Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

1. Introduction

Figure 1. Schematic life cycle of malaria in humans. Sporozoites are injected into human dermis through the bite of infected Anopheles mosquito. After inoculation, sporozoites migrate to liver cells to establish the first intracellular replicative stage. Merozoites generated from this exoerythrocytic phase then invade erythrocytes (RBCs), and it is during this erythrocytic stage that severe conditions of malaria occur. The life cycle is completed when sexual stages (gametocytes) are ingested by a mosquito. Some sporozoites deposited in the skin eventually penetrate capillaries or lymph vessels. Those entering the lymph vessels will penetrate lymph vascular endothelial cells in lymph nodes to establish a lymph node form, which appears not to continue the life cycle - but may be significant in priming an immune response. Adapted and reproduced by permission from Macmillan Publishers Ltd. [7].

Figure 1. Schematic life cycle of malaria in humans. Sporozoites are injected into human dermis through the bite of infected Anopheles mosquito. After inoculation, sporozoites migrate to liver cells to establish the first intracellular replicative stage. Merozoites generated from this exoerythrocytic phase then invade erythrocytes (RBCs), and it is during this erythrocytic stage that severe conditions of malaria occur. The life cycle is completed when sexual stages (gametocytes) are ingested by a mosquito. Some sporozoites deposited in the skin eventually penetrate capillaries or lymph vessels. Those entering the lymph vessels will penetrate lymph vascular endothelial cells in lymph nodes to establish a lymph node form, which appears not to continue the life cycle - but may be significant in priming an immune response. Adapted and reproduced by permission from Macmillan Publishers Ltd. [7].

Figure 2. Some traditional antimalarial drugs.

Figure 2. Some traditional antimalarial drugs.

2. Recently-Published Crude Extracts with Antiplasmodial Activity

Table 1. Recently-published plant extracts with antiplasmodial activity.

3. Antiplasmodial Non-Alkaloidal Natural Products

3.1. Terpenes and related compounds

Combined use of bioassay-guided fractionation based on in vitro antiplasmodial assay and dereplication based on HPLC–PDA–MS–SPE–NMR methods led to isolation of the sesquiterpene lactones 8-11 (Figure 3) as the main antiplasmodial constituents of the acetone extract of Distephanus angulifolius (Asteraceae), a scrambling shrub or climber commonly known as “Trailing Vernonia” due to its growth habit, which in South Africa is found from the Eastern Cape to Mozambique. The isolated compounds showed IC₅₀ values in the range 1.6–3.8 μM and 2.1–4.9 μM against chloroquine sensitive D10 and chloroquine resistant W2 P. falciparum strains, respectively. Compounds 8 and 9 show slightly better effect than 10, with 9 having the lowest resistance index. Moreover, compounds 9 and 10 show a selectivity index 2.8 and 3.6 times higher, respectively, than 8. In this work, resistance index has been defined as the ratio between the IC₅₀ values of a given compound on W2/D10 strains, while selectivity index has been conceptualized as the ratio between IC₅₀ values of such substance on D10 strain / Chinese Hamster Ovarian cell line. Under these concepts, a desirable chemotherapeutic lead structure should present both low resistance index and high selectivity index [62].

The CH₂Cl₂-MeOH extract of the roots of Scleria striatinux de Wild (syn. S. striatonux) (Cyperaceae), a local spice in parts of Cameroon, was shown to exhibit low activity against both D6 chloroquine-sensitive (IC₅₀ = 80.4 µg/mL) and W2 resistant (IC₅₀ = 89.4 µg/mL) strains of P. falciparum. A new and skeletally unique bicyclofarnesyl sesquiterpene endoperoxide, named okundoperoxide (12) (Figure 3), was isolated by bioassay-guided fractionation of extracts from this plant. This compound contains a cyclic endoperoxide structural moiety and was found to possess low antiplasmodial activity (IC₅₀ around 176 - 180 µM for both strains) [63].

Figure 3. Antiplasmodial terpenes 8-12.

Figure 3. Antiplasmodial terpenes 8-12.

From the stem bark of Ekebergia capensis, ten new triterpenoid compounds named ekeberins A (13), B (14), C1 (15), C2 (16), C3 (17), D1 (18), D2 (19), D3 (20), D4 (21) and D5 (22), were isolated together with the known compounds 23 and 24 (Figure 4), among 15 others. Several of these compounds were screened in vitro against both chloroquine-sensitive (FCR-3) and -resistant (K-1) P. falciparum isolates and were found to exhibit good antiplasmodial activity, with compounds 23 (7-deacetoxy-7-oxogedunin) and 24 (2-hydroxymethyl-2,3,22,23-tetrahydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene) showing IC₅₀ values of 6 and 7 μM, respectively. Compound 24 at a dose of 500 mg/kg showed moderate parasitemia suppression of 52.9% against P. berghei NK 65 in a mouse model [64].

Figure 4. Antiplasmodial terpenes 13-24.

Figure 4. Antiplasmodial terpenes 13-24.

A secoiridoid aglycone with an atypical skeleton, named fagraldehyde (25), as well as the known secoiridoids gentiopicroside (26), sweroside (27) and swertiamarin (28) (Figure 5), were isolated from the bark and leaves of Fagraea fragrans (Gentianaceae) collected in Cambodia. Compound 25 was weakly active in vitro against P. falciparum, exhibiting an IC₅₀ value of 116.6 ± 9.4 μM (W2 strain), whereas compounds 26-28, displaying IC₅₀ values higher than 200 μM, were considered to be inactive [65].

Figure 5. Antiplasmodial terpenes and related compounds 25-35.

Figure 5. Antiplasmodial terpenes and related compounds 25-35.

A new indanone derivative 29 and two new diterpenoids 30 and 31 (Figure 5), together with three known flavonoids, have been isolated from an ethanol extract of the leaves of Croton steenkampianus Gerstner (Euphorbiaceae), commonly known as “Marsh Fever-berry” and “Tonga Croton” in central and southern Africa. The isolated compounds were tested for their antiplasmodial activity and cytotoxicity. Antiplasmodial assays against chloroquine-susceptible strains (D10 and D6) and the chloroquine-resistant strains (Dd2 and W2) of P. falciparum showed that compound 30 gave good activities at 9.1-15.8 μM [66].

Japanese researchers have isolated two new cassane-type diterpenes, sucutiniranes A (32) and B (33), along with 6α-acetoxyvouacapane (34) and 6α,7β-diacetoxyvouacapane (35) (Figure 5) from the seeds of Bowdichia nitida (Fabaceae), a Brazilian Amazon species commonly known as “sucupira”. Compound 35 showed promising in vitro antiplasmodial activity against parasite P. falciparum 3D7 (IC₅₀ = 1 µM) and a good selectivity index with regard to the cytotoxicity on COLO201 cells (IC₅₀ > 250 µM), whereas other compounds were not active at a concentration of 3 µM (chloroquine: IC₅₀ = 0.019 µM) [67].

From the crude ethyl acetate extract of the medicinal plant Siphonochilus aethiopicus (Zingiberaceae), which showed a very good in vitro activity against the chloroquine-sensitive (D10) and chloroquine-resistant (K1) strains of P. falciparum with IC₅₀ values of 2.9 and 1.4 µg/mL, respectively, a bioassay-guided fractionation led to the isolation of three novel furanoterpenoids 36-38 (Figure 6) with moderate/good in vitro antiplasmodial activity, displaying IC₅₀ values of 73.0 µM (D10) and 67.3 µM (K1), for compound 36; 109.4 µM (D10) and 25.2 µM (K1), for compound 37; and 14.5 µM (D10) and 7.5 µM (K1), for compound 38. The crude ethyl acetate extract has also showed a very good in vivo activity, with a parasitemia reduction comparable to chloroquine. The compounds and crude extract were more active against the K1 strain than the D10 strain of P. falciparum [61].

Figure 6. Antiplasmodial terpenes and related compounds 36-42.

Figure 6. Antiplasmodial terpenes and related compounds 36-42.

As Salvia radula (Lamiaceae) exhibited the best antiplasmodial activity (IC₅₀ = 3.91 µg/mL) among 17 Salvia species used in traditional medicine in South Africa, it was selected for the bioassay-guided isolation of the active compounds. Fractionation of a 1:1 methanol/chloroform extract of this species afforded betulafolientriol oxide (39) and salvigenin (40) (Figure 6), which displayed similar or lower antiplasmodial activity [IC₅₀ values = 4.95 and 24.60 μg/mL (10.4 and 74.9 μM), respectively] when compared to the crude solvent extract. The loss of activity may be due to synergy that might account for the better activity of mixture than isolated compounds [68].

From bioassay-guided fractionation of the crude acetone leaf extract of Vernonia colorata (Asteraceae), Chukwujekwu and co-workers isolated two sesquiterpene lactones (Figure 6) which displayed antiplasmodial activity against the D10 chloroquine-sensitive strain of P. falciparum: vernolide (41, IC₅₀ = 5.16 μM) and vernodalin (42, IC₅₀ = 1.44 μM), with selectivity indices of 1.02 and 2.79, respectively. In conclusion, the authors considered that these compounds were not shown to be specific antiplasmodial agents towards this parasite [69].

Pure natural monoterpenes geraniol (43), (-)-linalool (44), (-)-perillyl alcohol (45), (-)-isopulegol (46), (-)-limonene (47) and (±)-citronellol (48) (Figure 7) were evaluated in vitro for their antiplasmodial activities against the chloroquine-resistant FcM29-Cameroon strain of P. falciparum. Chemically modified terpenes were also prepared and assayed against the same strain in order to see whether the introduction of an alkyne, a cyclopropane, a diene, or a cyclopentenone moiety had an influence on their biological activity. The results showed the moderate-low activity of most natural monoterpenes (IC₅₀ values ranging from 52 to 519 μM), geraniol (43, IC₅₀ = 52 µM) and limonene (47, IC₅₀ = 66 µM) being the most active ones in this study. However, the alkyne 49 (IC₅₀ = 39 µM) and cyclopentenone 50 (IC₅₀ = 1.8 µM) derivatives showed a promising enhancement of activity compared with their parent molecules, reaching a 13- and 290-fold increase in the activity for 49 and 50, respectively. Given the observed antiplasmodial activity of some of these modified monoterpenes, it was suggested that new monoterpene derivatives could be the basis for the research of new antimalarial drugs [70].

Figure 7. Antiplasmodial terpenes and related compounds 43-60.

Figure 7. Antiplasmodial terpenes and related compounds 43-60.

Although neither medicinal uses nor phytochemical studies had been reported before for Endodesmia calophylloides (Guttiferae), a tree found in Nigeria, Cameroon, Gabon and Angola, n-hexane (IC₅₀ = 9.3 μg/mL), AcOEt (IC₅₀ = 7.4 μg/mL) and MeOH (IC₅₀ = 12.8 μg/mL) extracts from the stem bark of this plant showed potent antiplasmodial activities. A novel friedelane triterpenoid named endodesmiadiol (51), as well as the known compounds friedelin (52), canophyllol (53), canophyllal (54), cerin (55), morelloflavone (56), volkensiflavone (57), 8-deoxygartanin (58), 3β-acetoxyoleanolic acid (59) and 1,8-dihydroxy-3-isoprenyloxy-6-methylxanthone (60) (Figure 7), were isolated from the ethyl acetate extract and assayed against the W2 chloroquine-resistant strain of P. falciparum. All compounds were found to be active with IC₅₀ values ranging from 7.2 to 23.6 µM. From these results, the authors could anticipate arguing that friedelane derivatives might be interesting sources for new potential antimalarial leads [71].

The chloroform-soluble fraction obtained from the methanol extract of Carpesium rosulatum (Asteraceae) was found to have high in vitro antiplasmodial activity (IC₅₀ = 8.2 μg/mL) against the chloroquine-resistant D10 strain of P. falciparum, this activity being attributed to Ineupatorolide A (61) (Figure 8), which displayed a very impressive antiplasmodial activity (IC₅₀ = 0.019 µM) [72]. More recently, Korean researchers demonstrated that 61 shows potent in vivo antimalarial activity when tested against P. berghei in mice at doses of 2, 5 and 10 mg.kg^-1·day^-1, exhibiting a significant blood schizontocidal activity in 4-day early infection, repository evaluation and in established infection with a significant mean survival time comparable to that of the standard drug, chloroquine (5 mg·kg^-1·day^-1). According to the authors, compound 61 possesses a promising antiplasmodial activity which can be exploited in malaria therapy [73].

Betulinic acid (62) and its derivative compounds betulonic acid (63), betulinic acid acetate (64), betulinic acid methyl ester (65) and betulinic acid methyl ester acetate (66) (Figure 8) have been evaluated for their antimalarial properties. These substances showed antiplasmodial activity against W2 chloroquine-resistant P. falciparum parasites in vitro, with IC₅₀ values of 9.89, 10.01, 5.99, 51.58 and 45.79 μM, respectively. Moreover, since betulinic acid acetate (64, SI = 9.6) displayed the best selectivity index among all substances tested, this compound was administered by intraperitoneal route to mice infected with P. berghei, causing a dose-dependent reduction of parasitemia of 70%, while mice treated with chloroquine had undetectable parasitemia. These results indicate that betulinic acid and its derivative compounds might be considered as potential lead compounds for the development of new antimalarial drugs, since the authors suggest that structural changes in the molecule significantly alter the anti-Plasmodium activity [74].

Figure 8. Antiplasmodial terpenes 61-66.

Figure 8. Antiplasmodial terpenes 61-66.

Leaves and flowers of Artemisia gorgonum (Asteraceae) collected in Fogo, Cape Verde islands, were phytochemically investigated, leading to the isolation and characterization of three new guaianolides 67, 68, 71, and a secoguaianolide 70, in addition to seven known guaianolides 69, 72-77 and two known germacranolides 78 and 79 (Figure 9). Most compounds exhibited mild antiplasmodial activities, ridentin (79) being the most interesting, with an IC₅₀ of 15.3 ± 2.8 μM against P. falciparum FcB1 and weak cytotoxicity in a vero cell line (IC₅₀ = 285.9 ± 15.7 μM) [75].

Figure 9. Antiplasmodial terpenes and related compounds 67-88.

Figure 9. Antiplasmodial terpenes and related compounds 67-88.

Three known 80-82 and two new halogenated monoterpenes 83 and 84, all of them with a 3,7-dimethyl-3,4-dichloro-octa-1,5,7-triene skeleton, were isolated from the endemic marine red alga Plocamium cornutum (Turner) Harvey (Plocamiaceae) collected in South Africa. These compounds, together with compounds 85-88 (Figure 9) previously obtained from P. corallorhiza, were evaluated for their antiplasmodial activity against the chloroquine sensitive D10 strain of P. falciparum. Although the compounds tested were significantly less active than the standard compound (chloroquine, IC₅₀ = 0.036 µM), it was interesting to note that compounds 81 and 82 containing the 7-dichloromethyl moiety were the most active ones (IC₅₀ values of 16 and 17 µM, respectively), followed by compound 80 which contains an aldehyde functional group at this position. In addition, almost all the other compounds were essentially inactive, including plocoralide A (85) which contains a 1-dichloromethyl moiety. The importance of a functional group at position 7 is further emphasized when considering the lack of antiplasmodial activity of other related halogenated monoterpenes [76].

Figure 10. Antiplasmodial terpenes 89-95.

Figure 10. Antiplasmodial terpenes 89-95.

Limonoids are highly oxidized secondary metabolites from Meliaceae species which are obtained through a unique biosynthetic route involving a tetranortriterpenoid nucleus. Numerous biological effects such as insecticidal, insect antifeedant, antibacterial, antifungal, antimalarial, anticancer and antiviral activities have been reported for them [77,78]. From the crude ethanol extract from the bark of Chisocheton ceramicus, Mohamad and co-workers isolated three new limonoids, named ceramicines B–D (89–91), together with ceramicine A (92) (Figure 10). Ceramicine B (89) showed a potent in vitro antiplasmodial activity against P. falciparum 3D7 (IC₅₀ = 0.56 µM), whereas ceramicines C (90) and D (91) exhibited a relative good activity (IC₅₀ = 4.83 µM and 5.06 µM, respectively) and ceramicine A (92) displayed a weak activity (IC₅₀ = 100.37 µM). The higher antiplasmodial activity of compounds 89-91 than that of 92 seems to be attributed to the presence of a tetrahydrofuran ring at C-4/C-6 and C-28 [79].

Starting from the first pharmacological screening of Cogniauxia podolaena (Cucurbitaceae) which confirmed that the roots of this species possesses antiplasmodial activity with IC₅₀ values lower than 27 µg/mL for all extracts obtained with different solvents, a phytochemical study of this plant was undertaken and three triterpenes have been isolated: cucurbitacin B (93), cucurbitacin D (94) and 20-epibryonolic acid (95) (Figure 10). All isolated compounds were shown to have good antiplasmodial activity against the chloroquine-resistant FcM29 strain of P. falciparum, displaying IC₅₀ values of 2.9, 7.7 and 4.3 µM, respectively. These results corroborate the conclusion that compounds 93-95 are the constituents responsible for the antiplasmodial activity of C. podolaena roots. In addition, compound 95 showed a better selectivity index than those from 93 and 94, indicating that this compound may be of therapeutic interest for further pharmacomodulation studies [80].

3.2. Flavonoids, chromones, xanthones, anthraquinones and related compounds

From the seedpods of Tephrosia elata (Fabaceae), a new β-hydroxydihydrochalcone (96) was isolated, along with the known flavonoids deguelin (97) and obovatin (98) (Figure 11). The crude MeOH-CH₂Cl₂ (1:1) extract showed antiplasmodial activities against chloroquine-sensitive Sierra Leone I (D6) (IC₅₀ = 8.4 ± 0.3 µg/mL) and chloroquine-resistant Indochina I (W2) (IC₅₀ = 8.6 ± 1.0 µg/mL) strains of P. falciparum.

Figure 11. Antiplasmodial flavonoids and related compounds 96-111.

Figure 11. Antiplasmodial flavonoids and related compounds 96-111.

Among the compounds isolated from the seedpods of T. elata, the new compound (96) exhibited the highest antiplasmodial activity with IC₅₀ values of 8.2 ± 0.8 and 16.3 ± 0.9 µM against D6 and W2 strains, respectively, while the other substances (97 and 98) showed IC₅₀ values ranging from 12.4 to 27.6 µM against these strains. This compound along with the other flavonoids appears to be responsible for the activities observed in the crude extract [81].

From a series of twelve biflavonoids 99-110 (Figure 11) containing amentoflavone and hinokiflavone derivatives isolated from the Indian medicinal herb Selaginella bryopteris (Selaginellaceae), eleven of them (99-104, 106-110) were investigated for their antiprotozoal activity using in vitro assays against the K1 strain of P. falciparum, besides Leishmania donovani, Trypanosoma brucei rhodesiense and Trypanosoma cruzi. The highest antiplasmodial activity was displayed by 107 and 109 which exhibited an IC₅₀ of 0.30 and 0.26 µM, respectively. To evaluate the in vivo activity against P. berghei of the most active compound (109), trimethylated amentoflavones were obtained by partial synthesis starting from amentoflavone (99). The synthesized mixture of trimethylated amentoflavones did not show activity in the P. berghei mouse model against female NMRI mice at 50 mg/kg by intraperitoneal administration [82].

A new bischromone, chrobisiamone A (111) (Figure 11), with a good in vitro antiplasmodial activity against parasite P. falciparum 3D7 (IC₅₀ = 5.6 µM), has been isolated from the leaves of Cassia siamea, a Fabaceae species widely used in traditional medicine, particularly for the treatment of periodic fever and malaria in Indonesia [83].

In their studies on the screening of medicinal plants produced in Thailand with antimalarial activity against the multi-drug-resistant P. falciparum (K1 strain), Khaomek and collaborators have reported that an ethyl acetate (EtOAc) extract of the stem bark of Erythrina fusca Lour. showed significant antiplasmodial activity (IC₅₀ = 7.5 µg/mL).

Figure 12. Antiplasmodial flavonoids 112-117.

Figure 12. Antiplasmodial flavonoids 112-117.

The flavonoids lupinifolin (112), citflavanone (113), erythrisenegalone (114), lonchocarpol A (115), liquiritigenin (116) and 8-prenyldaidzein (117) (Figure 12) were isolated from this extract, and three among them (113, 115 and 117) were found to show in vitro antiplasmodial activity at a concentration less than 12.5 µg/mL. Diprenylated flavanone 115 (IC₅₀ = 3.9 µM) displayed the most potent activity among the tested compounds, whereas 112 and 114 did not show such activity, even though these compounds also possess prenylated structures. This result postulates that appropriate introduction of prenyl groups into flavonoids may lead to more useful derivatives for construction of an antimalarial agent [55].

From the stem bark of Pentadesma butyracea Sabine (Clusiaceae), a multipurpose rain forest species commonly called “butter tree” and widely distributed in tropical West Africa including Cameroon, four new xanthones named butyraxanthones A-D (118-121), together with six known xanthones (122-127) (Figure 13) and a triterpenoid (lupeol), were isolated and assayed in vitro for antiplasmodial activity against the P. falciparum chloroquine-resistant FcB1 strain. Except for compound 121 (IC₅₀ > 23.3 µM), all of these xanthones exhibited good antiplasmodial activity with IC₅₀ values ranging from 4.4 to 8.0 µM [84].

Figure 13. Antiplasmodial xanthones 118-127.

Figure 13. Antiplasmodial xanthones 118-127.

Chemical investigation of the methanol extract from the leaves of Arrabidaea patellifera, a Bignoniaceae plant from Panama, afforded mangiferin (128) and six new derivatives (129-134).

Figure 14. Antiplasmodial flavonoids and related compounds 128-144.

Figure 14. Antiplasmodial flavonoids and related compounds 128-144.

Compounds 128-131 (Figure 14) were moderately active in vitro against chloroquine-sensitive P. falciparum 3D7 clone, displaying IC₅₀ values of 23.8, 26.5, 18.1 and > 38.2 µM, respectively [85]. Bioassay-guided fractionation of the ethanol extract of a Madagascar collection of the bark of Scutia myrtina (Rhamnaceae) led to the isolation of three new anthrone–anthraquinones named scutianthraquinones A, B and C (135–137), one new bisanthrone–anthraquinone, scutianthraquinone D (138), and the known anthraquinone aloesaponarin I (139). Compounds 135-138 exhibited very good antiplasmodial activities against P. falciparum Dd2, with IC₅₀ values ranging from 1.0 to 5.9 µM, while compounds 135 (IC₅₀ = 1.7 µM), 136 (IC₅₀ = 7.9 µM) and 138 (IC₅₀ = 5.0 µM) also exhibited significant antiplasmodial activities against P. falciparum FCM29 strain [86].

Interactions of two phytochemicals, artemisinin (4) and licochalcone A (140) (Figure 14), have been studied against synchronized erythrocytic stages of chloroquine-sensitive 3D7 and chloroquine-resistant RKL 303 strains of P. falciparum. These two compounds in combination showed synergistic antiplasmodial activity in vitro on these strains, provided by their antimalarial action on different metabolic pathways. According to the authors, artemisinin (4) but not licochalcone A (140) was shown to interfere with hemozoin formation, which could be either due to reduction in heme-detoxification or decrease in hemoglobin catabolism. The preferential inhibition of the bc1 complex of P. falciparum compared to that of mammals and the inhibition of new permeation pathways induced by the parasite in the host erythrocyte membrane have been suggested as the mode of action of licochalcone A (140) [87]. Neither of the phytochemicals alone or in combination obstructed sorbitol-induced hemolysis [88].

The effects of a range of common dietary flavonoids on the growth of two strains of P. falciparum have been investigated by Lehane and Saliba [89]. A chloroquine-sensitive (3D7) and a chloroquine-resistant (7G8) strain were tested for in vitro susceptibility to a range of individual dietary flavonoids and flavonoid combinations. Of the eleven flavonoids tested, eight showed antiplasmodial activity against the 3D7 strain (with IC₅₀ values between 11 and 66 µM), and all showed activity against the 7G8 strain (with IC₅₀ values between 12 and 76 µM). The most active compound against both strains was luteolin (141) (Figure 14), with IC₅₀ values of 11 ± 1 µM and 12 ± 1 µM for 3D7 and 7G8, respectively. Luteolin was found to prevent the progression of parasite growth beyond the young trophozoite stage, and did not affect parasite susceptibility to the antimalarial drugs chloroquine or artemisinin. Combining low concentrations of flavonoids was found to produce an apparent additive antiplasmodial effect. The authors conclude that flavonoid combinations warrant further investigation as antiplasmodial agents [89].

The ethanol extract of Zhumeria majdae (Labiateae) showed good antiplasmodial activity in vitro against chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2, Indo China) strains of P. falciparum, with IC₅₀ values of 8.8 and 7.5 μg/mL, respectively. Bioactivity-guided fractionation of this extract led to the isolation of 12,16-dideoxy aegyptinone B (142) (Figure 14), a rearranged abietane diterpene with a 1,4-naphthoquinone moiety, which exhibited a significant antiplasmodial activity with IC₅₀ values of 4.4 and 4.7 µM against D6 and W2 strains, respectively. This compound was further found to have potent antileishmanial and mild cytotoxic activities [90].

Cassia siamea L. (Fabaceae), used traditionally in the southwest Nigerian ethnobotany as a laxative, for insomnia, diabetes and hypertension, has been recently identified as an antimalarial remedy [91,92]. This led to the bioassay-guided fractionation of the crude methanol stem bark extract from this plant, using the parasite lactate dehydrogenase assay and multi-resistant strain of P. falciparum (K1) for assessing the in vitro antimalarial activity. Emodin (143) and lupeol (144) (Figure 14) were isolated from the ethyl acetate fraction by a combination of chromatographic techniques. Both compounds were found to be the active principles responsible for the antiplasmodial property of C. siamea, with IC₅₀ values of 18.5 µM for 143 and 11.7 µM for 144 [93].

Piptadenia pervillei Vatke (Fabaceae) was selected from a screening programme devoted to the search of naturally-occuring antimalarial compounds from plants of Madagascar. Bioassay-guided fractionation of the ethyl acetate extract of the leaves led to the isolation of four phenolic compounds, (+)-catechin (145), (+)-catechin 5-gallate (146), (+)-catechin 3-gallate (147) (Figure 15) and ethyl gallate. Compounds 146 and 147 displayed the highest in vitro activity against the chloroquine-resistant strain FcB1 of P. falciparum with IC₅₀ values of 1.2 μM and 1.0 μM, respectively, and no significant cytotoxicity against the human embryonic lung cells MRC-5 was measured (IC₅₀ values > 75 μM). Ethyl gallate was less active with an IC₅₀ value of 8.1 μM, and catechin 145 showed no significant activity. Thus, the antiplasmodial activity of compounds 146, 147 and ethyl gallate appears to be associated with the presence of a gallate ester which plays an important role in inhibition against P. falciparum [94].

Figure 15. Antiplasmodial flavonoids 145-147.

Figure 15. Antiplasmodial flavonoids 145-147.

3.3. Miscellaneous compounds

The bioassay-guided purification of CH₂Cl₂ bark extract of Tapirira guianensis (Anacardiaceae) led to the isolation of cyclic alkyl polyol derivatives 148 and 149 (Figure 16), which were active against the chloroquine-sensitive F32 strain (IC₅₀ = 4.7 µM) and the chloroquine-resistant FcB1 strain (IC₅₀ = 5.4 µM) of P. falciparum. These results show that it is the 148-149 mixture which is mainly responsible for the activities of this plant extract, since other compounds isolated from T. guianensis did not show any interesting activity against the pathogens tested, although they were chemically quite similar [95].

Piper glabratum and P. acutifolium were analyzed for their content of main secondary constituents, affording nine new benzoic acid derivatives (150, 151, 153, 154, 156, and 159-162), in addition to four known compounds (152, 155, 157, and 158) (Figure 16). Compounds 150, 152, 155, 156, 157, 159 and 161 were evaluated in vitro against Leishmania spp., Trypanosoma cruzi and P. falciparum. Among the evaluated compounds, only 155 and 156 exhibited a relative good antiplasmodial activity against F-32 Tanzania (chloroquine sensitive) strains of P. falciparum, with IC₅₀ values of 12.7 and 16.3 μM, respectively. The rest of the compounds were considered less active (IC₅₀ > 16.4 μM). Taking into account the results of the biological activities evaluated, a preliminary structure-activity relationship revealed that the prenylated 4-hydroxybenzoic acid derivatives with one side chain (150, 152, 155 and 156) were substantially more active as potential antiparasitic agents than those with two side chains (157, 158, 159 and 160) [96].

Eleven new polycyclic polyprenylated acylphloroglucinols (PPAPs) (165-170, 172-176) along with the known isogarcinol (163), cycloxanthochymol (164) and garcinol (171) (Figure 17), were isolated from the methanol extract of the trunk latex of Moronobea coccinea (Clusiaceae) which showed 95% inhibitory growth at 10 μg/mL against a chloroquine-resistant strain of P. falciparum (FcB1). Compounds 163-176 exhibited good antiplasmodial activity, being compounds 163-170 the most active ones with their IC₅₀ values ranging from 3.3 to 9.0 μM. These results indicated that the benzophenones with a tetrahydropyran ring are the most potent compounds. In contrast, compounds 171-176 showed lower antiplasmodial activities with IC₅₀ values over 10 μM [97].

Figure 16. Antiplasmodial miscellaneous compounds 148-162.

Figure 16. Antiplasmodial miscellaneous compounds 148-162.

From compounds such as crypthophilic acids A–C (177-179) (Figure 18), which are the first resin glycosides occurring in another family (Scrophulariaceae) that is not Convolvulaceae, along with buddlejasaponin III (180), L-tryptophan and other constituents isolated from the aerial parts of Scrophularia cryptophila, only compounds 179, L-tryptophan and 180 showed antimalarial activity against K1 strain of P. falciparum with IC₅₀ values of 4.0, 81.3 and 24.5 μM, respectively. In target identification studies, none of the three compounds inhibited PfFabI, a key enzyme from the P. falciparum type II fatty acid cascade, FAS-II. In addition, all compounds were found to be selective as they did not possess any cytotoxicity on mammalian L6 cells even at high concentrations (IC₅₀ values >> 470 μM) [98].

Figure 17. Antiplasmodial miscellaneous compounds 163-176.

Figure 17. Antiplasmodial miscellaneous compounds 163-176.

Fractionation of dichloromethane extracts from the leaves of Piper heterophyllum and P. aduncum afforded three new prenylated hydroxybenzoic acids (181-183), along with six known compounds (184-189) (Figure 18). Evaluation of the antiparasitic activity for all isolates showed that all the compounds were considered to be moderately active (IC₅₀ >> 10 µg/mL), except for compound 181, which exhibited a good activity against P. falciparum with an IC₅₀ of 7.0 µM, in comparison with chloroquine used as a positive control (IC₅₀ = 0.3 µM). In conclusion, a geranylgeranyl side chain along with a carboxyl acid group as in 181 seem to be relevant for the antiplasmodial activity [99].

Figure 18. Antiplasmodial miscellaneous compounds 177-204.

Figure 18. Antiplasmodial miscellaneous compounds 177-204.

Extracts from Holostylis reniformis were tested in vivo against P. berghei and in vitro against a chloroquine-resistant strain of P. falciparum. The hexane extract of the roots was the most active, causing 67% reduction of parasitemia in vivo. From this extract, six lignans 190-195 (Figure 18), including a new (7’R,8S,8’S)-3’,4’-methylenedioxy-4,5-dimethoxy-2,7’-cyclolignan-7-one (195), were isolated and assayed in vitro against P. falciparum. The three most active lignans (190-192) showed IC₅₀ values of <0.32 µM (<0.12 µg/mL), lignan 192 being the most active compound (IC₅₀ = 0.20 µM). Lignan 194 exhibited a lower activity (IC₅₀ = 8.00 µM), whereas lignan 195 did not exhibit any activity under the same experimental conditions. An evaluation of minimum lethal dose (30%) values showed low toxicity for these lignans in a hepatic cell line (Hep G2A16). Therefore, in vivo assays and clinical studies need to be undertaken with these compounds in order to confirm them as potential candidates for the development of antimalarial drugs [100].

Based on previous work which revealed that petroleum ether extracts of Viola websteri (Violaceae) showed inhibition value of 31.7 as percentage of parasite inhibition at 25 μg/mL, this extract was investigated for its activity against the chloroquine-sensitive D10 strain of P. falciparum. Bioassay-guided fractionation led to the identification of two structurally related compounds (196 and 197) (Figure 18) which were shown to be responsible for the observed activity of the extract. The main antiplasmodial principles, 6-(8’Z-pentadecenyl)-salicylic acid (196) and 6-(8’Z, 11’Z, 14’Z-heptadecatrienyl)-salicylic acid (197), have been isolated from V. websteri for the first time. In addition, this is the first report on the antiplasmodial activity of these compounds. Although compounds 196 (IC₅₀ = 10.1 ± 3.2 µM) and 197 (IC₅₀ = 13.3 ± 6.7 µM) are over 100 times less active than the positive controls, the data suggest that their antiplasmodial activity might not be due to general toxicity [101].

The dichloromethane, methanol and aqueous ethanol extracts of the stem bark of Pycnanthus angolensis (Myristicaceae) were evaluated for their in vitro activity against the 3D7 P. falciparum strain. The CH₂Cl₂ extract was the most active showing an IC₅₀ = 1.6 μg/mL. From this extract, a new dibenzylbutane lignan, threo-4,4′-dihydroxy-3-methoxylignan (198) named pycnantolol, together with the known lignans (-)-dihydroguaiaretic acid (199), heliobuphthalmin (200), talaumidin (201), hinokinin (202), the labdane type diterpene ozic acid (203) and the steroids stigmast-4-en-6β-ol-3-one (204) (Figure 18), β-sitosterol and stigmasterol were isolated. The antiplasmodial activity of lignans 198–202, ozic acid (203) and stigmast-4-en-6β-ol-3-one (204) was evaluated against 3D7 and Dd2 P. falciparum strains. In contrast with the crude extracts, these isolated compounds have not shown significant antiplasmodial activity against both strains, the lowest IC₅₀ value (60.5 µM) being obtained for talaumidin (201) against the Dd2-chloroquine resistant P. falciparum strain. These results might be explained by synergistic effects between the different constituents of the complex extract and, especially if the antimalarial activity remains being observed in clinical studies and/or animal models, they could suggest that a standardization of the bark extract might be the best solution to a rational use of this traditional antimalarial plant [102].

4. Perspectives and Remarks on the Development of New Drugs and Phytomedicines for Malaria

5. Conclusions

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