Antimalarial Activity of Plant Metabolites

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum. As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.


Introduction
Malaria is still considered as a major global health problem, affecting a large population of the world. According to World Health Organization (WHO), there were about 216 million malaria cases globally and 445,000 deaths in 2016. Most of the cases and the deaths occurred in the WHO African region and affected primarily children and pregnant women [1].
P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi are the five Plasmodium species that cause malaia disease in humans. P. falciparum is the deadliest strain that causes malaria and this form of parasite predominates in Africa [2,3]. Humans get infected with malaria parasites through the bites of female anopheline mosquitoes [4]. The Plasmodium parasites travel through blood and become mature and reproduce in the liver, leading to malaria disease. The common symptoms of malaria are fever and headache, and in severe cases, malaria causes death [5].
Currently, there is no commercially available malaria vaccine, though efforts to develop vaccines are still ongoing. The most promising vaccine candidate is RTS, S/AS01, which is in clinical trials for treatment of malaria caused by P. falciparum [1]. Several medications are available to prevent malaria for travellers in malaria-endemic countries, and a number of drugs are available for treatment of those who have the disease [6]. The current antimalarial drug of choice is artemisinin (Qinghaosu, IV), which was originally obtained from the leaves of Qinghao [Artemisia annua L. (Asteraceae)] in the 1970s. The compound is clinically effective against chloroquine-resistant malaria strains [11]. The plant Qinghao has been used as a traditional medicine in China for the treatment of fever of malaria origin for about 2000 years [12]. A large number of artemisinin analogs have also been synthesized. The best known among these derivatives are artemether, arteether (artemotil), artesunate and artenimol (βdihydroartemisinin, DHA) [13]. Artemisinin and its semi-synthetic derivatives have shown better efficacy than quinine for both children and adults patients [14].
Although the anti-parasitic mechanism of action of artemisinin is still in question [15], the endoperoxide bridge is regarded as the key functional group responsible for eliciting free radicalmediated parasite killing mechanisms. According to one school of thought, Plasmodium parasites live and reproduce in the host by ingesting red blood cell hemoglobin. This results in an accumulation of heme Fe 2+ in the parasite. Fe 2+ firstly interacts and cleaves the peroxide bridge of artemisinin to form highly reactive free radicals, which in turn cause a series of parasite molecular events and eventually kill the parasites [16]. The most used artemisinin derivative today is the prodrug, dihydroartemisinin (V), which is metabolized into the pharmacologically active artimisinin (IV) in the body [17]. Artesunate was investigated as a potential inhibitor of the essential P. falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase [18].
Clinically, it is unwise to use artemisinin as the lone therapy due to the potential risk of the parasites to develop resistance to this drug. Indeed, artemisinin drug resistance has been already detected in some Southern Asian countries: Lao People's Democratic Republic, Cambodia, Thailand, Myanmar and Viet Nam [1]. This risk has led to the withdrawal of artemisinin monotherapy from clinical applications.
At present, the use of artemisinins in combination with other drugs, known as artemisinin-based combination therapy (ACT), is the most effective to treat malarial disease caused by P. falciparum infection. Five currently available ACTs are artemether in combination with lumefantrine, and four other forms based on artesunate in combination with amodiaquine (two formulations), mefloquine and sulfadoxine+pyrimethamine [1]. Unfortunately, resistance has already been detected to both artemisinin and artesunate components of the multiple ACTs, as well as the non-artemisinin-based The current antimalarial drug of choice is artemisinin (Qinghaosu, IV), which was originally obtained from the leaves of Qinghao [Artemisia annua L. (Asteraceae)] in the 1970s. The compound is clinically effective against chloroquine-resistant malaria strains [11]. The plant Qinghao has been used as a traditional medicine in China for the treatment of fever of malaria origin for about 2000 years [12]. A large number of artemisinin analogs have also been synthesized. The best known among these derivatives are artemether, arteether (artemotil), artesunate and artenimol (β-dihydroartemisinin, DHA) [13]. Artemisinin and its semi-synthetic derivatives have shown better efficacy than quinine for both children and adults patients [14].
Although the anti-parasitic mechanism of action of artemisinin is still in question [15], the endoperoxide bridge is regarded as the key functional group responsible for eliciting free radical-mediated parasite killing mechanisms. According to one school of thought, Plasmodium parasites live and reproduce in the host by ingesting red blood cell hemoglobin. This results in an accumulation of heme Fe 2+ in the parasite. Fe 2+ firstly interacts and cleaves the peroxide bridge of artemisinin to form highly reactive free radicals, which in turn cause a series of parasite molecular events and eventually kill the parasites [16]. The most used artemisinin derivative today is the prodrug, dihydroartemisinin (V), which is metabolized into the pharmacologically active artimisinin (IV) in the body [17]. Artesunate was investigated as a potential inhibitor of the essential P. falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase [18].
Clinically, it is unwise to use artemisinin as the lone therapy due to the potential risk of the parasites to develop resistance to this drug. Indeed, artemisinin drug resistance has been already detected in some Southern Asian countries: Lao People's Democratic Republic, Cambodia, Thailand, Myanmar and Viet Nam [1]. This risk has led to the withdrawal of artemisinin monotherapy from clinical applications.
At present, the use of artemisinins in combination with other drugs, known as artemisinin-based combination therapy (ACT), is the most effective to treat malarial disease caused by P. falciparum infection. Five currently available ACTs are artemether in combination with lumefantrine, and four other forms based on artesunate in combination with amodiaquine (two formulations), mefloquine and sulfadoxine+pyrimethamine [1]. Unfortunately, resistance has already been detected to both artemisinin and artesunate components of the multiple ACTs, as well as the non-artemisinin-based combination comprising atovaquone and proguanil. The current availbale antimalarial drugs are listed in Table 1 [1,19,20]. In the search for drug candidates, the initial step is the employment of appropriate bioassays to evaluate the antiplasmodial activity of a candidate. Several strains of P. falciparum have been used for this purpose in the past. The strains of P. falciparum that are sensitive and resistant to chloroquine are frequently used for antimalarial drug discovery programs. D6, D10, 3D7, TM4 and PoW are chloroquine-sensitive strains, whereas, W2, FCR-3, FcB1 and Dd2 represent chloroquine-resistant strains, and K1 is a multidrug resistant strain.
The need to discover effective and non-drug resistant antimalarial drugs is urgent as Plasmodium strains have already developed resistance to all of today's available drugs including artemisinin. In that regard, it should be noted that natural products have proven to be a valuable source for the discovery of novel antimalarial therapeutic agents since the discovery of the first antimalarial drug in 1800s [20]. We, thus, pursued this approach in the search for new antimalarial potential drug leads.
In our antimalarial drug discovery program, we have evaluated more than 2000 plant extracts against D6 and W2 strains of P. falciparum. Dozens of these plants displayed antimalarial activity. Several of these plant leads were investigated further to uncover their antimalarial constituents. Phytochemical separation of these plant leads guided by bioassays led to the identification of ten new and 13 known active compounds [21]. Some of these compounds demonstrated potent antimalarial activity [22][23][24][25][26][27][28][29]. For example, polysyphorin (1) and rhaphidecurperoxin (2), isolated from Rhaphidophora decursiva (Araceae), showed antimalarial activities of 1.5 and 1.4 µM against the W2 clones of P. falciparum, respectively ( Figure 2) [22]. Two trichothecenes, roridin E (3) from R. decursiva (Araceae) and verrucarin L acetate (4) from Ficus fistulosa (Moraceae), were found to potently inhibit the parasite growth with IC 50 values in the sub-nano molar range [24]. De-replication to avoid duplication of previous efforts is an essential step in drug discovery protocols. To that end, we conducted a thorough review of the published literature on natural products possessing antimalarial activity. Previously, a literature review by Schwikkard and Van Heerden [30], covered plant-derived antiplasmodial active natural compounds up to the year 2000. The compounds were organized according to the origins of their corresponding plant families. The current review seeks to supplement the review of Schwikkard and Van Heerden. Compounds with antimalarial activity will also be organized according to their plant family of origin (Table 2). Literature published between 2001 and 2017 have been covered. In addition, we also included the ethnobotanic information of plants that have been used as folk medicines for the treatment of malarial disease (Table 3). De-replication to avoid duplication of previous efforts is an essential step in drug discovery protocols. To that end, we conducted a thorough review of the published literature on natural products possessing antimalarial activity. Previously, a literature review by Schwikkard and Van Heerden [30], covered plant-derived antiplasmodial active natural compounds up to the year 2000. The compounds were organized according to the origins of their corresponding plant families. The current review seeks to supplement the review of Schwikkard and Van Heerden. Compounds with antimalarial activity will also be organized according to their plant family of origin (Table 2). Literature published between 2001 and 2017 have been covered. In addition, we also included the ethnobotanic information of plants that have been used as folk medicines for the treatment of malarial disease (Table 3).
Miliusacunines A (9) and B (10) were identified from an acetone extract of the leaves and twigs of Miliusa cuneatas [33]. Compound 9 demonstrated inhibitory activity against the TM4 malarial strain (IC50 19.3 µM), and compound 10 displayed activity against the K1 malarial strain (IC50 10.8 µM). Both isolates showed no toxicity to the Vero cells at the elevated concentrations.

Araceae Family
Zhang et al. [22,23] performed extensive research on Rhaphidophora decursiva, a vine growing in Vietnam. The MeOH extract of the plant leaves and stems showed antimalarial activity against both D6 and W2 clones with no apparent cytotoxicity at a concentration of 20 µg/mL. Seven compounds were identified from the stems and leaves of the plant through a bioassay-guided separation ( Figure  4). Polysyphorin (1) and rhaphidecurperoxin (2) were among the most active compounds, which demonstrated antimalarial activity with IC50 values of 1.4-1.8 µM against the D6 and W2 strains and cytotoxicity with ED50 values of 8.3-13.1 µM against KB cells ( Figure 2). Rhaphidecursinols A (11) and B (12), grandisin (13), epigrandisin (14) and decursivine (15) also showed activities against P. falciparum (D6 and W2) with IC50 values of 3.4-12.9 µM and cytotoxicity of ED50 values of 23.9-37.0 µM against KB cells with an exception of compound 14, which showed no antimalarial activity against D6 strain at 23 µM. According to Mueller et al. [32], 5-hydroxy-6-methoxyonychine (8), an alkaloid obtained from the roots of the Australian tree plant Mitrephora diversifolia, showed IC 50 values of 9.9 and 11.4 µM against the 3D7 and Dd2 clones of P. falciparum, respectively.
Miliusacunines A (9) and B (10) were identified from an acetone extract of the leaves and twigs of Miliusa cuneatas [33]. Compound 9 demonstrated inhibitory activity against the TM4 malarial strain (IC 50 19.3 µM), and compound 10 displayed activity against the K1 malarial strain (IC 50 10.8 µM). Both isolates showed no toxicity to the Vero cells at the elevated concentrations.

Araceae Family
Zhang et al. [22,23] performed extensive research on Rhaphidophora decursiva, a vine growing in Vietnam. The MeOH extract of the plant leaves and stems showed antimalarial activity against both D6 and W2 clones with no apparent cytotoxicity at a concentration of 20 µg/mL. Seven compounds were identified from the stems and leaves of the plant through a bioassay-guided separation (  According to the further investigation of Zhang et al. [24], a potent but toxic trichothecene compound, roridin E (3), was identified from the same plant extract ( Figure 2). The investigators determined that the compound was able to inhibit parasite growth with IC50 values in the sub-nano molar range. However, roridin E was also very cytotoxic against KB cells. Interestingly, these researchers reported another trichothecene compound (4) from a plant in a different family, and the compound showed equally potent antimalarial activities as that of roridin E, but with much less cytotoxicity (see 2.   According to the further investigation of Zhang et al. [24], a potent but toxic trichothecene compound, roridin E (3), was identified from the same plant extract (Figure 2). The investigators determined that the compound was able to inhibit parasite growth with IC 50 values in the sub-nano molar range. However, roridin E was also very cytotoxic against KB cells. Interestingly, these researchers reported another trichothecene compound (4) from a plant in a different family, and the compound showed equally potent antimalarial activities as that of roridin E, but with much less cytotoxicity (see Section 2.8.3). According to the further investigation of Zhang et al. [24], a potent but toxic trichothecene compound, roridin E (3), was identified from the same plant extract (Figure 2). The investigators determined that the compound was able to inhibit parasite growth with IC50 values in the sub-nano molar range. However, roridin E was also very cytotoxic against KB cells. Interestingly, these researchers reported another trichothecene compound (4) from a plant in a different family, and the compound showed equally potent antimalarial activities as that of roridin E, but with much less cytotoxicity (see 2.   PoW and Dd2 strains of P. falciparum by Köhler et al. [36]. Two diterpenes, E-phytol (20) (IC50: 8.5 µM (PoW); 11.5 µM (Dd2)), and 6E-geranylgeraniol-19-oic acid (21) (IC50: 12.9 µM (PoW); 15.6 µM (Dd2)) were shown to be the most active compounds in their test system ( Figure 6).

Cecropiaceae Family
Cecropia pachystachya is a medicinal plant, which has been used in Brazil. The ethanol extracts of the different parts of the plants were evaluated for their activity against P. falciparum in vitro and P. berghei in vivo [39]. The parasitemia of malaria-infected mice was reduced by 35-66% with treatment of the ethanol extracts of the wood, root, and leaf materials in comparison with the non-treated control group. The plant root extracts were further analyzed and fractionated to provide subfractions, which were also active in an in vivo study. Two compounds, β-sitosterol (32) and tormentic acid (33)

Cecropiaceae Family
Cecropia pachystachya is a medicinal plant, which has been used in Brazil. The ethanol extracts of the different parts of the plants were evaluated for their activity against P. falciparum in vitro and P. berghei in vivo [39]. The parasitemia of malaria-infected mice was reduced by 35-66% with treatment of the ethanol extracts of the wood, root, and leaf materials in comparison with the non-treated control group. The plant root extracts were further analyzed and fractionated to provide subfractions, which were also active in an in vivo study. Two compounds, β-sitosterol (32) and tormentic acid (33), were identified from the subfractions (Figure 8). Both compounds showed plasmodial inhibitory activity. However, only tormentic acid (33) demonstrated inhibitory activity against P. falciparum chloroquine-resistant parasites (W2) (IC 50

Cecropiaceae Family
Cecropia pachystachya is a medicinal plant, which has been used in Brazil. The ethanol extracts of the different parts of the plants were evaluated for their activity against P. falciparum in vitro and P. berghei in vivo [39]. The parasitemia of malaria-infected mice was reduced by 35-66% with treatment of the ethanol extracts of the wood, root, and leaf materials in comparison with the non-treated control group. The plant root extracts were further analyzed and fractionated to provide subfractions, which were also active in an in vivo study. Two compounds, β-sitosterol (32) and tormentic acid (33), were identified from the subfractions (Figure 8). Both compounds showed plasmodial inhibitory activity. However, only tormentic acid (33) demonstrated inhibitory activity against P. falciparum chloroquine-resistant parasites (W2) (IC50 19.0-25.2 µM).  were obtained from C. serratus and C. spicatus, and compounds 55-57 were separated from Sarcandra glabra. Compound 65 was originated from C. multisachys. Among these isolates, fortunilide A (34), sarglabolide J (47) and chlorajaponilide C (52) exhibited low nanomolar activities with IC 50 values of 5.2, 7.2 and 1.1 nM, respectively, and their selectivity index values toward mammalian cells were greater than 500 (Figure 9).

Clusiaceae Family
Phytochemical separation of the concentrated acetone extract of the dried leaves and branches of Garcinia mckeaniana has led to the identification of three new xanthones, mckeanianones A-C (69-71), and two known ones, bannaxanthones I (73) and E (73) (Figure 11). These compounds all contain two isoprene units. They were evaluated for their activity against the TM4 and K1 strains of P.   The three compounds (66-68) also displayed cytotoxicity against Graham cells with ED 50 values in the range of 3.2-9.2 µM, which preclude them from further biological investigation. They could, however, be used effectively as lead compounds for drug optimization through synthesis.

Clusiaceae Family
Phytochemical separation of the concentrated acetone extract of the dried leaves and branches of Garcinia mckeaniana has led to the identification of three new xanthones, mckeanianones A-C (69-71), and two known ones, bannaxanthones I (73) and E (73) (Figure 11). These compounds all contain two isoprene units. They were evaluated for their activity against the TM4 and K1 strains of P. falciparum with IC 50

Clusiaceae Family
Phytochemical separation of the concentrated acetone extract of the dried leaves and branches of Garcinia mckeaniana has led to the identification of three new xanthones, mckeanianones A-C (69-71), and two known ones, bannaxanthones I (73) and E (73) (Figure 11). These compounds all contain two isoprene units. They were evaluated for their activity against the TM4 and K1 strains of P.

Cucurbitaceae Family
Cogniauxia podolaena Baill. is a folk medicine that has been traditionally used to treat malaria in Congo Brazzaville. Banzouzi et al. [44] identified cucurbitacins B (81) and D (82), and 20-epibryonolic acid (83), the three triterpenes from the stems of this plant ( Figure 14). These compounds exhibited inhibitory activity against FcM29 strain with IC50 values of 2.9, 7.8 and 4.4 µM, respectively. Both cucurbitacins B and D showed a high cytotoxicity with approximately 95% inhibition against KB cells at 1 µg/mL, while 20-epibryonolic acid displayed a better selectivity index (20% inhibition of KB cells at 1 µg/mL).

Cucurbitaceae Family
Cogniauxia podolaena Baill. is a folk medicine that has been traditionally used to treat malaria in Congo Brazzaville. Banzouzi et al. [44] identified cucurbitacins B (81) and D (82), and 20-epibryonolic acid (83), the three triterpenes from the stems of this plant ( Figure 14). These compounds exhibited inhibitory activity against FcM29 strain with IC50 values of 2.9, 7.8 and 4.4 µM, respectively. Both cucurbitacins B and D showed a high cytotoxicity with approximately 95% inhibition against KB cells at 1 µg/mL, while 20-epibryonolic acid displayed a better selectivity index (20% inhibition of KB cells at 1 µg/mL).

Cucurbitaceae Family
Cogniauxia podolaena Baill. is a folk medicine that has been traditionally used to treat malaria in Congo Brazzaville. Banzouzi et al. [44] identified cucurbitacins B (81) and D (82), and 20-epibryonolic acid (83), the three triterpenes from the stems of this plant ( Figure 14). These compounds exhibited inhibitory activity against FcM29 strain with IC 50 values of 2.9, 7.8 and 4.4 µM, respectively. Both cucurbitacins B and D showed a high cytotoxicity with approximately 95% inhibition against KB cells at 1 µg/mL, while 20-epibryonolic acid displayed a better selectivity index (20% inhibition of KB cells at 1 µg/mL).

Cucurbitaceae Family
Cogniauxia podolaena Baill. is a folk medicine that has been traditionally used to treat malaria in Congo Brazzaville. Banzouzi et al. [44] identified cucurbitacins B (81) and D (82), and 20-epibryonolic acid (83), the three triterpenes from the stems of this plant ( Figure 14). These compounds exhibited inhibitory activity against FcM29 strain with IC50 values of 2.9, 7.8 and 4.4 µM, respectively. Both cucurbitacins B and D showed a high cytotoxicity with approximately 95% inhibition against KB cells at 1 µg/mL, while 20-epibryonolic acid displayed a better selectivity index (20% inhibition of KB cells at 1 µg/mL).

Euphorbiaceae Family
Through the screening of a natural product-based synthetic compound library, Hadi et al. [45] discovered that jatrophones (the natural products from Jatropha isabelli) possess significant antiplasmodial activity. The jatrophone diterpene derivatives 85 and 86 displayed antiplasmodial activities against strains 3D7 and K1 of P. falciparum with IC50 values of 5.7/5.9 and 6.1/5.9 µM, respectively ( Figure 16). The two compounds showed low cytotoxicities against the human HepG2, RAJI, BJ and HEK293 cells with EC50 values at around 26 µM.

Euphorbiaceae Family
Through the screening of a natural product-based synthetic compound library, Hadi et al. [45] discovered that jatrophones (the natural products from Jatropha isabelli) possess significant antiplasmodial activity. The jatrophone diterpene derivatives 85 and 86 displayed antiplasmodial activities against strains 3D7 and K1 of P. falciparum with IC 50 values of 5.7/5.9 and 6.1/5.9 µM, respectively ( Figure 16). The two compounds showed low cytotoxicities against the human HepG2, RAJI, BJ and HEK293 cells with EC 50 values at around 26 µM.  (84)

Euphorbiaceae Family
Through the screening of a natural product-based synthetic compound library, Hadi et al. [45] discovered that jatrophones (the natural products from Jatropha isabelli) possess significant antiplasmodial activity. The jatrophone diterpene derivatives 85 and 86 displayed antiplasmodial activities against strains 3D7 and K1 of P. falciparum with IC50 values of 5.7/5.9 and 6.1/5.9 µM, respectively ( Figure 16). The two compounds showed low cytotoxicities against the human HepG2, RAJI, BJ and HEK293 cells with EC50 values at around 26 µM.

Hypericaceae Family
Vismia orientalis, a traditional medicine used in Tanzania, was studied by Mbwambo et al. [50]. Vismione D (98), isolated from the stem barks of this plant, exhibited activity against the K1 strain with an IC50 value of 2.4 µM ( Figure 18). However, the compound also showed cytotoxicity against human L6 cells with an IC50 value of 10.0 µM.
Pure isolates from the hexane extract of the stem barks of the African plant Psorospermum glaberrimum were evaluated for their antimalarial activity against the W2 clone of P. falciparum by Ndjakou Lenta et al. [51]. The isolates 3-geranyloxyemodin anthrone (99) and acetylvismione D (100) displayed inhibition activity against the W2 strain with IC50 values of 1.7 and 0.1 µM, respectively ( Figure 19). According to the work of Samoylenko et al. [49], prosopilosidine (92) and isoprosopilosidine (93), isolated from the leaves of Prosopis glandulosa var. glandulosa, showed potent antimalarial activity against the D6 and W2 strains of P. falciparum with high selectivity index (SI) values ( Figure 17).

Hypericaceae Family
Vismia orientalis, a traditional medicine used in Tanzania, was studied by Mbwambo et al. [50]. Vismione D (98), isolated from the stem barks of this plant, exhibited activity against the K1 strain with an IC50 value of 2.4 µM ( Figure 18). However, the compound also showed cytotoxicity against human L6 cells with an IC50 value of 10.0 µM.
Pure isolates from the hexane extract of the stem barks of the African plant Psorospermum glaberrimum were evaluated for their antimalarial activity against the W2 clone of P. falciparum by Ndjakou Lenta et al. [51]. The isolates 3-geranyloxyemodin anthrone (99) and acetylvismione D (100) displayed inhibition activity against the W2 strain with IC50 values of 1.7 and 0.1 µM, respectively ( Figure 19).

Hypericaceae Family
Vismia orientalis, a traditional medicine used in Tanzania, was studied by Mbwambo et al. [50]. Vismione D (98), isolated from the stem barks of this plant, exhibited activity against the K1 strain with an IC 50 value of 2.4 µM (Figure 18). However, the compound also showed cytotoxicity against human L6 cells with an IC 50 value of 10.0 µM.
Pure isolates from the hexane extract of the stem barks of the African plant Psorospermum glaberrimum were evaluated for their antimalarial activity against the W2 clone of P. falciparum by Ndjakou Lenta et al. [51]. The isolates 3-geranyloxyemodin anthrone (99) and acetylvismione D (100) displayed inhibition activity against the W2 strain with IC 50 values of 1.7 and 0.1 µM, respectively ( Figure 19).  Figure 19. Compounds from Hypericaceae plants.

Lamiaceae Family
An EtOH extract of the dried root barks of Ocimum sanctum exhibited considerable in vitro antimalarial activity. Bioactivity-directed separation of the EtOH extract resulted in the isolation of a new antimalarial natural compound (101) (Figure 20). The compound showed comparable activity to the positive controls, chloroquine and amodiaquine, against the P. falciparum 3D7 strains with an IC50 value of 0.1 µM [52]. The extracts of 17 Salvia species, which are used as folk medicines in South Africa, were subjected to biological testing by Kamatou et al. [54]. The potential activity of the Salvia plant extracts against the FCR strain of P. falciparum and their cytotoxic effects against MCF-7 cells were investigated. These extracts showed antiplasmodial activity with IC50 values in the range of 3.9-26.0 µg/mL. The extracts from S. radula demonstrated the most potent activities. Two compounds, betulafolientriol oxide (104) and salvigenin (105), were subsequently isolated (Figure 20), and they showed antimalarial activity with IC50 values of 10.4 and 75.0 µM, respectively.

Loganiaceae Family
A phytochemical study was carried out for the stem barks of Strychnos icaja for the first time by Tchinda et al. [55], which led to the isolation of the monomers 15-hydroxyvomicine (106) and Nmethyl-sec-iso-pseudostrychnine (107). The isolates were evaluated against the P. falciparum 3D7 strain with IC50 values of 101.0 and 110.6 µM, respectively ( Figure 21).  The extracts of 17 Salvia species, which are used as folk medicines in South Africa, were subjected to biological testing by Kamatou et al. [54]. The potential activity of the Salvia plant extracts against the FCR strain of P. falciparum and their cytotoxic effects against MCF-7 cells were investigated. These extracts showed antiplasmodial activity with IC50 values in the range of 3.9-26.0 µg/mL. The extracts from S. radula demonstrated the most potent activities. Two compounds, betulafolientriol oxide (104) and salvigenin (105), were subsequently isolated (Figure 20), and they showed antimalarial activity with IC50 values of 10.4 and 75.0 µM, respectively.

Loganiaceae Family
A phytochemical study was carried out for the stem barks of Strychnos icaja for the first time by Tchinda et al. [55], which led to the isolation of the monomers 15-hydroxyvomicine (106) and Nmethyl-sec-iso-pseudostrychnine (107). The isolates were evaluated against the P. falciparum 3D7 strain with IC50 values of 101.0 and 110.6 µM, respectively ( Figure 21). The extracts of 17 Salvia species, which are used as folk medicines in South Africa, were subjected to biological testing by Kamatou et al. [54]. The potential activity of the Salvia plant extracts against the FCR strain of P. falciparum and their cytotoxic effects against MCF-7 cells were investigated. These extracts showed antiplasmodial activity with IC 50 values in the range of 3.9-26.0 µg/mL. The extracts from S. radula demonstrated the most potent activities. Two compounds, betulafolientriol oxide (104) and salvigenin (105), were subsequently isolated (Figure 20), and they showed antimalarial activity with IC 50 values of 10.4 and 75.0 µM, respectively.

Loganiaceae Family
A phytochemical study was carried out for the stem barks of Strychnos icaja for the first time by Tchinda et al. [55], which led to the isolation of the monomers 15-hydroxyvomicine (106) and N-methyl-sec-iso-pseudostrychnine (107). The isolates were evaluated against the P. falciparum 3D7 strain with IC 50

Moraceae Family
According to the investigation of Zhang et al. [24], an antimalarial trichothecene compound, verrucarin L acetate (4), was identified from Ficus fistulosa (Figure 2). The antimalarial potency of 4 was equivalent to that of roridin E (3) isolated from Rhaphidophora decursiva, a plant from a different family. However, 4 was observed to be much less cytotoxic to KB cells (ED50 0.2 µM) than 3.
Bioassay-directed separation of the MeOH extract of the twigs of Ficus septica afforded three known phenanthroindolizine alkaloids, dehydrotylophorine (115), dehydroantofine (116) and tylophoridicine D (117) by Kubo et al. (Figure 25) [60]. They showed antiplasmodial activity against the P. falciparum 3D7 strain with IC50 values in the range of 0.03-0.4 µM. Compound 115 also displayed cytotoxicity against the mouse fibroblast cells L929 with an IC50 value of 8.2 µM, while the other two compounds showed no toxicity at a concentration of 50 µM.

Myristicaceae Family
Phytochemical investigation of the fruits of Knema glauca by Rangkaew et al. [61] led to the isolation of malabaricone A (118) as an active compound against the P. falciparum K1 strain with an IC50 value of 8.5 µM (Figure 26). The compound was cytotoxic towards KB cell with an ED50 value of >61 µM.

Moraceae Family
According to the investigation of Zhang et al. [24], an antimalarial trichothecene compound, verrucarin L acetate (4), was identified from Ficus fistulosa (Figure 2). The antimalarial potency of 4 was equivalent to that of roridin E (3) isolated from Rhaphidophora decursiva, a plant from a different family. However, 4 was observed to be much less cytotoxic to KB cells (ED 50 0.2 µM) than 3.

Moraceae Family
According to the investigation of Zhang et al. [24], an antimalarial trichothecene compound, verrucarin L acetate (4), was identified from Ficus fistulosa (Figure 2). The antimalarial potency of 4 was equivalent to that of roridin E (3) isolated from Rhaphidophora decursiva, a plant from a different family. However, 4 was observed to be much less cytotoxic to KB cells (ED50 0.2 µM) than 3. Bioassay

Myristicaceae Family
Phytochemical investigation of the fruits of Knema glauca by Rangkaew et al. [61] led to the isolation of malabaricone A (118) as an active compound against the P. falciparum K1 strain with an IC 50 value of 8.5 µM (Figure 26). The compound was cytotoxic towards KB cell with an ED 50 value of >61 µM.

Myristicaceae Family
Phytochemical investigation of the fruits of Knema glauca by Rangkaew et al. [61] led to the isolation of malabaricone A (118) as an active compound against the P. falciparum K1 strain with an IC50 value of 8.5 µM (Figure 26). The compound was cytotoxic towards KB cell with an ED50 value of >61 µM.

Rutaceae Family
Based on an ethnomedicinal survey of the plants in Uganda, Citropsis articulata was selected for phytochemical study to investigate its antimalarial constituents [64]. From the ethyl acetate extract of the root barks of this plant, two known alkaloids, 5-hydroxynoracronycine (132) and 1,5-dihydroxy-2,3-dimethoxy-10-methyl-9-acridone (133), were identified as the best growth inhibitors of P.

Rutaceae Family
Based on an ethnomedicinal survey of the plants in Uganda, Citropsis articulata was selected for phytochemical study to investigate its antimalarial constituents [64]. From the ethyl acetate extract of the root barks of this plant, two known alkaloids, 5-hydroxynoracronycine (132) and 1,5-dihydroxy-2,3-dimethoxy-10-methyl-9-acridone (133), were identified as the best growth inhibitors of P. falciparum with IC 50

Rutaceae Family
Based on an ethnomedicinal survey of the plants in Uganda, Citropsis articulata was selected for phytochemical study to investigate its antimalarial constituents [64]. From the ethyl acetate extract of the root barks of this plant, two known alkaloids, 5-hydroxynoracronycine (132) and 1,5-dihydroxy-2,3-dimethoxy-10-methyl-9-acridone (133), were identified as the best growth inhibitors of P.

Verbenaceae Family
Chromatographic separation of the ethyl acetate extract of the aerial parts of Lippia javanica yielded a new antimalarial α-pyrone, lippialactone (150) (Figure 34). This compound is active against the D10 strain with an IC50 value of 23.8 µM. Compound 119 is also mildly cytotoxic [70].

Marine Plant-Derived Antimalarial Compounds
Marine organisms offer unique opportunity to discover lead compounds for the treatments of malaria.
Separation of the extracts of Fijian red alga Callophycus serratus by Lane et al. led to the isolation of bromophycolides J-Q (151-158) [94] (Figure 35), the macrolide diterpene-benzoate derivatives represented as two novel carbon skeletons. These diterpenes, together with the previously reported ten bromophycolides, bromophycolides A-I (159-167) and debromophycolide A (168) from this alga ( Figure 36

Verbenaceae Family
Chromatographic separation of the ethyl acetate extract of the aerial parts of Lippia javanica yielded a new antimalarial α-pyrone, lippialactone (150) (Figure 34). This compound is active against the D10 strain with an IC 50 value of 23.8 µM. Compound 119 is also mildly cytotoxic [70].

Verbenaceae Family
Chromatographic separation of the ethyl acetate extract of the aerial parts of Lippia javanica yielded a new antimalarial α-pyrone, lippialactone (150) (Figure 34). This compound is active against the D10 strain with an IC50 value of 23.8 µM. Compound 119 is also mildly cytotoxic [70].

Marine Plant-Derived Antimalarial Compounds
Marine organisms offer unique opportunity to discover lead compounds for the treatments of malaria.
Separation of the extracts of Fijian red alga Callophycus serratus by Lane et al. led to the isolation of bromophycolides J-Q (151-158) [94] (Figure 35), the macrolide diterpene-benzoate derivatives represented as two novel carbon skeletons. These diterpenes, together with the previously reported ten bromophycolides, bromophycolides A-I (159-167) and debromophycolide A (168) from this alga ( Figure 36) [95], were evaluated for their antimalarial activity against P. falciparum. The IC50 values of bromophycolides A, D, E, H and M (159, 162, 163, 164 and 154) were observed to be 0.9, 0.3, 0.8, 0.9 and 0.5 µM, respectively. Some of these compounds also exhibited strong cytotoxicity toward DU4475, a human breast cancer cell line. The ED50 values of bromophycolides N and Q (155 and 158) were 1.5 and 2.0 µM, respectively.

Marine Plant-Derived Antimalarial Compounds
Marine organisms offer unique opportunity to discover lead compounds for the treatments of malaria.
Separation of the extracts of Fijian red alga Callophycus serratus by Lane et al. led to the isolation of bromophycolides J-Q (151-158) [94] (Figure 35), the macrolide diterpene-benzoate derivatives represented as two novel carbon skeletons. These diterpenes, together with the previously reported ten bromophycolides, bromophycolides A-I (159-167) and debromophycolide A (168) from this alga ( Figure 36) [95], were evaluated for their antimalarial activity against P. falciparum. The IC 50 values of bromophycolides A, D, E, H and M (159, 162, 163, 164 and 154) were observed to be 0.9, 0.3, 0.8, 0.9 and 0.5 µM, respectively. Some of these compounds also exhibited strong cytotoxicity toward DU4475, a human breast cancer cell line. The ED 50

Ethnologic Antimalarial Compounds
At present, more than 80% of the world's population relies on ethnopharmacologic healing modalities and plants for their primary health care and wellness [97]. In Africa and many other developing countries, ethnomedicines are often regarded as their primary choice to treat diseases as they are obtained most affordable and accessible from locally available plants or other natural sources

Ethnologic Antimalarial Compounds
At present, more than 80% of the world's population relies on ethnopharmacologic healing modalities and plants for their primary health care and wellness [97]. In Africa and many other developing countries, ethnomedicines are often regarded as their primary choice to treat diseases as they are obtained most affordable and accessible from locally available plants or other natural sources

Ethnologic Antimalarial Compounds
At present, more than 80% of the world's population relies on ethnopharmacologic healing modalities and plants for their primary health care and wellness [97]. In Africa and many other developing countries, ethnomedicines are often regarded as their primary choice to treat diseases as they are obtained most affordable and accessible from locally available plants or other natural sources [78]. Plants are the major resource for the treatment of malaria infections in sub-Saharan Africa, where health care facilities are limited [98]. Ethnomedicinal plants have played a pivotal role in the treatment of malarial for centuries [71,99].
Early writing of over 6000 years ago in Egypt and China, and those of the Vedic civilisation dated 1600 B.C. in India, indicate that malaria has afflicted humans since antiquity, and there is ample evidence that antimalarial traditional medicaments have been used in virtually all cultures as the mainstay for the treatment of this disease. In the 5th century B.C., Hippocrates rejected superstition as a cause for the fevers that afflicted ancient Greeks. He instead recognized the seasonality of fevers and described the early clinical manifestations and complication of malaria [71].
The widely used antimalarial drug, artemisinin, was isolated from the traditional Chinese herb Artemisia annua L. (Qinghao) [11], which has been used in China as an ethnomedicine for close to 2000 years. The treatment of malaria with Qinghao was first recorded in "Zhouhou Bei Ji Fang", the handbook of prescriptions for emergencies in 243 A.D. [71,77].

Conclusions
It is imperative that the search for new antimalarial agents continues at an unabated pace in order to meet the challenges posed by the development of antimalarial drug resistance. During the last decade, numerous antimalarial compounds have been isolated from plants, and many of these compounds exhibit significant activity against P. falciparum in vitro. It is, therefore, evident that plant secondary metabolites continue to play an important role in pre-clinical antimalarial drug discovery.
We present in this comprehensive review, the structures of 175 plant-derived antiplasmodial compounds that have been published during the period of 2001-2017. The relevant plants are organized according to the geographical origins of their corresponding plant families.
Among the 175 plant-derived antiplasmodial compounds, several classes of compounds that showed nanomolar range of activity can be regarded as lead compounds to further explore their antimalarial potential. The trichothecene roridin E (3) from Rhaphidophora decursiva (Araceae family) showed potent inhibitory effects against the parasite growth with IC 50 values in the sub-nano molar range (IC 50 : 0.4 nM (D6), 1 nM (W2)) with high cytotoxicity against KB cells (ED 50 : 0.4 nM). However, its closely related structural analog, verrucarin L acetate (4), identified from Ficus fistulosa (Moraceae family), displayed much lower cytotoxicity to KB cells (ED 50 200 nM) while retaining the same level of the antiplasmodial activity as 3. Identified from the plant (Ficus septica) in the same genus as that of 4, the phenanthroindolizine alkaloids dehydroantofine (116) and tylophoridicine D (117) demonstrated potent antiplasmodial activity against the P. falciparum 3D7 strain with IC 50 values of 30 and 60 nM, respectively, and the compounds showed no toxicity at a concentration of 50 µM. A recent study found that the lindenane-type sesquiterpenoids fortunilide A (34), sarglabolide J (47) and chlorajaponilide C (52) from the plant in Chloranthaceae family displayed potent antiplasmodial activity against Dd2 strain of with IC 50 values of 5.2, 7.2 and 1.1 nM, respectively, and these compounds also showed low cytotoxicity to the mammalian cells WI-38 with IC 50 values of 8.8, 4.0 and 5.4 µM, respectivley. More prominently, fortunilide E (38) containing a peroxide group showed antiplasmodial activity of 43 nM with no cytotoxicity at 100 µM.
This review also describes 25 antimalarial compounds that were reported from marine plants during the time period covered. In addition, we included ethnologic information on antimalarial plants from 50 families that are used as folk medicines for the treatment of malaria. Taken together, all the information presented attests to the fact that the phytochemical investigation of terrestrial plants coupled with the biological validation of ethnomedicines constitute proven strategies for the discovery of potential lead compounds for antimalarial drug development.
Author Contributions: All authors contributed to surveying the literature, preparation and editing of the manuscript.