Potential antimalarials from African natural products: A reviw.

Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Resistance to antimalarial drugs has become one of the most momentous challenges to human health, and thus has necessitated the hunt for new and effective drugs. Consequently, few decades have witnessed a surfeit of research geared to validate the effectiveness of commonly used traditionally medicines against malaria fever. The present review work focuses on documenting natural products from African whose activity has been reported in vivo or in vitro against malaria parasite. Literature was collected using electronic search of published articles (Google Scholar, PubMed, Medline, Sciencedirect, and Science domain) that report on antiplasmodial activity of natural products from differernts Africa region. A total of 652 plant taxa from 146 families, 134 isolated antimalarial compounds from 39 plants species, 2 herbal formulations and 4 insect/products were found to be reported in literature from 1996 to 2015. Plants species from family Asteraceae (11.04%), Fababceae (8.128%), Euphorbiaceae (5.52%), Rubiaceas (5.52%), and Apocyanaceae (5.214%), have received more scientific validation than others. African natural products possess remarkable healing properties as revealed in the various citations as promising antimalarial agents. Some of these natural products from Africa demonstrate high, promising or low activities against Plasmodium parasite. This study also shows that natural products from Africa have a huge amount of novel antimalarial compounds that could serve as a leads for the development of new and effective antiplasmodial drugs. However, in a view of bridging the gap in knowledge, clinical validation of these natural products are of paramount importance.

INTRODUCTION

Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Over the last decade, prevalence of malaria has been increasing at an alarming rate, especially in third world countries. According to the rescent reports 3.3 billion peoples are at risk of contacting the infection of which 1.2 billion are at high risk. In 2013, an estimated 198 million cases of malaria with 755,000 deaths, 90% of which occur in Africa were documented [1]. According to Joy et al. [2], in Africa 3000 children die of malaria daily. Nigeria, the giant of Africa has been reported with the highest prevalence of malaria cases in African region, with all-year round transmission in the South, and more seasonal in the North [3]. About 60 million Nigerians, have malaria more than once in a year, with pregnant women and children (under 5 years) being more susceptible to the attack due to their low resistance and therefore constitute 92% of the prevalence [4].

The species of Plasmodium vivax, Plasmodium ovale, Plasmodium Malariae, and Plasmodium falciparum have been implicated in the etiology of the infection [5]. However, the control of these parasites using synthectic antimalarial drugs such as primaquine and chloroquine have been hindered by rapid parasite resistance to these drugs over the few decades [3]. The drug resistance developed by these parasites has therefore necessitated the hunt for more effectual antimalarial agents from natural products. In malaria endemic countries of the world, natural and traditional products (plants and insects/products) are commonly used arsenal to to combat malaria [6]. Therefore, there exists a brawny thought that if these natural products used by the traditional herbalists were not helpful, malaria would have shattered Africa long time ago [7]. Following an extensive survey of the literature, Willcox and Bodeker [8], documented over 160 families of plants with over 1200 species traditionally used for malaria treatment, some of which have been scientifically validated in vitro and/or in vivo for their claimed activity against the infection. Furthermore, conventional antimalarial drugs such as: Quinine and artemisinin were originated from plant extracts: Cinchona calisaya [9] and Artemisia annua [10], respectively. This has enthused many researchers especially in Africa to further intensify the search for antimalarial agents from plant/insect compendium. Currently, the available review on anti-malarial agents focus only on Nigerian plants [11,12], alkaloids, and terpenoids only [5]. This paper has been presented to detail the efforts of African scientists toward finding more effective and cost efficient antimalarial agents from plants and insect (natural products). This will serve as an updated source for recent progress in the recognition of promising antimalaria agents. This paper will also motivate and served as point of reference for scientists, who are willing to work on the subject matter.

MATERIALS AND METHODS

Information for this study was obtained as described previously [11,13], using electronic search of published articles on Google Scholar, PubMed, Medline, Sciencedirect, Science domain. The search keywords include malaria, antimalarial, ethnobotany, African medicinal plants, natural product, antimalaria compounds, suppressive, curative, in vitro, in vivo, P. falciparum, and P. berghei. Informations documented on the natural products reviewed in here include the plant species, family, part of the plant used, extraction solvent, methods of antimalarial study (in vivo/in vitro or suppressive/curative), strain of the parasite tested, degree of activities and isolated compounds of African grown natural product from 1996 to 2015. Natural products whose level of antimalarial activities was not indicated by author, as well as that were reported outside African countries were completely excluded from this study.

RESULTS AND DISCUSSION

Figure 1 presented the regional distribution of African plants with antimalaria activities. A total of 652 plant species from 146 families and 4 insects/products were found. The activities of 558 plants were found to be reported in vivo, while 94 were reported in vivo. Plants species from family Asteraceae (11.04%), Fababceae (8.128%), Euphorbiaceae (5.52%), Rubiaceas (5.52%), Apocyanaceae (5.214%), Rutaceae (4.90%), Anonaceae (3.844%), Meliaceae (3.844%), Lamiaceae (3.52%), Combrataceae (2.76%), and Poaceae (2.60%) have received more scientific validation than others. About 36.80% of plants reviewed were grown in West Africa especially Nigeria, Bennin, 31.90% from South Africa, 13.03% from North Africa, 10.88% from Central Africa while 7.36% of the plants were grown from East Africa. The species, family, part use, extraction solvent, as well as inhibitory concentration 50% (IC50) or minimal inhibitory concentration of in vitro assayed plant were presented in Tables 1-5. Datas on in vivo assayed plants were shown in Table 6. Phyto-chemistry studies of the anti-malarial plants led to the isolation of 134 specific antimalarial compounds from 39 plants species (Table 7).

Figure 1

Malaria cases and death in Africa: Countries with negligible burden, such as Algeria, Botswana, Cape Verde, Egypt, Eritrea, Mayotte, Morroco, Swaziland, and South Africa, are not shown

Table 5

Anti-malarial activity of plants from Central Africa

Table 6

Anti-malarial activity of isolated compounds from African plant

Table 7

In vivo antiplasmodial activities of African plants

For the purpose of this work and in accordance with WHO guidelines [14], antimalarial activity of plant extract reviewed in here was classified as highly active (IC50 < 5 µg/ml), promising activity (IC50 = 5-15 µg/ml), moderate activity (IC50 = 15-50 µg/ml), while extract with IC50 > 50 µg/ml were considered to be inactive. Furthermore, some authors presented their results in form of parasite inhibition at particular dose; however, degree of activities reported for such plants could not be classified.

Regional distribution of African plant with potential antimalarial activities

Anti-malarial Activity of Plants from West Africa

Out of the total 170 plants species (53 family) found in West Africa, only 23 were highly active (IC50 < 5 µg/ml). The most outstanding activity were demonstrated by methanol stem barks extract of Parkia biglobosa (IC50 = 0.51 µg/ml) [15]. Ether leaf extract of the Tithonia diversifola (IC50 = 075 µg/ml) [16], aqueous (AQS) leaf extract of the Nauclea latifolia (IC50 = 0.60 µg/ml) [17], and Guiera senegalensis (IC50 = 0.79 µg/ml) [18]. The high antiplasmodial activities demonstrated by these plants render them a good candidate for the identification and isolation of anti-malarial compounds that could serve as a backbone for drug development [13]. A total of 27 plants species demonstrate promising activity (IC50 = 5-15 µg/ml), 55 plants species demonstrate moderate activity (IC50 = 15-50 µg/ml), while extract from remaining plant species were inactive (IC50 > 50 µg/ml).

It is generally known that the bioactive constituents of plant extracts varies with the solvent used in the extraction process [19,20]. These variations were observed in antimalarial activity of West Africa plant. For example dichloromethane (DCM) extracts from leaf of Celtis integrifolia show promising activity (IC50 = 10.0) while the methanol and AQS extract were moderately active (IC50 = 30.2 and 38.4) against Pfk1 [21]. DCM extract from aerial part of Acanthospermum hispidum show promising activity (IC50 = 7.5) while the methanol extract were completely inactive (IC50 = 55.6) against P. f3D7 [22]. DCM extract from leaf of Carica papaya was highly active (IC50 = 2.6) while the aqueous extract was inactive [23]. The differences reported in antiplasmodial activities with variations in extraction solvent reflect the differences in the availability and concentration of bioactive agents in the extracts [13]. Although traditional healers commonly use water in preparing plants extract for medicinal application, it is surprising that most of the AQS plants extracts reported were either inactive poorly active. These poor activities could be explained by the fact that the AQS extracts were not prepared according to the traditional methods, which often involves boiling for several hours [24].

Structure of some antimalarial chemical compounds isolated from African plants

A total of 64 compounds from extracts of West African plants were reported for antiplasmodial activities. Alkaloids, flavonoids, quinines, terpenes, triterpenoids, polyphenols, and to a lesser extend sterols are the most common implicated phytochemicals in the extracts. Out of the 64 compounds isolated from West African plant 28 were highly active (IC50 < 5 µg/ml), 11 demonstrate promising activity (IC50 = 5-15 µg/ml), 4 shows moderate activity (IC50 = 15-50 µg/ml) while others were completely inactive in vitro against malaria parasites. The most interesting results were those of Simalikalactone D from leaf of Quassia amara [25], Samaderines B, X and Z from stem of Quassia indica [26], Picratidine and Picranitidine from seed of Picralima nitida [27], gedunin from leaf of Azadiracta indica [28], Fagaronine from roots of Fagara zanthoxyloides [29] and Ellagic acid from leaf of Alchornea cordifolia [30]. All these compounds excerpt high antiplasomodial activity with IC50 < 0.1 µg/ml.

Anti-malarial Activity of Plants from South Africa

Although literature survey revealed a very few researcher (working on antimalaria potency of indigenous plants) from South Africa, Quantitatively South African plants were the most in vitro investigated (198 plants from 59 families) plants from Africa. However, only 16 of the plant extracts from this region were highly active (IC50 < 5 µg/ml), 54 demonstrated promising activity (IC50 = 5-15 µg/ml), 39 demonstrate moderate activity (IC50 = 15-50 µg/ml), while others were inactive (IC50 > 50 µg/ml) in vitro against plasmodial parasite. Although AQS leave extract of Vahlia capensis, Nicolasia costata, and Dicerocaryum eriocarpum exhibit 48.0%, 26.6%, and 21.5 48% parasite inhibition at 50 µg/ml [59], their level of activities could not be ascertained. A total of 15 compounds were isolated from South African plant, 7 of which demonstrated high activities (IC50 > 5 µg/ml) while others show promising activities (IC50 5-15 µg/ml). The most highly active compound is 13-epi-dioxiabiet-8(14)-en-18-ol isolated from leave extracts of Hyptis suaveolens (IC50 = 1.0 µg/ml) [60]. Despite the traditional use against malarial fever, most of the plants reviewed show no noticeable antiplasmodial activity, the traditional uses of this plant against malarial infection could only be linked to their antipyretics or immune modulatory effect to alleviate the malarial symptoms rather than exerting direct antiplasmodial activity [61].

Anti-malarial Activity of Plants from North Africa

Appreciable amounts of plants were found in north Africa, out of the 79 plants found in this region only 4 plants had IC50 > 5 µg/ml (highly active), although IC50 not documented, 100% inhibition were documented for methanol extract from Helianthus annus seed at 4 µg/ml and methanol fruit extracts of senna alexandrina at 2 µg/ml [65], the activities demonstrated by this plants could be considered highly active if compared with the WHO guideline. However, Pet ether/chloroform extract from Aerva javanica, Aristolochia bracteo-lata, Gardenia lutea, Citrullus colocynthis, and Nigella sativa from Sudan show 100% parasite inhibition at 500 µg/ml [66]. Despite the significant parasite inhibition demonstrated by these plants, there activities could be classified under not active due to large dose of extract. A total of 23 compounds were isolated from north African plant, this extracts demonstrate interesting and varied antiplasmodial activities, however, the most noticeable activities is 3’,4’,7-trihydroxyflavone (IC50 = 0.078 µg/ml) from Albizia zygia against Pfk1 [67].

Anti-malarial Activity of Plants from East Africa

Only 44 plants from East Africa were reviewed for in vitro activities against malarial parasite. 15 plants extracts reviewed from this region had IC50 > 5 µg/ml (highly active), 4 extracts had IC50 = 5-15 µg/ml (promising active), 32 extract had IC50 = 15-50 µg/ml (moderate active), while others were inactive (IC50 > 50 µg/ml).

Anti-malarial Activity of Plants from Central Africa

The majority of the plants grown in this region show very poor activities against Plasmodium parasite.

Out of 67 plants found to have been studied for anti-plasmodial (in vitro) activity in Central African, only 17 extracts from the plants demonstrate high antiplasmodial activity (IC50 value < 5 µg/ml). The most noticeable activities was demonstrated by AQS leaf extract of Quassia africana IC50 = 0.46 µg/ml [76] and methanol root back extract from Strychnos icaja, IC50 = 0.69 µg/ml [77]. How ever 15 out of the 17 isolated compounds from central Africa were highly active (IC50 value < 5 µg/ml) against Plasmodium, the most noticeable compounds were TCA1 to TCA4 isolated from DCM leaf extract of Cassia alata and TOG1 to TOG7 isolated from DCM extracts of Ocimum gratissimum from Congo [78], as well as palmitine from stem bark extract of Penianthus longifolius from Cameroon [79], all these compounds excerpt there in vitro antimalarial activities with IC50 < 1 µg/ml.

African Plants with Ameliorative Effects on Plasmodial-Induced Pathological Changes

Histopathology

Methanol bark extract of Chrysophyllum albidum (750-1500 mg/kg/day) exhibited significant antiplasmodial effects both. The extract also ameliorated the liver pathological symptoms of enlarged liver, hepatocellular necrosis, aggregations of periportal mononuclear cell, and Kup-ffer cell hyperplasia that were severe in the untreated mice [129].

Histological study of kidney and pancreas of P. berghei infected rat treated with Mormodiaca charantia (100 mg/kg) revealed and mild atropy of the glomeruli and mild degeneration of the islet of langerhan as oppose to severe degeneration observed in untreated controls [131]. Aframomum sceptrum leaf extract (350 mg/kg) shows moderately brought central vein, hepatic cell with preserved cytoplasm and prominent nucleus as oppose to severe effect expressed by the parasitized untreated mice [163]. Histological study on P. berghei parasitized rats treated with methanol extract from leaves of Acalypha wilkesiana reveals that the extract may excerpt meso hepatoprotective effect during malarial infection as there were no observable cellular defects on the liver histo-structure as observed in there untreated control [164].

Liver photomicrograph study of Plasmodium berghei infectedmice treated with ethanol extract from stem bark of Ficus platyphylla at 300 mg/kg shows the clearance of K¨upffer’s cells-laden malaria pigment and normal lobular architecture as opposed to the dilated hepatic sinusoids congested with hypertrophied, K¨upffer’s cells-laden malaria pigment and parasitized red blood cells that were observed in untrated mice. The extracts also produced chemosuppression of 43.50% and increase the life span of the mice (28 days) [141].

Biochemical parameters

Methanol bark extract of Chrysophyllum albidum has been reported to prevented hyperproteinemia due to hyperglobulinaemi in P. berghei parasitized mice (Adewoye et al., 2010). According to Ketema et al. [128], administration of at 300 mg/kg to P. berghei infected rats significantly elevated the activites of serum aspartate aminotransferase (AST), alanine transaminase (ALT) and decrease albumin level compare to the controls. There reports could be translated that administration of that following malarial infection could increase the risk of jaundice or jeopardized the integrity of renal and liver functions.

Recently, Akanbi, [109], investigated AST, ALT, and ALP activities in heart and liver of P. berghei parasitized mice treated with Anogeissus leiocarpus methanol extract at 100 and 200 mg/kg. There results revealed that the extract at 200 mg/kg was not able to prevent the parasite induced alteration in the organs (heart and liver) ALP, ALT, and AST activities. However, the activities reported at 100 mg/kg were comparable with the normal control mice. These findings could be explained by our earlier discussion, that natural products excert dose dependent effect, the extract A. leiocarpus at 100 mg significantly prevented P. berghei induced organs damage, this could be an interaction between the infective condition and the constituents of the extract. A. sceptrum extract (250 and 350 mg/kg) when administered to P. berghei infected mice prevent parasite induced liver damage by preventing the elevations of liver and serum ALP, AST, and ALT, than in parasitized mice. The extract was able to preserve the ALT activity to a comparable level with the normal rat [166]. Methanol leaf extract of A. wilkesiana significantlyameliorated parasite-induced oxidative stress as revealed by significant reduction in liver malondialdehyde and reversed effects on reduced superoxide dismutase, glutathione-P (GSH-P), reduced-GSH and catalase as reported in the parasitized untreated rats [164].

Hematology

Balogun et al., 2012 evaluated the effectiveness of M. charantia (100 mg/kg) in ameliorating biochemical and histological alteration in malarial and diabetic co-infected rats, and reported that the extracts improved the packed cell volume (PCV), hemoglobin (Hb), and red blood cell (RBC) of the mice comparable with the chloroquine treated mice. According to Balogun et al. [129], ethanol leaf extracts from Clerodendrum violaceum at 13 mg/kg for 14 days significantly improved the P. berghei induced alteration in RBC, PCV, Hb, white blood cell (WBC), and platelet count of infected mice. Methanol leaf extract from Nigerian Abrus precatorius at 25-100mg/kg also improve weight gain, RBC, Hb, MCV, and MCH of P. berghei infected mice [32]. Methanol extract from Catha edulis obtained from Ethiopia, when administered to P. berghei infected mice at dose of 300 mg/kg reduced the levels of hematological parameters including platelets count, WBCs and Hb levels [128]. Ethanol extract from leaves of H. suaveolens had a dose dependent effect on P. berghei in infected mice with chemosuppresion of 10.22% and 33.69% at 25 mg/kg and 42.7% and 18.03% at 50 mg/kg against established and early infection respectively. The extract was however unable to prevent parasite induced anemic condition as indicated by significant reduction in RBC, HB, and PCV of the treated mice [140]. Crude extract from Croton macrostachyus prevented weight loss but produce no ameliorative affect on hematocrite of P. berghei infected mice [172].

Antiplasmodial Activity of Insect/Products

While more than 95% of African scientist who works on validating the therapeutic claims of natural product against infectious and protozoan disease focused on plants very few documentation [167,168,173, 178], exist on validation of other natural products like insect against malarial disease.

Musca domestica

Adult houseflies (M. domestica) are known as carriers of disease, supprisingly in the study of Shittu et al. [167], methanol extract from fourth instar stage (maggot) of the fly was able to suppressed P. berghei replication, improved mice life span (34 days) and ameliorated parasite induced anemia when evaluated for it antimalarial activities at 600 mg/kg against P. berghei parasitized mice. Maggot of housefly has also been reported to be effective against other protozoan disease [18]. This is not supprising as several literatures have documented the therapeutic effects of house fly maggot. Clinically, live maggots has been used to aid wound healing back then in 19thCentury (Maggot Debridement Therapy), traditionally it has been reported to be used as antibacterial, antiviral, anti-osteomyelitis, anti-decubial necrosis, antitumor, anti-immunosuppressive agents and also for curing malnutritional stagnation [169-172].

Honey bee

Shittu and Eyihuri [173], evaluated the antiplasmodial effect of bee sting, from their reports P. berghei paeasitisized mice were treated with intradermal bee sting. According to their results bee stings produce 56.6% chemosupression and prolong the lifespan to 20 and 15 days for early and established infection, respectively. The hematological studies show that the level of packed cell, the bee sting also improved the PCV, HB, RBC compared to untreated control, the bee sting however was reported to increase the WBC of the mice. Their study justify the traditional believe that mild honey bee attacked could be useful against malarial fever, however, the bee sting induced elevation of WBC reported by Shittu and Eyihuri [170], point out immunostimulatory effect of the constituent release from the bee sting.

Honey and propolis

Although honey from Apis florea and Apis andreniformis, were reported to excert no significant activity at 10 ug/l when tested against pfk1 parasitized mice ethanol extract of propolis from the same species exhibit significant activities with IC50 value of 4.48 g/ml [174]. Olayemi [178], also administered bee propolis to P. berghei parasitize rat at dose of 600 mg/kg and reported that the extract significantly inhibited the parasite replication and improve the PCV of the mice.

Herbal Formulations

UDU

Duru et al. [173], studied the effect of “udu,” an herbal preparation commonly use to treat malaria by Isiala Mbano people of Imo State, Nigeria on visceral organ, lipid profiles, and weight of rats. There results revealed that the herbal preparation produces no significant effect on organs. However, blood lipid profile parameters were altered in test rats compared with the reference value [176].

Saabmal

Antimalarial herbal formulation called SAABMAL was investigated at 200 and 400 mg/kg against P. berghei infected mice in a four days suppressive test. The formulation was able to suppress the (29.39-100%) parasite replication in a dose-dependent fashion. The formulation was also more effective than chloroquine in prolonging the survival time of mice [177].

CONCLUSION AND FUTURE PROSPECTS

This study has documented the list of African natural products with potential antimalaial activities. Some of these natural products demonstrated, high, promising, or low activities against Plasmodium species. Some of the plant ameliorated the parasite induced pathological changes while few others did not. The study also shows that natural products from Africa have a considerably huge amount of novel antimalarial compounds that could serve as a lead for the development of new and effective antiplasmodial drugs. It is hoped that pertinent scientist stakeholders will look further into some of these compounds for detailed authentication and subsequent commercialization. However, despite incessant comprehensive and mechanism-orientated assessments of Africa natural products, there is still inadequate information concerning procedures to be adopted for quality control, authentication and standardization of crude plant products. Furthermore, in a view of bridging the gap in knowledge, clinical validation of some of these natural products is of paramount importance.

Table 1

In vitro antimalarial activities of West African plants

Table 2

In vitro antimalarial activities of South African plants

Table 3

In vitro antimalarial activities of North African plants

Table 4

In vitro antimalarial activities of plants from East African