisynthetic derivatives were found to inhibit theformation of mobile male gametes in vitro. This study indicatedthat the presence of a hemiacetal group at C-11 was vital to theactivity. Dhar et al.98 investigated the seeds of A. indica, andfound that the extract was active against all the erythrocyticstages of P. falciparum. In addition to inhibiting the asexualstages of the parasite, the neem extracts also revealed a gameto-cytocidal effect. All stages of maturation of the gametocyteswere affected, unlike artemisinin and primaquine that justaffect the immature stages.98

Khalid et al.99 isolated three limonoids of the mexicanolidetype from Khaya senegalensis. One of them, fissinolide (95),showed slight activity against chloroquine-resistant P. falci-parum. In a study on the related species Khaya grandifoliola byAgbedahunsi et al.,100 it was observed that the hexane extract ofthe stem bark was the most potent when tested againstP. berghei in mice and P. falciparum in vitro. The resultsobtained were similar to those obtained with chloroquinediphosphate, the reference drug used.100

5.3 Menispermaceae

Antimalarial activity has been reported for the genera Abuta,101

Anisocycla,102 Cyclea,103 Pachygone,104 Spirospermum,105 Steph-ania,106,107 Strychnopsis,105 Tiliacora,108 Tinospora,109 andTriclisia.110 It has been shown that the activity can be attributedmainly to the presence of a variety of bisbenzylisoquinolinealkaloids. These compounds, with a few exceptions, showreasonable antimalarial activity but this is often coupled withcytotoxicity. The large number of bisbenzylisoquinoline deriv-atives that occur not only in members of the Menispermaceae,but also in members of the Annonaceae, Berberidaceae,

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Laureaceae, Monimiaceae, and Ranunculaceae, promptedAngerhofer et al.111 to compare the antiplasmodial andcytotoxic activity of fifty-three compounds isolated from thesefamilies. A wide range of biological potencies was observed inantiplasmodial assays, and the majority exhibited some degreeof activity against human KB cells. However, more than half ofthe compounds tested showed selective antiplasmodial activity,with 100-fold greater toxicity towards the malaria parasite thantowards the cultured mammalian cells. The most active com-pounds against the D6 P. falciparum clone were candicusine(96) and 12-O-methyltricordatine (97), whereas cycleapeltine(98) and cepharanthine (99) were the most active ones againstclone W2. However, when the selectivity index (i.e. the ratio ofcytotoxicity over antiplasmodial activity) is considered, themost selective alkaloid was cycleanine (100), which has arelatively potent antiplasmodial activity but low cytotoxicity.There are also reports that in vitro, bisbenzylisoquinolinescan act as modulators of chloroquine resistance in P.falciparum.112–114 Based on these results, the authors concludedthat certain bisbenzylisoquinolines are worth considering aspotential antimalarial agents. However, most of the results arebased on in vitro studies, and need to be confirmed by in vivoexperiments.

In the plant families mentioned above, monomeric isoquino-line alkaloids often co-occur with the bisbenzylisoquinolines.Wright et al.45 assessed the activities of twenty-one of thesecompounds and found that two protoberberine alkaloids,dehydrodiscretine (101) and berberine (33), have antiplas-modial IC50 values less than 1 µM. Potent activity was alsoobserved for dehydrostephanine (102), isolated for Stephaniavenosa.115

5.4 Molluginaceae, Monimiaceae, Moraceae, Myristaceae andMyrtaceae

Extracts of Glinus oppositifolius (Molluginaceae) exhibit notonly antimalarial,116 but also antifungal, larvicidal, mollusc-icidal and antioxidant activity.117 Two triterpenoids, 16-O-β-arabinopyranosyl-3-oxo-12,16β,21β,22-tetrahydroxyhopaneand 16-O-β-arabinopyranosyl-3-oxo-12,16β,22-trihydroxyhop-ane, with only low activity, were isolated. (�)-cis-3-Acetoxy-4�,5,7-trihydroxyflavanone, a compound with moderateantiplasmodial activity, was isolated from a lyophilised extractof the leaves of Siparune andina (Monimiaceae) that exhibitedantiplasmodial activity in vitro.118 The edible fruit of Artocarpusinteger (Moraceae) are popular among the people in Thailand.Three prenylated stilbenes, a novel compound (103) and twoknown stilbenes (104, 105), with moderate activity (EC50 valuesof 1.7, 8.2 and 9.4 µg ml�1, respectively) were isolated from

the aerial parts of the plant.119 The tree Virola surinamensis(Myristaceae) frequently grows on Amazonian riverbanks andit is used in folk medicine for a variety of ailments. The WaiãpiIndians treat malaria with the inhalation of vapour obtainedfrom leaves of this tree. The essential oil of the leaves causeda 100% growth inhibition in the development of the youngtrophozoite to schizont stage, and the sesquiterpenoid nerolidolwas identified as one of the active compounds.120

The leaves of Eucalyptus robusta (Myrtaceae) are usedin China for the treatment of dysentery, malaria and bacterialdiseases. Three active compounds, robustaol A (106), robust-adial A (107) and robustadial B (108), were isolated fromthe ethanol extract of the leaves.121 These compounds arestructurally related to the phloroglucinol derivatives found inHypericum (Clusiaceae) species.

5.5 Nepenthaceae

The Nepenthaceae, consisting of only one genus Nephenthes, isfound in tropical Asia and in the northern parts of Australia.122

A decoction of the stem of N. ampullaria is used to treatmalaria in Malaysia. An investigation 122 of a member from

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Thailand, N. thorelii, for which there is no reported medicinaluse, resulted in the isolation of five compounds with someactivity against P. falciparum. The most active one wasplumbagin (109) with an IC50 value of 0.27 µM.

6 Olacaceae–Rutaceae

6.1 Olacaceae, Periplocaceae and Piperaceae

Minquartia guianensis (Olacaceae) has been used in SouthAmerican medicine to treat tuberculosis, malaria and to treatlung cancer. Bioassay-guided fractionation of an extractshowed that the in vitro antiparasitic activity was associatedwith the main constituent of the extract, minquartynoic acid(110).123 However, there are indications that this activity may bedue to general cytotoxocity.

The focus of antimalarial research in the Periplocaceaehas been Cryptolepis sanguinolenta,124–128 a plant that is used bytraditional healers in Central and West Africa to treat infec-tious diseases, amoebiasis and fever, including malaria. Fouralkaloids have been isolated from the root bark, cryptolepine(111), 11-hydroxycryptolepine (112), quindoline (113) andneocryptine (114), all of which showed good antimalarialactivity in vitro. Three of them, 111, 112 and 113, are moreactive than chloroquine against chloroquine-resistant P. falci-parum. Conflicting results were reported for the in vivo eval-uation of cryptolepine (111). Cimanga et al.124 and Grellieret al.126 reported that in in vivo tests on mice it was active againstP. berghei yoelii and P. vinckei petteri. However, Kirby et al.128

found no in vivo activity for the compound. It was reportedthat, in agreement with observations for antimalarialquinolines, in in vitro experiments, the weakly basic indolo-quinolines were active whereas other structurally related alka-loids with different acid–base profiles were inactive.129

A bioactivity-guided fractionation of Piper hispidum (Piper-aceae) by Jenett-Siems et al.130 resulted in the isolation ofasebogenin (115) as an active compound.

6.2 Ranunculaceae

Thalictrum faberi is a Chinese perennial herb that is used bytraditional healers to treat stomach cancer and as an anti-phlogistic. Studies on this plant have yielded several aporphine–

benzylisoquinoline alkaloids and bisbenzylisoquinoline alka-loids.131,132 Three alkaloids isolated from the roots of this plant,thalifaberidine, thalifaberine and thalifasine (116), have beenevaluated by Lin et al. for cytotoxic and antimalarial activity.131

The best activity was shown by 116, although it was less activethan chloroquine. All three compounds were found to becytotoxic against human cancer cell lines. The roots ofIsopyrum thalictroides 133 yielded the bisbenzylisoquinolinealkaloid penduline (117), which was active against chloroquine-resistant strains of P. falciparum. It was, however, also moretoxic than chloroquine.

Takahara et al.134 carried out an extensive investigation intothe antimalarial effects of the triterpenoids isolated fromseveral species of the genus Cimicifuga. Fifty-nine compoundsbelonging to five different structural groups were investigated.Almost all the compounds tested showed activity in the 1–56µM concentration range. The most active compound tested was(26S )-O-methylactein (118).

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6.3 Rubiaceae

Members of the Rubiaceae from Southern and CentralAmerica, Africa and tropical Asia have been investigated.Psychotria camponutans, growing in Panama and Costa Rica,was found to contain two active compounds, 119 being themost active. However, both compounds also display somecytotoxicity.135 Morinda lucida is widely used in West Africa andthe aerial parts, stem bark or root bark is used to treat malariaand other tropical diseases. Both Koumaglo et al.136 and Sittieet al.137 isolated active anthraquinones from M. lucida, the mostactive being damnacanthal (120).

A chemical investigation of the bark of Anthocephaluschinensis, a medium-sized tree found growing in tropical Asia,yielded fourteen compounds, one of which showed antimalarialactivity. Cadambine (121) gave an IC50 value of 6.77 µM on achloroquine-resistant strain of P. falciparum.138 Pogonopustubulosus, a Bolivian plant used by traditional healers in thetreatment of malaria, was found to contain three active alka-loids, tubulosine (122), psychotrine and cephaeline. Tubulosine(122) was the most active compound with an IC50 value of 0.006µg ml�1 on a chloroquine-sensitive strain of P. falciparum andan IC50 value of 0.011 µg ml�1 on a resistant strain. This com-pound was also tested for toxicity against 9KB cells andalthough it did display some toxicity, it was more toxic to themalaria parasite than to mammalian cells. Tubulosine (122) wasalso tested in vivo against P. vinckei petteri and P. berghei inmice, and in each case, good results were obtained at lowerconcentrations than the lethal dose. The results showed somesupport for the traditional use of the bark of this plant in thetreatment of malaria.139

6.4 Rutaceae

A number of members of the Rutaceae have been reportedto exhibit antimalarial activity and in most cases, this wasdue to the presence of alkaloids. 2-n-Pentylquinoline, isolatedfrom Galipea longiflora, showed good in vivo activity againstP. vinckei.140 Shibuya et al.141 investigated the bark of Fagararhetza, known as ‘Hazalea’ in Indonesia, and isolated hazale-amide (123) with activity against a chloroquine-resistant strainof P. falciparum. The investigation of Glycosmis citrifolia by

Furukawa et al.142 resulted in the isolation of three alkaloids,one of which, glycobismine A (124) showed antimalarialactivity comparable to that of chloroquine diphosphate.Gakunju et al.,143 after consulting with a herbalist from Kenya,chose fourteen plants for evaluation for antimalarial activity.Of the fourteen plants, two showed good in vitro activity againstthree Kenyan strains of P. falciparum. The one, Maytenus arbu-tifolia (Celastraceae), was not further investigated. Bioassay-guided fractionation of the other plant that showed activity,Toddalia asiatica (Rutaceae), resulted in the isolation of thealkaloid nitidine (125). Nitidine is a well-known cytotoxic agentand showed good activity against both chloroquine-sensitiveand chloroquine-resistant strains of P. falciparum.143 A secondinvestigation of T. asiatica resulted in the isolation of 5,7-dimethoxy-8-(3�-hydroxy-3�methyl-1�-butenyl)coumarin as theactive principle of the ethyl acetate extract.144 Weenen et al.,73 aspart of their study of Tanzanian medicinal plants, investigatedthe root bark of Zanthoxylum gilletii. The two active com-ponents found were N-isobutyldeca-2,4-dienamide (IC50 = 5.37µg ml�1) and fagaramide (126) (IC50 = 12.34 µg ml�1).

7 Saxifragaceae–Zingiberaceae

7.1 Saxifragaceae

Some of the earliest work done on novel antimalarials fromplant sources, was on the South-East Asian plant Dichroafebrifuga.145–147 In China the powdered roots are known asCh’ang Shan and are used to treat fevers. Two interconvertible,isomeric alkaloids were isolated, febrifugine (127) and isofebri-fugine (128). Isofebrifugine (127) was inactive at the maximumtolerated dose when tested on ducks, but febrifugine (128) was ahundred times as active as quinine when tested in monkeys. Thetoxicity was however also in the region of a hundred times thatof quinine when tested on white mice. Clinical trials showedthat it was such a powerful emetic that it could not be usedsuccessfully as an antimalarial drug.

7.2 Simaroubaceae

In a comprehensive in vivo survey in chicks and ducks bySpencer et al. in 1947,148 600 plants from 128 families were

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investigated. Thirty-three genera gave positive results and,in particular, significant activity was present in members ofthe Simaroubaceae and Amaryllidaceae families. The activeprinciples of the Simaroubaceae are mainly quassinoids.Quassinoids have also shown anticancer activity and some arecytotoxic. Results do indicate that cytotoxicity and antimalarialactivity do not correlate, suggesting that the antimalarial activ-ity is not merely cytotoxicity, but that selectivity is present.149

Initial and subsequent work on the Simaroubaceae hasfocused on Brucea javanica. This plant is widespread in Asiaand has been used to treat malaria, dysentery and cancer.150

Usually an aqueous extract of the fruits would be consumedin the form of a tea.151 Investigations have resulted in theidentification of two compound types showing antimalarialactivity, the quassinoids 151–154 and the apotirucallane-typetriterpenoids.150 Kitagawa et al.150 isolated three apotirucallane-type triterpenoids: bruceajavanin A (129), dihydrobruceajava-nin A (130) and bruceajavanin B (131) from the stems of B.javanica. Compounds 129 and 130 exhibited moderate activity.In addition to the three new triterpenoids isolated, a novelβ-carboline alkaloid glycoside, bruceacanthinoside, with weakantimalarial activity, was also isolated. Two moderately activeβ-carboline alkaloids were also isolated from Picrasmajavanica.155

Pavanand et al.151 isolated the quassinoids bruceine A (132),bruceine B (133) and bruceine C (134) from the chloroformextract of the fruits of B. javanica. These three compoundsshowed in vitro activity against multidrug-resistant P. falci-parum comparable to the antimalarial drug mefloquine.Bruceine A (132) had previously been shown by Guru et al.,153

along with bruceantin (135), to have activity againstchloroquine-resistant P. falciparum. O’Neill et al.154 isolatedand tested twelve quassinoids from the fruits of B. javanica:bruceantin (135), bruceantinol (136), bruceine A (132),bruceine B (133), bruceine C (134), dehydrobruceine A (137),brusatol (138), bruceine D (139), yadanziolide A (140),yadanzioside C (141) (not tested), yadanzioside F (142),yadanzioside I (143), each of which were more active thanchloroquine diphosphate used as a standard during the test.Bruceine A (132), bruceine B (133), bruceine C (134), brusatol(138) and bruceine D (139) were tested in vivo using P. bergheiinfected mice. All five showed some activity, especially bruceineB (133) and brusatol (138). All five compounds were found tobe toxic, but at higher levels than necessary for antimalarialactivity. In Thai and Chinese traditional medicine, a tea of thefruits of B. javanica is used to treat malaria, often in con-junction with chloroquine. Allen et al.156 found that this teawas antagonistic to chloroquine action and concluded that itmay contribute to the development of chloroquine-resistant

strains of malaria. Work on the Vietnamese species Bruceasumatrana 157 found that the chloroform extract was activeagainst P. berghei in mice and that the active component wasbruceolide (144).

Eurycoma longifolia, a plant found in Burma, Thailand,Indo-China and South-East Asia has been used locally as atreatment for dysentery, glandular swelling, persistent fever andmalaria.158 The antimalarial quassinoids 145–150 were isolatedfrom the roots along with a weakly antimalarial alkaloid,7-methoxy-β-carboline-1-propionic acid.158–160

A common approach when searching for novel activecompounds is to investigate those plants already being used bylocal healers for the disease in question. Cabral et al.161 utilizedthis approach when looking for potential antimalarials fromBrazilian plants. Of the eleven different plant extracts tested,Simaba guianensis showed the most promise. In line with othermembers of this family, the active components were quassi-noids, gutolactone (151) (IC50 4 ng ml�1) and simalikalactone D(152) (IC50 1.6 ng ml�1). In comparison, chloroquine gave an

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IC50 of 63.2 ng ml�1 and mefloquine an IC50 of 1.5 ng ml�1 inthe same assay.

O’Neill and co-workers,162 continuing their work on theSimaroubaceae, investigated the fruits of Simarouba amara.They collected their plant material in the Colon region ofthe Republic of Panama and isolated four active quassinoids(153–156). These were tested in vitro against a multidrug-resistant strain (K1) of P. falciparum and in vivo againstP. berghei in mice. Although the in vitro tests indicated activityin the region of 23–52 times greater than that for chloroquine,the toxicity was greater. Their results also substantiated thefact that antimalarial activity of specific quassinoids and theirtoxicity are not directly related. Two quassinoids were isolatedby Moretti et al.163 from Simana cedron. Cedronin (157) showedgood activity against chloroquine-resistant and chloroquine-sensitive strains of P. falciparum and activity against P. vinckeipetteri in mice.

Active quassinoids have also been isolated from Ailanthusaltissima,164 the Central African Hannoa chlorantha andHannoa klaineana,165 the Guinanan Picrolemma pseudocoffea,166

and stems of the Indonesian plant Quassia indica.167

Studies on the structure–activity relationships of the quassi-noids,168,169 indicated that the type and presence of an estergroup at C-15 was vital for activity. Ring A substitution alsoaffected the activity, with a diosphenol moiety in ring A givingthe highest activity. The glycosides were found to be generallyless active than the corresponding aglycones. In agreement withother studies on quassinoids,164,166 Kim et al.170 reported that3,15-di-O-acetylbruceolide has potent in vivo activity.

7.3 Solanaceae and Strychnaceae

As part of ongoing work on the medicinal plants of Bolivia,the shrub Saracha punctata (Solanaceae) was investigated. Theresult of bioassay-guided fractionation of the ethanol extractof the leaves was the isolation of sarachine (158), a novel

aminosteroid.171 This compound was active against malaria,but also cytotoxic. Compound 158 was also active in vivoagainst P. vinckei, with a 83% inhibition of parasitaemia at100 mg kg�1 per 2 days.171

Work on the Strychnaceae has centered on the genus Strych-nos, with three species being investigated, S. usambarensis,172,173

S. myrtoides 174 and S. icaja 175,176 The rural Malagasy peopleused either an infusion or decoction of S. myrtoides togetherwith chloroquine to treat malaria. The crude extract of the stembark showed no intrinsic antimalarial effects but significantlyenhanced the action of chloroquine both in vitro and in vivo(against a chloroquine-resistant P. yoelii in mice). Two alkaloidswere isolated from the stem bark—strychnobrasiline (159) andmalagashanine (160).174 These were subsequently tested againsta chloroquine-resistant strain of P. falciparum in vitro 174 andin vivo.177 Both showed no intrinsic antimalarial effect, but sig-nificantly enhanced the effect of chloroquine. No cytotoxicitywas observed.

S. usambarensis is traditionally used by the Banyambo peoplewho live along the Akagera River on the border of Rwanda andTanzania. The leaves and roots are used as an arrow poison.Seven alkaloids were isolated and tested for antiplasmodialactivity both in vitro and in vivo. All of the alkaloids showedsome activity in vitro, the most active being dihydrousambaren-sine (161) and strychnopentamine (162).173 These two werethen tested in vivo against P. berghei in mice but were found tobe neither antimalarial nor cytotoxic. Subsequent work onS. usambarensis resulted in the isolation of 10�-hydroxyusam-barensine (163) with moderate in vitro activity against twostrains of P. falciparumi.172 The most active compound obtainedfrom S. icaja is strychnogucine B (164).175,176

7.4 Taccaceae, Taxaceae, Valerianaceae and Zingiberaceae

Tacca plantaginea (Taccaceae) is a herbaceous plant growing inSouth China. Traditional healers have used its rhizome as ananalgesic, an antipyretic, as an antiinflammatory and onwounds.178 Chen et al.178 reported the isolation of two bittercompounds from this plant, one of which, taccalonolide A(165) showed cytotoxic activity against p-388 leukemia cellsand antimalarial activity against P. berghei.

Taxol (paclitaxel), a diterpenoid isolated from the Pacificyew, Taxus brevifolia (Taxaceae), is currently used in thetreatment of a variety of human cancers. Pouvelle et al.179

tested taxol in vitro against a chloroquine-resistant and apyrimethamine-resistant strain of P. falciparum as well asagainst P. chabaudi adami in mice. The activity was dosedependent, comparable to chloroquine in its effectiveness. Itwas not clear whether taxol inhibited P. falciparum by the samemechanism as seen for its antitumour action which is as amitotic spindle poison and inhibitor of cell replication. The invivo results were also promising in that a single dose of taxol ata concentration known to be tolerated by humans, completelycleared mice of blood parasitemia. The good activity of taxol,at a dose that has been tolerated by humans indicates that it haspotential as an antimalarial drug.179

In oriental medicine, the roots and rhizomes of Nardostachyschinensis (Valerianaceae) are used as a sedative and as ananalgesic. Earlier work on this plant resulted in the isolationof nardosinone (166),180 which demonstrated antimalarialactivity. In the light of this fact, further work was done on this

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plant resulting in the isolation of several other endoperoxidesesquiterpenoids.181,182 All showed good antimalarial activityand low cytotoxicity, the most active one being nardoperoxide(167), with a lower in vitro activity than chloroquine (1).

The spice cardamom is used worldwide and it consists ofthe aromatic fruits of a number of Amomum (Zingiberaceae)species. In Thailand, the most commonly used species isAmomum krevanh, known locally as ‘Kra-Waan’ or ‘RoundSiam Cardamom’.183 The crude hexane extract of the fruit

showed good antimalarial activity against P. falciparum andbioassay-guided fractionation resulted in the isolation of aditerpene peroxide 168.183 The structure is related to the potentantimalarial, artemisinin (3), but the activity is only about onetenth of that of artemisinin.

In Cameroon, the powdered fruits of Reneilmia cincinnata(Zingiberaceae) are the major constituents of the ingredientsof a steam bath used to treat fevers. A bioassay-guidedfractionation of the dichloromethane extract of the fruits led tothe isolation of six sesquiterpenoids of which two known ones,169 and 170, were the most active.184

8 Conclusion

A large number of antimalarial compounds with immensestructural variety have been isolated from plants. However,despite advances made during the last decade, many of thesecompounds have been subjected to in vitro testing only, and invivo results are still lacking. Furthermore, many of the com-pounds identified as antimalarials are also cytotoxic, and maynot be suitable as drugs. Notwithstanding these problems, plantmetabolites will still play an important role in the developmentof a new generation of antimalarial drugs.

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