Antiplasmodial Natural Products

Abstract

Malaria is a human infectious disease that is caused by four species of Plasmodium. It is responsible for more than 1 million deaths per year. Natural products contain a great variety of chemical structures and have been screened for antiplasmodial activity as potential sources of new antimalarial drugs. This review highlights studies on natural products with antimalarial and antiplasmodial activity reported in the literature from January 2009 to November 2010. A total of 360 antiplasmodial natural products comprised of terpenes, including iridoids, sesquiterpenes, diterpenes, terpenoid benzoquinones, steroids, quassinoids, limonoids, curcubitacins, and lanostanes; flavonoids; alkaloids; peptides; phenylalkanoids; xanthones; naphthopyrones; polyketides, including halenaquinones, peroxides, polyacetylenes, and resorcylic acids; depsidones; benzophenones; macrolides; and miscellaneous compounds, including halogenated compounds and chromenes are listed in this review.

1. Introduction

Malaria is an infectious disease caused by four protozoan species of the genus Plasmodium (Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax) [1]. Small human infection outbreaks caused by a malaria parasite of monkeys, Plasmodium knowlesi, have also been reported in Southeast Asia [2]. The majority of the cases of malaria and deaths (malaria kills 1-2 million people each year) are caused by P. falciparum. P. vivax is generally considered less dangerous than P. falciparum, although both can cause deadly complications in infected people. Nearly 3 billion people are at risk of infection with the malaria parasite P. vivax. A new map of areas where this parasite has been reported, including risk areas, has been drawn [3]. These grim statistics could become even worse if resistance to the existing antimalarial drugs develops further [4]. According to WHO [5], the elimination of malaria from countries with high transmission rates is a long-term goal that will depend on the success of research and development to deliver a more robust arsenal of tools than those available today – tools of greater potency and effectiveness, especially those with an impact on transmission, and replacements for medicines and insecticides that are being lost to resistance. The growing resistance to existing antimalarial drugs could nullify efforts to eliminate this deadly disease. Unfortunately, there are still very few drugs that are active against malaria (artemisinin, atovaquone, and chloroquine analogues) [4,6] and vaccines against malaria are not yet available [6].

At present, drug resistance of the malaria parasite is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996, and there has recently been an increase in parasite strains with reduced sensitivity to the newest drugs [7]. Meanwhile, recent advances in genome-based technologies and in vitro screening of whole parasites and a great number of compounds (natural and synthetic) have broadened the range of therapeutic targets and are accelerating the development of a new generation of treatments for both the control and eradication of malaria [6].

Several excellent reviews on antiplasmodial compounds, including natural products, have been published in recent years [8,9,10,11,12,13,14,15,16,17,18]. Thousands of chemicals have been assayed for antiplasmodial activity, such as those described by Gamo et al. [7].

The current review provides an overview of a great number of bioactive natural products that have recently been described in the literature (from January 2009 to November 2010) as showing antiplasmodial activity (in vitro), along with a few compounds that were tested for antimalarial activity in animal models [19] using Plasmodium knowlesi (in simians), Plasmodium yoelii, Plasmodium berghei, Plasmodium chabaudi (in mice), and Plasmodium gallinaceum (in birds). In most of these bioassays, antiplasmodial activities were assessed using different P. falciparum strains, which include chloroquine-sensitive (NF54, NF54/64, 3D7, D6, F32, D10, HB3, FCC1-HN, Ghana, MRC-02, TM4), chloroquine-resistant (BHz26/86, Dd2, EN36, ENT30, FcB1, FCM29, FCR3, FCR-3/A2, FCR3F86, S20, W2,), chloroquine-resistant and pyrimethamine-resistant (K1, TM91C235), pyrimethamine-resistant (HB3), cycloguanil-resistant (CDC1), and chloroquine- and antifolate-resistant (K1CB1). Most of evaluations used the [³H]-hypoxanthine-incorporation assay to assess parasite inhibition of growth in the presence of the test-drugs. Antimalarial activity of new compounds has also been determined by using: i) the fluorometric method based on the intercalation of the fluorochrome PicoGreen (SYBR) in the parasite DNA, [20]; ii) enzyme-linked immunosorbent assays (ELISAs) with monoclonal antibodies, which measure the P. falciparum-specific antigen histidine-rich protein 2 (HRP2) or lactate dehydrogenase protein (pLDH). A chemical reaction using ferriprotoporphyrine biocrystallization (FBTI Inhibition Test) has been used to provide a possible action mechanism for presumed antimalarial compounds [21]. Protein farnesyltransferase (FTase) bioassays have also been used to provide insight into their mode of action against P. falciparum [22]. The effects of natural products on glutathione (GSH), which plays a key role in redox mechanisms, and on cysteine (Cys), which is one of the substrates needed for the de novo synthesis of P. falciparum GSH, as well as their impact on β-hematin formation have been investigated, since GSH participates in heme detoxification [23]. The advantages and disadvantages of the different in vitro screening methods have been discussed by Krettli et al. [24] and Wein et al. [25]. For in vivo bioassays P. berghei and P. chabaudi chabaudi have been used most often. The cytotoxicities of the active compounds compiled in this review have generally been evaluated in HEK293, Vero or HeLa cells. For the details of the methodologies, see the appropriate references cited herein.

Several criteria have been proposed for considering a compound as active. Generally, a compound is considered to be inactive when it shows an IC₅₀ > 200 μM, whereas those with an IC₅₀ of 100-200 μM have low activity; IC₅₀ of 20-100 μM, moderate activity; IC₅₀ of 1-20 μM good activity; and IC₅₀ < 1 μM excellent/potent antiplasmodial activity [12]. In this review, regardless of the in vitro or in vivo method adopted for antiplasmodial or antimalarial evaluation, we list the active and moderately active compounds in accordance with the corresponding cited literature (data for inactive compounds are not shown in this review).

A total of 360 antiplasmodial natural products comprised of terpenes, including iridoids, sesquiterpenes, diterpenes, terpenoid benzoquinones, steroids, quassinoids, limonoids, curcubitacins, and lanostanes; flavonoids; alkaloids; peptides; phenylalkanoids; xanthones; naphthopyrones; polyketides, including halenaquinones, peroxides, polyacetylenes, and resorcylic acids; depsidones; benzophenones; macrolides; and miscellaneous compounds, including halogenated compounds and chromenes are listed in this compilation (Figures 1-44).

2. Terpenes

2.1. Iridoids and halogenated monoterpenes

Phenylpropanoid conjugated iridoids 1-5 (Figure 1) have been isolated from Morinda morindoides (Rubiaceae). All of these compounds except for 3 potently inhibited parasite proliferation (P. falciparum strain CDC1, IC₅₀ values of 0.04 to 4.1 µM) with little cytotoxicity against the host mammalian cells (KB 3-1) [26]. The iridoid swertiamarin (6) has been obtained from Enicostemma littorale (Gentianaceae) and showed promising results in vitro in a schizont maturation inhibition assay, with an IC₅₀ value of 44.4 µΜ [27].

Figure 1. Structures of iridoids and halogenated monoterpenes 1-9.

Figure 1. Structures of iridoids and halogenated monoterpenes 1-9.

Halogenated monoterpenes 7-9 with a 3,7-dimethyl-3,4-dichloro-octa-1,5,7-triene skeleton obtained from the marine red alga Plocamium cornutum (Plocamiaceae) exhibited antiplasmodial activity toward a chloroquine-sensitive strain of P. falciparum. Those bearing a 7-dichloromethyl substituent showed higher activity, with IC₅₀ values ranging from 16 to 27 μM [28].

2.2. Sesquiterpenes

The eremophilane sesquiterpenoids berkleasmins A (10) and C (11) (Figure 2), obtained from the saprobic fungus Berkleasminum nigroapicale, showed antiplasmodial activity with IC₅₀ values of 6.0 and 5.4 µΜ, respectively [29]. The sesquiterpene lactones vernaguline A and B, vernodalol, and vernodalin (12-15) were isolated from Distephanus angulifolius (Asteraceae), and while they exhibited antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) P. falciparum strains (IC₅₀ values of 1.5 to 4.9 μM), they also exhibited cytotoxicity in a hamster ovarian cell line [30].

Figure 2. Structures of sesquiterpenes 10-17.

Figure 2. Structures of sesquiterpenes 10-17.

Okundoperoxide (16) was isolated by the bioassay-guided fractionation of extracts from Scleria striatinux (syn. S. striatonux, Cyperaceae). This compound contains a cyclic endoperoxide structural moiety and showed antiplasmodial activity against W2 and D6 (IC₅₀ ~1.8 µΜ), K1 (IC₅₀ = 5.6 µΜ), and NF54 (IC₅₀ = 4.9 µΜ) [31].

Studies on the Carpesium genus (Compositae) suggest that the antiplasmodial activity against P. falciparum is due to the presence of 11(13)-dehydroivaxillin (17) in the EtOAc extracts of C. cernuum. The antimalarial activity of 17 was evaluated against P. berghei in mice. Its LD₅₀ was determined to be 51.2 mg/kg, while doses of 124 mg/kg and above were found to be lethal to mice. DDV (2, 5, 10 mg/kg/day) exhibited a significant blood schizonticidal activity in 4-day early infection, repository evaluation and in an established infection with a significant mean survival time comparable to that of the standard drug (chloroquine, 5 mg/kg/day) [32].

Figure 3. Structures of sesquiterpenes 18-46.

Figure 3. Structures of sesquiterpenes 18-46.

In tests of 33 sesquiterpene lactones from several genera, including Arnica, Xanthium, and Inula (Asteraceae), Schmidt et al. [33] found that the antiprotozoal activities were significantly correlated with cytotoxicity, and the major determinants of this activity were α,β-unsaturated structural elements. Among the tested sesquiterpene lactones, 29 (compounds 18-46, Figure 3) showed activity against P. falciparum (K1) with IC₅₀ values of 0.3 to 27.5 µM [33].

2.3. Diterpenes

Aberrarone A (47, Figure 4) is a natural product from the Caribbean sea whip Pseudopterogorgia elisabethae (Gorgoniidae). This compound, together with colombiasin A (48), showed in vitro activity against a chloroquine-resistant strain of P. falciparum (W2, IC₅₀ values of 30.3 and 31.8 μM, respectively) with the use of a fluorometric method (PicoGreen) [34].

Figure 4. Structures of diterpenes 47 and 48.

Figure 4. Structures of diterpenes 47 and 48.

The dolabellanes 49-63 (Figure 5) and dolastane 64 from a Eunicea species Caribbean octocoral (Gorgoniidae) were tested for their inhibitory activity toward the growth of P. falciparum (W2). These compounds were active with IC₅₀ values of 9.4 to 59.6 μM [35].

Figure 5. Structures of dolabellanes 49-63.

Figure 5. Structures of dolabellanes 49-63.

Gomphostenin clerodane diterpenes 65 and 66 (Figure 6) obtained from Gomphostemma niveum (Lamiaceae) were tested against P. berghei in mice and produced a dose-dependent chemo-suppression effect. Diterpene 65 exhibited the highest percent of chemo-suppression, i.e. 92.65% at a dose of 200 mg/kg/day. In a curative test, the survival period of the infected mice was significantly prolonged at 200 mg/kg dose of 66 [36]. Gomphostenin (65) and Gomphostenin-A (66) exhibited in vitro antiplasmodial activities against the MRC-02 strain of P. falciparum with IC₅₀ values of 114.9 and 9.8 µM, respectively [37]. In contrast, the antiplasmodial activity of ent-kaur-16-en-19-oic acid (67) from Schefflera umbellifera (Araliaceae) against the chloroquine-susceptible strain D10 (IC₅₀ = 106.5 µM) was not very significant [38].

Figure 6. Structures of clerodane and kaurane diterpenes 65-67.

Figure 6. Structures of clerodane and kaurane diterpenes 65-67.

2.4. Nitrogenated diterpenes

Isonitrile diterpenes 68-71 (Figure 7) of the amphilectane family have been isolated from the sponge Ciocalapata sp. (Halichondriidae). They exhibited strong activities against P. falciparum (K1) with IC₅₀ values of 0.09 to 1.07 µM. Except for 8,15-diisocyano-11(20)-amphilectene (68), which was cytotoxic against both MCF-7 and fibroblast cell lines, these diterpenes showed no significant cytotoxicity against either of the targeted cell lines [39]. Alkaloid 72 is also a formamide and isonitrile, diterpene that was isolated from the tropical marine sponge Cymbastela hooperi (Axinellidae). In in vitro antiplasmodial bioassays using three strains (FCR3F86, W2, and D6) of the malaria parasite P. falciparum, 72 was found to have good activity (IC₅₀ = 1.5 µM), whereas the corresponding di-formamide derivative 73 showed only moderate activity (IC₅₀ = 41.0 µM) [40].

Figure 7. Structures of nitrogenated diterpenes 68-73.

Figure 7. Structures of nitrogenated diterpenes 68-73.

2.5. Tetranorditerpenes

Tetranorditerpenoid dilactones 74-81 and an oidiolactone 82 (Figure 8), isolated from the fungus Sclerotinia homoeocarpa, exhibited excellent to good antiplasmodial activity (IC₅₀ values of 0.1 to 8.0 µM). However, they also showed high cytotoxicity, which preclude their use as potential antimalarial agents [41].

Figure 8. Structures of tetranorditerpenes 74-82.

Figure 8. Structures of tetranorditerpenes 74-82.

2.6. Terpenoid benzoquinones and analogues

Terpenoid benzoquinones and analogues 83-89 (Figure 9) isolated from the root extract of Cordia globifera (Boraginaceae) exhibited antiplasmodial activity against the P. falciparum strain K1 with IC₅₀ values of 0.8 to 13.9 μM. The antifungal and cytotoxic activities of these compounds were also evaluated [42].

Figure 9. Structures of terpenoid benzoquinones and analogues 83-89.

Figure 9. Structures of terpenoid benzoquinones and analogues 83-89.

2.7. Steroids

The major steroid 90 together with three other steroids 91-93 (Figure 10) isolated from the marine sponge Callyspongia fibrosa (Callyspongiidae) showed antiplasmodial activity (P. falciparum strains 3D7 and K1 with IC₅₀ values of 20.5 to 54.8 µM). Parasite growth was assessed as pLDH activity and 90 exhibited better activity against a chloroquine-resistant strain of P. falciparum than on a chloroquine-sensitive strain [43]. Two steroidal peroxides 94 and 95 from another marine sponge Ciocalapata sp. (Halichondriidae) showed antiplasmodial activity against P. falciparum K1 (IC₅₀ values of 6.28 and 7.13 µM, respectively), and cytotoxicity against human cells in a breast cancer cell line MCF-7 (IC₅₀ values of 0.025 and 0.003 µM, respectively), with very little toxicity against human fibroblasts [39].

An evaluation of the effects of four steroid derivatives 96-99 and a sapogenin 100 extracted from Solanum nudum (Solanaceae) on the total glutathione (GSH) and cysteine contents in P. falciparum in vitro showed that 96 increased total glutathione and cysteine concentrations while 99 decreased the concentrations of both thiols. Acetylation at C16 was crucial for the effect of 96 while type furostanol and terminal glucosidation were necessary for the inhibitory properties of 99. The combination of steroids and buthionine sulfoximine, a specific inhibitor of a step-limiting enzyme in GSH synthesis, did not modify the glutathione contents. In addition, 96 inhibited more than 80% of β-hematin formation at 5.0 mM, while the other steroids did not show any effect [23].

Figure 10. Structures of steroids 90-100.

Figure 10. Structures of steroids 90-100.

2.8. Quassinoids

Delaumonones A (101) and B (102) (Figure 11) have been isolated from the bark of Laumoniera bruceadelpha (Simaroubaceae). These quassinoids showed antiplasmodial activity against the P. falciparum strain 3D7 (IC₅₀ values of 0.6 and 1.2 µM, respectively) and cytotoxicity against HL-60 cells (IC₅₀ 101: 3.1 µM; 102: 4.6 µM). Another isolated quassinoid, the isobrucein A (103) (IC₅₀ = 0.05 µM), was more active than delaumonones A and B, but it also showed a potent cytotoxicity against HL-60 cells (IC₅₀= 0.01 µM) [44]. The tea of young leaf of Quassia amara (Simaroubaceae) also contains several quassinoids 104-111, including simalikalactone D (104) and simalikalactone E (105) [45,46]. These quassinoids inhibited the growth of P. falciparum cultured in vitro (with IC₅₀ values of 1 to 420 nM), independently of the strain sensitivity to chloroquine. Compound 105 decreased gametocytemia with an IC₅₀ value seven-fold lower than that of primaquine, and was also less toxic than simalikalactone D (104) when tested on nontumorogenic cells. In vivo, 105 inhibited murine malaria growth of P. vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively [45,46].

Figure 11. Structures of quassinoids 101-111.

Figure 11. Structures of quassinoids 101-111.

2.9. Limonoids

In vitro antiplasmodial tests using the D10 and W2 strains of P. falciparum showed that gedunin (112), azadirone (113), and neemfruitin A (114) had significant activity, and limonoids 115-121 from Azadirachta indica (Meliaceae) had a good activity (IC₅₀ values of 1.2 to 10.0 µM) (Figure 12) [47].

Figure 12. Structures of limonoids 112-121.

Figure 12. Structures of limonoids 112-121.

Figure 13. Structures of cucurbitacins 122-134.

Figure 13. Structures of cucurbitacins 122-134.

2.10. Cucurbitacins

Thirteen cucurbitane-type triterpenes 122-134 (Figure 13) have been isolated from Momordica balsamina (Curcubitaceae) and have been shown to exhibit antiplasmodial activity against the P. falciparum chloroquine-sensitive strain 3D7 and the chloroquine-resistant strain Dd2. Triterpenes 130 and 133 had the highest antiplasmodial effects against both strains (IC₅₀130: 4.6 and 133: 7.4 μM, 3D7; 130: 4.0 and 133: 8.2 μM, Dd2). Furthermore, a preliminary evaluation of the toxicity of compounds 122-126 and 130 toward human cells in a breast cancer cell line (MCF-7) showed that these triterpenes were inactive or showed only weak toxicity (IC₅₀ values >19.0 μM) [48].

2.11. Lanostanes

Ethyl acetate extract of the mushroom Ganoderma lucidum (Polyporaceae) yielded six lanostanes 135-140 (Figure 14). These lanostanes exhibited in vitro antiplasmodial activity with IC₅₀ values of 6 to 20 μM [49]. Another lanostane, garcihombronane D (141), from Garcinia cymosa (Clusiaceae) showed a selective activity against P. falciparum (IC₅₀ 7.7 µM) [50].

Figure 14. Structures of lanostanes 135-141.

Figure 14. Structures of lanostanes 135-141.

2.12. Other triterpenes

The triterpene 3β-hydroxy-glutin-5-ene, which was also isolated from Garcinia cymosa (142) (Figure 15), showed activity against P. falciparum (IC₅₀ 31.0 µM) and a cytotoxicity of 6.9 µM toward MRC-5 cells [50]. Hop-17(21)-en-6R,12-diol (143) was isolated from the scale insect pathogenic fungus Aschersonia paraphysata. It exhibited antiplasmodial activity with an IC₅₀ value of 15 μM [51]. Tingenin B, (22β- hydroxytingenone) (144), has been isolated as the main antibacterial constituent from Elaeodendron schlechteranum (Celastraceae). It was active against T. cruzi (IC₅₀ < 0.6 μM), T. brucei (IC₅₀ < 0.6 μM), L. infantum (IC₅₀ = 1.2 μM), and P. falciparum (IC₅₀ = 0.8 μM). Tingenin B was highly cytotoxic to MRC-5 cells (CC₅₀ 1.0 μM), which indicates poor selectivity [52]. Betulin (145) has been isolated from Schefflera umbellifera (Araliaceae), and exhibited good antiplasmodial activity (IC₅₀ = 7.2 μM) against a chloroquine-susceptible strain (D10) [38]. Betulinic acid (146) showed antiplasmodial activity against chloroquine-resistant P. falciparum parasites (W2 strain, chloroquine-resistant and mefloquine sensitive) in vitro, with an IC₅₀ value of 9.9 μM [53].

Figure 15. Structures of terpenes 142-146.

Figure 15. Structures of terpenes 142-146.

3. Flavonoids

Flavonoids 147 and 148 have been isolated from Neoraputia magnifica (Rutaceae). These flavonoids, together with 149 (Figure 16), isolated from Lonchocarpus subglaucescens (Leguminosae), exhibited antiplasmodial activity against the P. falciparum strain 3D7 with IC₅₀ values of 7.6, 6.9, and 9.5 µM, respectively [54]. The luteolin 7-O-β-D-glucopyranoside 150 also showed antiplasmodial activity (IC₅₀ = 4.9 μM for the D6 strain and 4.0 μM for the W2 strain), and this compound did not exhibit cytotoxicity in Vero cells up to a concentration of 10.6 μM [55].

The flavone 3-methoxycarpachromene (151) isolated from Pistacia atlantica (Anacardiaceae) showed an IC₅₀ value of 3.4 µM toward the P. falciparum strain K1 [56], whereas dalparvone (152) from the stems of Dalbergia parviflora (Leguminosae) exhibited moderate antimalarial activity with an IC₅₀ value of 24.8 μM [57].

The in vitro antiplasmodial activities of the main hop chalcone xanthohumol (153) and seven of its derivatives were evaluated against two strains of P. falciparum (poW, Dd2). Xanthohumol had the highest activity, with IC₅₀ values of 8.2 (poW) and 24.0 μM (Dd2) [58].

Compounds obtained from Morinda morindoides (Rubiaceae) were evaluated in vitro for antiplasmodial activity against a Congolese chloroquine-sensitive strain of P. falciparum. Quercetin (154) exhibited good antiplasmodial activity with an IC₅₀ value of 19.2 μΜ, whereas alizarin and chrysazin displayed only moderate activity (58.3 < IC₅₀ < 124.9 μM) [59].

The isoflavanone 155 has been isolated from Ormocarpum kirkii (Papilionaceae) and has been shown to have antiplasmodial activity with an IC₅₀ value of 23.7 μM [60].

Figure 16. Structures of flavonoids 147-155.

Figure 16. Structures of flavonoids 147-155.

Ormocarpum kirkii also gave four biflavonoids 156-159 (Figure 17) that showed antiplasmodial activity toward P. falciparum strain K1; isochamaejasmin (159) was the most active, with an IC₅₀ of 7.3 μM, but its selectivity was rather limited [60].

Figure 17. Structures of biflavonoids 156-159.

Figure 17. Structures of biflavonoids 156-159.

4. Alkaloids

Cassiarin A (160) (Figure 18) from the leaves of Cassia siamea (Leguminosae) showed promising antimalarial activities. Cassiarin A had inhibitory effects against P. falciparum (IC₅₀ = 0.02 μM). Antimalarial activity was assessed in vivo using the 4-day suppressive test procedure. The ED₅₀ value of cassiarin A was 0.17 [61]. In contrast, cassiarins C-E (161-163) exhibited moderate antiplasmodial activity (IC₅₀ values of 24.2 to 2.3 µM) and no cytotoxicity (IC₅₀> 100 µM) [62].

Acridone alkaloids have been isolated from the fruits of Zanthoxylum leprieurii (Rutaceae), and among them arborinine (164) and xanthoxoline (165) (Figure 18) exhibited a good in vitro antiplasmodial activity against the P. falciparum strain 3D7, with IC50 values of 15.8 and 17.0 μM, respectively [63].

Figure 18. Structures of alkaloids 160-165.

Figure 18. Structures of alkaloids 160-165.

Flinderole A (166) and isoborreverine (167) have been isolated from Flindersia acuminata (Rutaceae) and dimethylisoborreverine (168), flinderoles B (169), and C (170) (Figure 19) have been isolated from Flindersia ambionensis. These indole alkaloids were found to have selective antiplasmodial activities, with IC₅₀ values of 0.08 to 1.42 μM against the P. falciparum strain Dd2 and with selectivity assessed using the mammalian cell line HEK-293 [64]. In addition, the antiplasmodial activities of alkaloids 166-170 and voacamine (171) were evaluated using P. falciparum strains with different drug-resistance profiles (3D7, FCR3, HB3, and K1). Some differences in the IC₅₀ values between the strains were observed. Among these alkaloids, including lirodenine (172) and xylopine (173), the dimethylisoborreverine (168) was the most active, with IC₅₀ values between 0.02 μM and 0.81 μM [65].

Violacein (174) is a violet pigment extracted from the gram-negative bacterium Chromobacterium violaceum. It presents bactericidal, tumoricidal, trypanocidal, and antileishmanial activities. In addition, at micromolar concentrations it efficiently killed chloroquine-sensitive (3D7) and -resistant (S20) P. falciparum strains in vitro, inhibited parasitemia in vivo, even after parasite-establishment; and protected P. chabaudi chabaudi-infected mice from a lethal challenge [66].

Figure 19. Structures of alkaloids 166-185.

Figure 19. Structures of alkaloids 166-185.

A benzylisoquinoline alkaloid 175 and an aporphine alkaloid 176 (Figure 19) isolated from Doryphora sassafras (Monimiaceae), when tested against these same P. falciparum strains, exhibited IC₅₀ values of 3.0 and 4.4 μM, respectively. Compound 175 was tested for cytotoxicity toward a human embryonic kidney cell line (HEK293) and showed no activity at 120 μM [67]. The alkaloidal components of the Bhutanese medicinal plant Corydalis calliantha (Fumariaceae), which is used for the treatment of malaria, have been assessed. Among them, protopine (177) and the cheilanthifoline (178) showed promising in vitro antiplasmodial activities against P. falciparum, both wild type (TM4) and multidrug-resistant (K1) strains, with IC₅₀ values of 2.78 to 4.29 µM [68]. Alkaloids 179 and 180 have been isolated from Clausena harmandiana (Rutaceae) and they showed antiplasmodial activity with IC₅₀ values of 15.5 and 12.2 µM, respectively, against the P. falciparum strain K1 [69]. Furoquinoline alkaloids (181-184) have been obtained from Teclea afzelii (Rutaceae). When evaluated against P. falciparum (NF54) in vitro, 3 µM of compounds 181-184 showed a partial suppression of parasitic growth [70]. The azafluorenone 5-hydroxy-6-methoxyonychine (185) obtained from Mitrephora diversifolia (Annonaceae) was shown to be active against P. falciparum strains 3D7 and Dd2, with IC₅₀ values of 9.9 and 11.4 μM, respectively [71].

Figure 20. Structures of guanidine alkaloids 186-194.

Figure 20. Structures of guanidine alkaloids 186-194.

Nine guanidine alkaloids 186-194 (Figure 20) from Caribbean marine sponges, including Monanchora arbuscula and Clathria calla, were evaluated to determine their activities against human cancer cell lines and malaria protozoa; they exhibited IC₅₀ values of 0.1 to 4.5 μM using the P. flaciparum strain FcB1 [72]. Zamamidines 195-198 and manzamine A (199) (Figure 21) have been isolated from the marine sponge species Amphimedon and have been shown to exhibit inhibitory activities against T. brucei (IC₅₀: 1.4, 1.4, 0.4, 7.9, and 0.1 µM, respectively), and P. falciparum (IC₅₀: 9.6, 16.3, 0.8, 12.4, and 1.8 µM, respectively) in vitro [73].

Figure 21. Structures of alkaloids 195-202.

Figure 21. Structures of alkaloids 195-202.

Acanthostrongylophora ingens has yielded (+)-8-hydroxymanzamine A (200), (+)-manzamine A (199), (+)-8-hydroxymanzamine A hydrochloride (201), and (+)-manzamine A hydrochloride (202). Compounds 200 and 201 showed equally potent in vitro antiplasmodial activity against chloroquine-sensitive (D6) and -resistant (W2) strains of P. falciparum (IC₅₀ = 34.6 and 36.6 nM vs. 47.8 and 60.7 nM, respectively), while 199 was >3-fold less potent than 202 (IC₅₀ = 37.9 and 47.1 nM vs. 10.5 and 12.5 nM, respectively) [74].

Atisinium chloride (203) (Figure 22) is the major alkaloid from Aconitum orochryseum (Ranunculaceae). It was tested for in vitro antiplasmodial activity against the malarial P. falciparum strains TM4/8.2 (wild type) and K1CB1 (chloroquine- and antifolate-resistant), and was shown to have good antiplasmodial activities, with IC₅₀ values of 4.0 and 3.6 µM, respectively, against the TM4 strain and the K1 strain of P. falciparum [75].

Glycoalkaloids have been isolated from Solanaceae species, and five of them, chaconine (204), solanine (205), solamargine (206), solasonine (207), and tomatine (208) (Figure 22), were evaluated against P. yoelii 17XL in mice at different concentrations with a 4-day parasitemia suppression test. Chaconine (204) showed a dose-dependent suppression of malaria infection, with an ED₅₀ of 4.49 mg/kg; therapeutic index (TI) ~9. At a dose of 7.50 mg/kg, the percent parasitemia suppression values of chaconine, tomatine, solamargine, solasonine, and solanine were 71.38, 65.25, 64.89, 57.47, and 41.30%, respectively. At 3.75 mg/kg, the percent parasitemia suppression of chaconine was 42.66% [76].

Figure 22. Structures of alkaloids 203-208.

Figure 22. Structures of alkaloids 203-208.

The pyridinone alkaloid 209 (Figure 23) has been isolated from an EtOAc extract of a culture medium of the fungus Septoria pistaciarum. It exhibited excellent in vitro antiplasmodial activity against chloroquine-sensitive (D6) and -resistant (W2) strains of P. falciparum (IC₅₀ values of 0.9 and 0.5 µM, respectively) and cytotoxic activity toward Vero cells [77].

Pyrroloiminoquinone alkaloids, discorhabdins A (210) and C (211), and dihydrodiscorhabdin C (212) (Figure 23), have been isolated from a deep-water Alaskan sponge species of the genus Latrunculia (Latrunculiidae). These alkaloids exhibited anti-HCV activity, antiplasmodial activity against P. falciparum strains D6 and W2 (IC₅₀ values of 53, 2800, and 170 nM vs. 53, 2000, and 130 nM, respectively), and selective antimicrobial activity. Although compounds 210 and 212 displayed potent and selective in vitro antiprotozoal activity, P. berghei-infected mice did not respond to these metabolites due to their toxicity in vivo [78].

Figure 23. Structures of alkaloids 209-212.

Figure 23. Structures of alkaloids 209-212.

The bromotyrosine alkaloids psammaplysin G (213) and psammaplysin F (214) (Figure 24) have been isolated from the marine sponge Hyattella sp. (Spongiidae). When tested against two different strains of the parasite P. falciparum (Dd2 and 3D7), 214 displayed IC₅₀ values of 1.4 and 0.87 μM, respectively, while 213 showed 98% inhibition at 40 μM against a chloroquine-resistant (Dd2) strain of P. falciparum [79].

Figure 24. Structures of alkaloids 213-216.

Figure 24. Structures of alkaloids 213-216.

Fermentation culture from the endophytic fungus Pestalotiopsis sp. yielded pestalactams A (215) and B (216) (Figure 24), which were tested against two different strains of the malaria parasite P. falciparum (3D7 and Dd2) and parasite growth inhibition of ~16-41% was achieved at 25 µM. Citotoxicity toward mammalian cell lines (MCF-7 and NFF) was also evaluated, and modest in vitro activity in all assays was observed [80].

The β-carboline (+)-7-bromotrypargine (217) (Figure 25) has been isolated from the marine sponge Ancorina sp. (Ancorinidae). This alkaloid was tested against both a chloroquine-resistant (Dd2) and chloroquine-sensitive (3D7) P. falciparum strains. Preliminary toxicity toward human cells was investigated using a human embryonic kidney cell line (HEK293), and 217 had IC₅₀ values of 5.4 μM (Dd2) and 3.5 μM (3D7), and was not cytotoxic toward the HEK293 cell line at up to 80 μM [81].

Figure 25. Structures of β-carboline and bromopyrrole alkaloids 217-232.

Figure 25. Structures of β-carboline and bromopyrrole alkaloids 217-232.

Bromopyrrole alkaloids 218, 220, 223, 224, 226, 228, 229, and 232 (Figure 25) obtained from marine sponges in the genera Axinella (Axinellidae) and Agelas (Agelasidae) have been screened in vitro against four parasitic protozoa, i.e., two Trypanosoma species (T. brucei rhodesiense and T. cruzi), Leishmania donovani and P. falciparum (strain K1). Longamide B (226) and dibromopalau’amine (229) have been shown to be promising trypanocidal and antileishmanial agents, while dispacamide B (220) and spongiacidin B (224) showed the highest antiplasmodial activity (IC₅₀ values of 3.3 and 3.4 µM, respectively). In addition, an evaluation of the activity of the alkaloids (218-232) tested against three different enzymes (PfFabI, PfFabG, PfFabZ), that are involved in de novo fatty acid biosynthesis in P. falciparum (PfFAS-II), identified bromopyrrolohomoarginin (230) as a potent inhibitor of PfFabZ. Tests against the mammalian L6 cells revealed important clues regarding the therapeutic index of the metabolites [82].

5. Peptides and Macrocyclic Compounds

Gallinamide A (233) (Figure 26) from the cyanobacteria Schizothrix sp. (Schizotrichaceae) showed a reasonably effective antimalarial potency against the P. falciparum strain W2 (IC₅₀ 8.4 μM) and cytotoxicity toward mammalian Vero cells (IC₅₀ 10.4 μM). However, it did not show in vitro cytotoxicity toward NCI-H460 human lung tumor or neuro-2a mouse neuroblastoma cell lines at the highest concentration tested (16.9 μM) [83].

The macrocycles 234 and 235 (Figure 26) are histone deacetylase inhibitors (HDACi) that cause a diverse range of responses in biological systems [84]. The antiparasitic capabilities of these macrocyclic HDACi were determined against malarial and leishmanial pathogens. Antiparasitic activities of macrocyclic HDACi derived from macrolide skeletons are dependent on the length (n) of the spacer group that separates their zinc-binding and surface-recognition moieties. Antimalarial activities peak when n=6 (IC₅₀ 234: 95 nM), whereas antileishmanial activities are optimum when n=8–9 (IC₅₀ 235: ~3.3 µM). This observation could facilitate the identification of other HDACi that are more selective for either parasite [84].

Figure 26. Structures of peptide and macrocyclic compounds 233-235.

Figure 26. Structures of peptide and macrocyclic compounds 233-235.

6. Phenylalkanoids

6.1. Phenylpropanoids

The lignan butyrolactone 236 (Figure 27) from the fungus Aspergillus terreus BCC 4651 showed antiplasmodial activity against the P. falciparum strain K1 with an IC₅₀ value of 18 µM [85]. The main constituent (39.0%) of the volatile constituents of Daucus crinitus was isochavicol isobutyrate (237). This compound, together with isochavicol (238) and isochavicol propionate (239), exhibited antiplasmodial activity against P. falciparum (strain FcB1) with IC₅₀ values of 68.7, 14.2 and 70.0 µM, respectively [86]. In contrast, coumarin 240 did not exhibit any significant antiplasmodial activity (IC₅₀ value of 146.9 µM against strain D10) [38].

Figure 27. Structures of phenylpropanoids 236-240.

Figure 27. Structures of phenylpropanoids 236-240.

6.2. Phenylethanoids

Jacaranda glabra (Bignoniaceae) yielded phenylethanoid glucosides (241-244) and jacaranone (245) (Figure 28), which were found to be active in vitro against the P. falciparum strain K1 (IC₅₀ 241: 1.5; 242: 1.0; 243: 0.8; 244: 0.8 and 245: 7.3 μM). All of the compounds except for 241 showed low cytotoxicity toward L-6 cells [87].

Figure 28. Structures of phenylethanoids 241-245.

Figure 28. Structures of phenylethanoids 241-245.

6.3. Phenylmethanoids, benzylesters, and phenolics

A phenol 246 and two phenolic glycosides 247 and 248 (Figure 29) have been isolated from Flacourtia indica (Flacourtiaceae), and they have been shown to have antiplasmodial activity toward the W2 strain of P. falciparum (IC₅₀ values of 0.7 to 27 µM) [88]. Norbergenin derivatives 249-251 (Figure 29) isolated from the stem bark of Diospyros sanza-minika (Ebenaceae) were evaluated for their in vitro activity against the P. falciparum K1 and cytotoxicity toward MRC-5 cells (249: IC₅₀ 8.4 μM; CC₅₀> 137.4 μM, 251: IC₅₀ 11.3 μM; CC₅₀> 147.5 μM, 250: IC₅₀ 1.3 μM; CC₅₀ 51.5 μM). Compound 251 possesses an O-p-hydroxybenzoyl group at C-11, while 249 and250 have O-galloyl, and O-(3′-methylgalloyl) groups, respectively, at C-4, which may play an important role in their antimalarial activity [89].

Figure 29. Structures of phenylmethanoids and phenolics 246-251.

Figure 29. Structures of phenylmethanoids and phenolics 246-251.

7. 4-Aryl-3,4-dihydrocoumarins

In addition to antiplasmodial biflavonoids, Ormocarpum kirkii (Papilionaceae) yielded 4-aryl-3,4-dihydrocoumarins 252 and 253, which were active against the P. falciparum strain K1 (IC₅₀ values of 39.5 and 21.1 μM, respectively) (Figure 30) [90].

Figure 30. Structures of 4-aryl-3,4-dihydrocoumarin dimers 252 and 253.

Figure 30. Structures of 4-aryl-3,4-dihydrocoumarin dimers 252 and 253.

8. Xanthones, Naphthopyrones, and Analogues Vismiones

The xanthone 1,5-dihydroxy-3,6-dimethoxy-2,7-diprenylxanthone (254) (Figure 31) showed selective activity against P. falciparum with an IC₅₀ value of 7.25 µM. When screened for activity against T. cruzi, T. brucei, L. infantum (Ghana strain), S. aureus, and E. coli, and for cytotoxicity against MRC-5 cells, it showed IC₅₀ values >64 µM [50]. Xanthones 255-258 and their analogues 259-261 have been isolated from Cratoxylum maingayi and Cratoxylum cochinchinense (Clusiaceae) [91]. These compounds showed antiplasmodial activity against P. falciparum at concentrations of 11.0 to 1.9 µM. Most of these compounds also showed cytotoxicity toward the NC1-H187 cancer cell line [91].

Aschernaphthopyrone A (262) has been isolated from the scale insect pathogenic fungus Aschersonia paraphysata, and its antiplasmodial activity against the P. falciparum strain K1 (IC₅₀ = 7.3 μM) is higher than that of hopene triterpene 143 (Figure 15) isolated from the same fungus [51].

Figure 31. Structures of xanthones, naphthopyrones, and analogues vismiones 254-262.

Figure 31. Structures of xanthones, naphthopyrones, and analogues vismiones 254-262.

9. Anthraquinones and Anthrones

Demethylmacrosporine (263) (Figure 32) isolated from Rumex obtusifolius (Polygonaceae) showed significant activity in the FBIT (Ferriprotoporphyrine biocrystallization inhibition test, IC₅₀ = 0.3 μM) [21]. The anthrone–anthraquinones scutianthraquinones A, B, and C (264–266), and the bisanthrone–anthraquinone scutianthraquinone D (267) have been isolated from the bark of Scutia myrtina (Rhamnaceae). Compounds 264-267 and 268 (aloesaponarin I, which was isolated from Aloe saponaria - Asphodelaceae) exhibited good antiplasmodial activities against the P. falciparum Dd2 (IC₅₀ values of 1.1 to 5.6 μM), while compounds 264, 265, and 267 also exhibited good antiplasmodial activity against the P. falciparum strain FCM29 (IC₅₀ values of 1.2 to 5.6 μM), these compounds also showed weak antiproliferative activity against the ovarian cancer cell line A2780 [92].

Figure 32. Structures of anthraquinones and anthrones 263-268.

Figure 32. Structures of anthraquinones and anthrones 263-268.

10. Halenaquinone Derivatives

Compounds 269-271 (Figure 33) were the most active of a series of halenaquinone derivatives from South Pacific marine sponges of the genus Xestospongia (Petrosiidae). The exhibited antiplasmodial activity did not depend on the chloroquine-sensitivity of the strain tested, since there was no significant difference between the IC₅₀ values for strains FcB1 (IC₅₀ 1.1, 3. 9, and 9.2 μM, respectively) and 3D7 (IC₅₀ 1. 7, 4.1, and 10.9 μM, respectively). The three active compounds were also active in protein farnesyltransferase bioassays, which may provide insight into their mode of action against P. falciparum [22].

Figure 33. Structures of halenaquinone derivatives and analogues 269-271.

Figure 33. Structures of halenaquinone derivatives and analogues 269-271.

11. Endoperoxides, Peroxides and Other Polyketides from Sponges

Endoperoxyketal polyketides manadoperoxides A-D (272-275) (Figure 34) have been isolated from the Indonesian sponge Plakortis cfr. Simplex (Plakinidae), and were assayed in vitro against the D10 and W2 strains of P. falciparum, where they showed good antimalarial activity (IC₅₀ values of 4.5 to 10.4 and 2.3 to 7.9 µM, respectively) compared to those of plakortin (276, IC₅₀ value of 0.9 and 0.4 µM, respectively) and peroxyplakoric B3 ester (277, P. falciparum strain FCR3, IC₅₀ = 1.1 µM), the latter of which differs from manadoperoxide B (P. falciparum strain FCR3, IC₅₀ = 6.8 µM) by only minor structural details. This difference in the antiplasmodial activity has been explained on the basis of a model for the interaction of 1,2-dioxanes with heme and the production of C-centered radicals that are toxic to the parasite. For the manadoperoxides, either the endoperoxide linkage is inaccessible to the heme iron or the O1 radical cannot evolve to produce a C-centered radical [93]. Another polyketide-peroxy, plakortide F (methyl ester 278), has been isolated from a species of Plakortis (Plakinidae) from Jamaica. It exhibited good in vitro antiplasmodial activity (IC₅₀ values of 3.4 and 2.5 µM against P. falciparum D6 and W2 strains, respectively), whereas a non peroxide-polyketide, plakortone D (279) (Figure 35), exhibited IC₅₀ values of 7.8 and 8.7 µM, respectively [94]. Five-membered-ring polyketide endoperoxides 280 and 281, and a cyclic peroxide 282 (Figure 34) have been isolated from the sponge Plakortis halichondrioides (Plakinidae). Biological screening of these cycloperoxides for cytotoxic activity against various human tumor cell lines revealed that compounds 281 and 282 are very active. In assays for antiplasmodial activity, compounds 280-282 also showed good activity against the pathogenic microbe P. falciparum (IC₅₀ values of 4.0, 0.3 and 3.0 µM, respectively). Compound 280 also showed antitubercular activity against Mycobacterium tuberculosis (IC₅₀ values of 62 and 71 µM, respectively) [95].

Gracilioethers A-C (283-285) (Figure 34 and Figure 35) have been isolated from the marine sponge, Agelas gracilis (Agelasidae), and they showed antimalarial activity against the ItG strain of P. falciparum with IC₅₀ values of 1.6 to 31 μM, and gracilioether B (284) also showed antileishmanial activity [96]. Malyngolide dimer (286) (Figure 35) has been isolated from the marine cyanobacterium Lyngbya majuscule (Oscillatoriaceae). It exhibited moderate in vitro antiplasmodial activity against chloroquine-resistant P. falciparum (W2, IC₅₀ = 19 μM), but roughly equivalent toxicity toward H-460 human lung cell lines [97].

Figure 34. Structures of peroxide polyketides 272-278 and 280-282.

Figure 34. Structures of peroxide polyketides 272-278 and 280-282.

Figure 35. Structures of other polyketides 279 and 284-286 from sponges.

Figure 35. Structures of other polyketides 279 and 284-286 from sponges.

12. Acetylenes

Three acetylenic compounds, 1-phenyl-hepta-1,3,5-triyne (287), (R)-1,2-dihydroxytrideca-3,5,7,9,11-pentayne (288), and its glycoside, 2-β-D-glycopyrasyloxy-1-hydroxytrideca-3,5,7,9,11-pentayne (289) (Figure 36) have been isolated from Bidens pilosa (Compositae). Among other activities, these compounds showed potential antimalarial activity in vitro (determined spectrophotometrically by measuring the activity of the pLDH, in control and drug-treated cultures or using the Nagel method against the RCR-3 strain of P. falciparum) [98,99]. Compound 287 when tested in vitro showed an IC₅₀ = 37.2 µM (P. falciparum strain NF54), while compound 288 showed an IC₅₀ = 1.8 µM. In in vivo assays the average 32.8% malaria parasite growth (P. berhei strain NK-65) diminished to 12.1% by administration of a dose 0.8 mg/kg of 288 for four days in mice [98,99].

The roots of Tagetes erecta (Compositae) yielded 2-hydroxymethyl-non-3-ynoic acid 2-[2,2']-bithiophenyl-5-ethyl ester (290). This compound was evaluated for its in vitro antiplasmodial activity using the schizont maturation inhibition assay, and showed significant schizonticidal activity against both chloroquine-sensitive (MRC-pf-2) and -resistant (MRC-pf-56) strains of P. falciparum with IC₅₀ values of 26 and 53 nM, respectively [100].

Figure 36. Structures of polyacetylenes 287-290.

Figure 36. Structures of polyacetylenes 287-290.

13. β-Resorcylic Acid Lactones

The β-resorcylic acid lactones paecilomycins (291-294), aigialomycin B (295), aigialomycin D (296), and aigialomycin F (297) (Figure 37) were isolated from the mycelial solid culture of Paecilomyces sp. (Trichocomaceae, fungus). These lactones exhibited antiplasmodial activity against the 3D7 line of P. falciparum, and 294 and 297 were the most active, with IC₅₀ values of 20.0 and 10.9 nM, respectively, whereas compounds 293-295 showed good activity against the P. falciparum strain Dd2, with IC₅₀ values of 1.7 to 13.5 µM [101].

Figure 37. Structures of β-resorcylic acid lactones 291-297.

Figure 37. Structures of β-resorcylic acid lactones 291-297.

14. Depsidones

The depsidones mollicellins B (298), C (299), E (300), K-M (301-303), and J (304) (Figure 38) isolated from Chaetomium brasiliense (Chaetomiaceae) exhibited in vitro antimalarial activity against P. falciparum (K1 multidrug-resistant, IC₅₀ = 12.3, 22.0, 7.2, 7.0, 3.1, 8.6, and 12.2 µM, respectively). These compounds also showed in vitro cytotoxicity against KB, BC1, and NCI-H187 cells, as well as five cholangiocarcinoma cell lines [102].

Figure 38. Structures of depsidones 298-304.

Figure 38. Structures of depsidones 298-304.

15. Benzophenones

A series of antiplasmodial benzophenones 305-318 (Figure 39), with IC₅₀ values of 3.3 to 37.2 μM, were isolated from Moronobea coccinea (Clusiaceae). The benzophenone cytotoxicities were also evaluated toward the human cell line MRC-5 [103]. Isoxanthochymol (330) from Garcinia spp. (Clusiaceae) exhibited broad but non-selective antiprotozoal activity, with an IC₅₀ value of 4.47 µM against P. falciparum, and was also cytotoxic (IC₅₀ 7.46 µM) [50]. Symphonia globulifera (Clusiaceae) also contains polycyclic polyprenylated acylphloroglucinol compounds 317-327 and two oxidized derivatives 328 and 329 (Figure 39). All compounds showed antiplasmodial activity when evaluated in vitro against a chloroquine-resistant strain of P. falciparum (FcB1), with IC₅₀ values of 2.1 to 10.1 µM [104].

Figure 39. Structures of benzophenones 305-330.

Figure 39. Structures of benzophenones 305-330.

16. Miscellaneous Compounds

16.1. Diterpene-benzoate macrolides and analogues

Several bromophycolides 331-347 (Figure 40) with a diterpene-benzoate macrolide carbon skeleton have been obtained from the red alga Callophycus serratus (Solieriaceae), and have been shown to exhibit excellent to moderate antiplasmodial activity against the P. falciparum strain 3D7 (IC₅₀ values of 0.3 to 56 μM) [105].

Figure 40. Structures of diterpene-benzoate macrolides and analogues 331-347.

Figure 40. Structures of diterpene-benzoate macrolides and analogues 331-347.

16.2. Strobilurins

Strobilurins 348-352, two of which (348 and 349) are monochlorinated (Figure 41), have been obtained from the fungus Favolaschia tonkinensis. In addition to their antifungal and cytotoxic activities, they also exhibited antiplasmodial activity against the P. falciparum strain K1, with IC₅₀ values of 0.06 to 10.3 µM [106].

Figure 41. Structures of strobilurins 348-352.

Figure 41. Structures of strobilurins 348-352.

16.3. Other compounds

Isariotin F (353) (Figure 42) isolated from the fungus Isaria tenuipes also exhibited activity against the malaria parasite P. falciparum K1 with an IC₅₀ value of 5.1 μM, as well as cytotoxic activities toward cancer cell lines (IC₅₀ values of 15.8, 2.4, and 1.6 μM, in KB, BC, and NCI-H187, respectively) and nonmalignant (Vero) cells (IC₅₀ = 2.9 μM) [107].

Figure 42. Structures of compounds 353-355.

Figure 42. Structures of compounds 353-355.

From the marine sponge Pseudoceratina sp. (Pseudoceratinidae) was isolated a derivative of homogentisic acid (354) (Figure 43), which inhibited a specific protein kinase of P. falciparum (Pfnek-1) with an IC50 of around 1.8 μM. This product was active in vitro assays against the P. falciparum strain FcB1 (IC50 = 12 μM) [108].

Compound 355 (Figure 42) has been obtained from the fungus Emericella rugulosa. It exhibited good antiplasmodial activity against the P. falciparum strain K1 (IC₅₀ value of 5.1 μM), antimycobacterial (MIC value of 33.1 μM) activity, and cytotoxicity against three cancer cell lines (IC₅₀ value of 3.5, 6.9, and 3.5 μM, in BC1, KB, and NCI-H187, respectively) [109].

Chromenes from Cassia siamea (Leguminosae) 356-358 (Figure 43) exhibited good antiplasmodial activity against the P. falciparum strain 3D7 (IC₅₀ 356: 2.3 μM; 357: 4.7 μM; 358: 8.6 μM) and no cytotoxicity (IC₅₀> 100 µM) [62].

Figure 43. Structures of chromenes 356-358.

Figure 43. Structures of chromenes 356-358.

The 6-(8'Z-pentadecenyl)-salicylic acid (359) (Figure 44) isolated from Viola websteri (Violaceae) was found to have antimalarial activity in vivo. When tested against P. berghei in mice 6-SA, at 5, 10 and 25 mg/kg/day exhibited a significant blood schizonticidal activity, and at these concentrations no marked toxicity was observed in mice [110]. Another polyketide derivative (malabaricone A, 360) has been isolated from Knema glauca (Myristicaceae). It showed moderate cytotoxicity, antituberculosis activity against M. tuberculosis, and antiplasmodial activity against the parasite P. falciparum strain K1 with an IC₅₀ value of 8.6 μM [111].

Figure 44. Structures of compounds 359 and 360.

Figure 44. Structures of compounds 359 and 360.

4. Conclusions

A few drugs, alone or in combination—chloroquine, primaquine, mefloquine, halofantrine, artemisinin, atovaquone, among others—have been used in chemotherapy for malaria. However, the evolution of drug- or multidrug-resistance has been a challenge for the effectiveness of such chemotherapy. None of the papers in this review claim to have discovered the next antimalarial drug. Instead, they provide a remarkable diversity of new natural products on which to base the discovery and development of antimalarial drugs. This considerable structural diversity is represented in the 360 relevant structures that we examined (as illustrated in Figures 1-44). Several potent antiplasmodial natural products have been described, and those belonging to alkaloid (manzamine, pyridinone, and pyrroloiminoquinone), polyacetylene, phenylethanoid, anthraquinone, polyketide (endoperoxide), nonpeptide macrocyclic, and β-resorcylic lactone classes have high antiplasmodial activity. Most of the active compounds described here have only been evaluated by in vitro assays, few have been evaluated for cytotoxicity, and still fewer have been assayed in vivo. The compounds listed (Figures 1-44) have been included based on the potency and/or selectivity of their biological properties, and reflect the tremendous effort that is being devoted to recognizing the potential of natural products as lead compounds in the treatment of malaria.