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265References
Medicinal Plants as Anti-infectives
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CHAPTER
8
Medicinal plants from West Africa
used as antimalarial agents: an
overview
Agne
`
s Aubouy
1
, Aissata Camara
2
and Mohamed Haddad
1
1
UMR 152 PharmaDev, Universite
´
de Toulouse, IRD, UPS, Toulouse, France
2
Institute for
Research and Development of Medicinal and Food Plants of Guinea (IRDPMAG), Dubre
´
ka,
Guinea
Introduction
Despite a decrease in malaria mortality over the last 10 years due to extensive malaria
control through insecticide-impregnated bednets and increased use of artemisinin deriva-
tives, malaria prevalence and burden in terms of morbidity and mortality is still extremely
high. In 2019 the World Health Organization (WH O) reported 229 million cases of malaria
and 409,000 deaths worldwide, the vast majo rity of which occurred in sub-Saharan
African region (94% of malaria cases and deaths). African children pay the heaviest price,
since they accounted for 67% (274,000) of all malaria deaths worldwide
(WHO, 2019).
Numerous factors contribute to the complexity of this pathology and the difficulty of
eradicating it, an objective that has already been claimed several times by the WHO in the
past through the “roll back malaria” initiative. These factors include the Plasmodium para-
site, the Anopheles vector, the human host, and the socio-geographical environment.
Plasmodium is an extremely complex parasite with a high genetic diversity, in particular,
due to its sexual multiplication. P. falciparum, the far most widespread and most danger-
ous species in sub-Saharan Africa, has a tremendous antigenic variability, which compli-
cates vaccine research. Such genetic diversity is also a key factor in the emergence of
parasites resistant to the antimalarial drugs used in a given area. Vector control is similarly
hampered by the development of insecticide-resistant mosquitoes. The human host also
offers a genetic and immunological complexity that contributes to a range of various clini-
cal expressions of P. falciparum malaria. Finally, the geographical, economic, and social
267
Medicinal Plants as Anti-infectives
DOI:
https://doi.org/10.1016/B978-0-323-90999-0.00014-8 Copyright © 2022 Elsevier Inc. All rights reserved.
environment of a given area contributes to the level of transmission, which in turn affects
the level of immunity of the population, the effectiveness of the health system in the man-
agement of malaria, the means of control deployed, including the type of antimalarial
drugs and insecticide used, the level of access to health care for the population, and so on.
In West African countries, the main characteristics of the malaria problem are a high level
of transmission, parasite resistance to most antimalarial drugs available on the pharmaceuti-
cal market (except for artemisinin-based combination therapies at the moment), the resis-
tance of Anopheles to insecticides, and limited access to health care. Natural products and
more particularly plant-derived products constitute an enormous reservoir of bioactive
molecules with novel biological targets and mode-of-action. The malaria field has already
benefited from such biodiversity with quinine extracted from Cinchona bark, and artemisinin
from Artemisia annua leaves, two molecules that are extremely active on Plasmodium falcipar-
um, still in use today, and which have resulted in several derivative molecules by synthesis
or hemisynthesis. Plant-derived compounds are therefore one of the answers to face the
problem of the scarcity of effective antimalarial molecules due to the selection of resistant
parasites. However, herbal products are not only molecules but also preparations based on
whole plants or parts of plants (herbal teas, decoctions, etc.). The use of such preparations is
commonly linked to strong cultural practices and offers the advantage of public acceptance
and easy access (low cost, availability in markets and small shops). Thus, there are two
ways to deal with the issue of medicinal plants traditionally used against malaria:
• the search for new active molecules to feed the antimalarial drug pipeline. This way is
long and expensive, but it is how two of the most widely used molecules for the
management of malaria were discovered: quinine and artemisinin.
• the evaluation and validation of the use of whole plant or plant part preparations.
However, the use of this type of preparation raises the problem of the quality of the
remedy, linked to the origin of the plant, the storage method of the plant, the method of
preparation, the dosage used, and so on. Indeed, the chemical composition of a plant is
influenced by genetic, agricultural, and environmental factors. If the content of the main
active molecules is altered, the efficacy may be impacted. To circumvent this difficulty,
the standardization of these remedies may be a solution. However, this would have an
impact on the cost of such products, thereby limiting their value in terms of lower cost
and wider access for the poorest populations. Thus, given that malaria is a fatal disease
and that effective drugs exist, the recommendation of plant-based preparations that are
difficult to standardize raises obvious ethical questions.
This chapter will focus on the medicinal plants from West Africa used as antimalarial
agents. West African countries explored here are malaria-endemic areas, and for which
data are available on the use of antimalarial plants. It includes, from the West to the East:
Senegal, Cape Verde, The Gambia, Mali, Guinea-Bissau, Guinea, Sierra Leone, Liberia,
Ivory Coast, Burkina Faso, Ghana, Togo, Benin, Niger, and Nigeria. In this chapter, we
will discuss the traditional use of plants against malaria, and present the plants scientifi-
cally validated for their antimalarial activity, in the form of plant extracts (from traditional
preparations or chemical solvents), or isolated molecules. Finally, we will discuss the spe-
cial case of Artemisia afra and A. annua, two plants of Chinese origin and not endemic to
West Africa, whose use as an antimalarial is beginning to spread to this part of the world.
268 8. Medicinal plants from West Africa used as antimalarial agents: an overview
Medicinal Plants as Anti-infectives
Traditional use of medicinal plants in West Africa
Traditional Me dicine is defined by the sum total of knowledge or practices whether
explicable or inexplicable, used in diagnosing, preventing, or eliminating a physical, men-
tal, or social disease which may rely exclusively on past experience or observations
handed down from generation to generation, verbally or in writing. It also comprises ther-
apeutic practices that have been in existence often for hundreds of years before the devel-
opment of modern scientific medicine and are still in use today without any documented
evidence of adverse effects.
The rich flora of West Africa has been known in Europe since the first contact with the
populations of the Gulf of Guinea by the Portuguese in the 15th century and represents an
inexhaustible source of remedies available to the population. This richness of West African
flora is notably linked to two different environments: the tropical forest along the coast, and
the savannah in the hinterland (
Oguakwa, 1980). Thus, it is estimated that there are 300,000
plant species in the world, of which more than 200,000 are found in the intertropical zone,
including West Africa (
Abayomi, 2010). In the absence of modern western medicine, tradi-
tional African medicine provided most of the health needs of the population during the pre-
colonial period. In Africa, a large majority of the population uses only local plants to treat
themselves for various reasons: lack of essential medicines, lack of access to so-called “mod-
ern” medicines, inadequate health care, lack of proximity to health centers, and high cost of
medicines. Moreover, sociocultural practices are also to be taken into account in the success
of the widespread use of traditional medicine, since it is an integral part of the culture of the
people who rely on it. The use of plants for treatment is an ancestral practice, particularly in
Africa, and frequently there is an oral transmission of knowledge from generation to genera-
tion to certain categories of initiates such as traditional practitioners and herbalists.
According to 2008 world statistics, West Africa has about 1.5 doctors for every 10,000
inhabitants, whereas the ratio in France, for example, is 6.6 for the same number of inhabi-
tants
(WHO, 2008) (Fig. 8.1). Furthermore, it is estimated that there are more traditional
healers (100 times more) than conventional doctors or nurses in the region, and a high pro-
portion of the 300 million West Africans exposed to malaria prefer to use inexpensive and
handy traditional medicines when they have malaria symptoms rather than seeking treat-
ment from the formal health system (
Bodeker & Kronenberg, 2002; Soh & Benoit-Vical,
2007
). In terms of health expenditures, a West African spends between $10 and $40 on
medical care per year, whereas in France this amount is $4719 (more than 100 times). In
this context, the contribution of traditional medicine in the fight against certain patholo-
gies, in particular malaria represents an important asset for the well-being of populations.
Regarding malaria, the treatments available are mainly based on the use of traditional
herbal remedies. However, there is a lack of data on their efficacy and safety, while the valida-
tion of traditional practices could lead to innovative strategies in malaria control. Moreover,
natural products from plants or other organisms represent an almost inexhaustible reservoir
of molecules, most of which are poorly explored and may constitute lead molecules for new
antimalarial drugs, such as artemisinin, initially isolated from Artemisia annua (
Kayser &
Kiderlen, 2003
). The West African region has incredible biodiversity and many indigenous
plants are used as antimalarial agents, although few formal studies have examined the safest
and most effective dosages and delivery mechanisms (
Soh & Benoit-Vical, 2007).
269Traditional use of medicinal plants in West Africa
Medicinal Plants as Anti-infectives
Through ethnopharmacology, it is possible to validate traditional uses, especially for anti-
malarial plants. In West Africa, four families of plants are widely used as antimalarial reme-
dies: plants of the Combretaceae, Euphorbiaceae, Meliaceae, and Rubiaceae families (
Soh &
Benoit-Vical, 2007
). The Euphorbiaceae family includes species such as Jatropha sp. or
Ricinus sp., used against fever or malaria by populations in three continents: Africa, South
America, and Asia; while Meliaceae and Rubiaceae are used in Africa and South America.
Fig. 8.2 shows the main antimalarial plants listed in the West African pharmacopoeia.
However, despite the richness of the West African pharmacopoeia, the majority of plant
extracts used in traditional medicine are still produced using ancient traditional methods that
do not always guarantee the efficacy, stability, and safety of the remedy. One of the most diffi-
cult but crucial tasks in the search for new antimalarial drugs from traditional medicine is the
selection of plants or compounds that have the best chance to produce safe and effective anti-
malarial drugs for use in phytomedicine. For this purpose, it is therefore essential to evaluate
the efficacy of the isolated plants and compounds by in vitro and in vivo approaches.
Plant extracts and plant compounds validated by in vitro and/or in vivo
approach
To confirm the antimalarial effect of a plant, several factors should be considered:
1. From an ethnopharmacologic perspective, the traditional way of use needs to be
known, particularly for the following points:
The part of plant used: the whole plant may be used, but usually a specific part of
the plant is used: roots, all aerial parts together, the stem, the leaves, the flowers, and
the root or stem bark.
FIGURE 8.1 Density of medical doctors in West Africa. Data are from the latest available year ranging from
2004 to 2019 (WHO,2008).
270 8. Medicinal plants from West Africa used as antimalarial agents: an overview
Medicinal Plants as Anti-infectives
The mode of preparation: a plant-based preparation can be an infusion, a decoction,
a maceration, or an extraction of juice. This point is of high importance for validating
the traditional preparation. The nature of the extracted molecules present in the
preparation depends on the method of preparation. The preparation may also involve a
phase of shaking or crushing the plant.
Infusion: simmering or boiling water (or brought to an appropriate temperature) is
poured over the herb, before an appropriate incubation time in the liquid. Decoction: the
plant is immersed in cold water and then the mixture is boiled for an appropriate time,
before being left to infuse for a defined period of time. Maceration: room temperature
liquid (usually water or alcohol) is poured over the herb and left to macerate during a
defined period of time.
FIGURE 8.2 Main antimalarial plants listed in the West African Pharmacopoeia.
271Plant extracts and plant compounds validated by in vitro and/or in vivo approach
Medicinal Plants as Anti-infectives
The mode of absorption: it can also vary and includes absorption by oral route, body
bath, drop in eyes or on the skin, and so on. In this chapter, only orally absorbed plants
will be discussed.
The use of the plant alone or mixed with other plants: plants are also often mixed
with others to combine effects against several symptoms, like fever and malaria, or to
potentialize the activity.
2. From a research perspective, the method used to test the plant has to be known to get
an idea of the comparability of the results. Thus, the main elements to know are the
following:
The method of extraction used: depending on the purpose of the study, the researchers
will test the traditional preparation or other modes of plant extraction. The traditional
preparation will be studied to validate a traditional use. To isolate and identify the bioac-
tive molecules in a complex mixture of compounds, specific plant extracts will be pre-
pared and bioguided fractionation will be carried out. This involves testing the activity of
less and less complex fractions until a single molecule is identified. The nature of the sol-
vent chosen for extraction determines the type of molecule that will be present in the sol-
ute. A solvent will extract molecules whose polarity is close to its own polarity, according
to the law of similarity and intermiscibility (like dissolves like). Water, alcohol (ethanol,
methanol), chloroform, pentane, hexane, and methylene chloride are the main solvents
used for extraction and isolation of plant products. Please, see the review proposed by
Zhang, Lin, and Ye (2018) for more details about the different types of extraction pro-
cesses. More recent techniques, such as dereplication, metabolomics, and molecular net-
working, allow also us to identify bioactive molecules from a complex extract (
Chassagne
et al., 2018; Vial et al., 2020
).
The biological test used: unfortunately, research teams do not follow a unique method
to evaluate antimalarial activity of plants. Each team adapts his method according to its
means, material, and biological facilities. Three types of antimalarial activities can be mea-
sured: in vitro, in animal models, or in humans through clinical assays.
In vitro antimalarial evaluation of plant extracts
In vitro, antimalarial activity is measured by incubating the plant preparation with P.
falciparum strains. Parasite strains used are the most often lab strains, but some teams
also test P. falciparum isolates from patients. In vitro c ulture conditions may also differ
from one lab to the other. The main used P. falciparum lab strains are the chloroquino-
resistantK1,FcB1,Dd2,andW2,andthechloroquino-sensitive 3D7, FCM29, and D6.
These lab strains di ffer by their geographical origin and their resistance phenotype
toward antimalarial reference molecules as chloroquine. Finally, the level of antimalarial
efficacy is assessed by measuring the concentration that inhibits the growth of the para-
site by 50% called IC
50
. In addition, laboratories frequently measure the toxicity of the
extract or molecule on human cells, in order to calculate the selectivity index, which is
equal to the cytotoxic dose over the antimalarial dose. Again, the methods differ between
laboratories in the choice of cells used for t he cytotoxicity measurement, either primary
cells or cell lines.
272 8. Medicinal plants from West Africa used as antimalarial agents: an overview
Medicinal Plants as Anti-infectives
Among the plants we have listed in Table 8.1, six families of plants have been the most
worked on in vitro, with four to nine species per family tested for their antiplasmodial
activity in vitro: Asteraceae, Combretaceae, Euphorbiaceae, Fabaceae, Meliaceae, and
Rubiaceae. Twelve species presented interesting IC
50
s for their crude extracts, below
0.1 μg/mL. However, these results are interesting if the selectivity index is relati vely high
( . 25), which reduces the number of species to six, as follows: Enantia polycarpa
(Annonaceae), Acalypha wilkesiana (Euphorbiaceae), Phyllanthus fraternus (Euphorbiaceae),
Tectona grandis (Lamiaceae), and Bambusa vulgaris (Poace ae). Unfortunately, many studies
do not report the selectivity index. These species were tested on the chloroquine-sensitive
strain 3D7, except for Enantia polycarpa which was tested on the chloroquine-resistant
strain K1. It is unfort unate that the teams do not systematically test the extracts on
two strains, one chloroquine-sensitive and the other chloroquine-resistant. It will also be
interesting in the future to work with artemisinin-resistant strains.
In vivo antimalarial evaluation of plant extracts
In vivo, the most often rodent models are used, either mice or rats, infected by murine
Plasmodium strains. Depending on both the genetic background of the mouse and on the
Plasmodium species, the infection will be more or less severe, and parasitemia more or less
high (
Li, Seixas, & Langhorne, 2001; Wykes & Good, 2009). There are four species of
rodent malaria: P. chabaudi, P. vinckei, P. berghei, and P. yoelii and various strains (e.g., P.
yoelii YM, P. yoelii 17XNL, P. chabaudi chabaudi AS, P. chabaudi adami, P. berghei ANKA)
with different parasite biology and pathogenicity. P. berghei ANKA has the specificity to
cause cerebral malaria characterized by low parasitemia and by the onset of neurological
symptoms followed by death 710 days after infection in the BALB/c, C57BL/6, CBA
mice, whereas its infection resolves in DBA/2j mice. Conversely, P. berghei K173 is lethal
in all four species of mice but without neurological symptoms. P. chabaudi chabaudi (Pcc) is
nonlethal in BALB/c, C57BL/6, CBA mice, causing hyperparasitemia, while Pcc AS is
lethal in A/J and DBA/2 mice. P. yoelii 17XL and YM are lethal in the main species of
mice (BALB/c, C57BL/6, CBA, DBA/2j), wh ereas P. yoelii 17XNL is nonlethal. Finally, P.
vinckei vinckei is lethal in BALB/c mice, but not in the other species of mice.
In murine models (
Table 8.2), 12 plant species were reported for their highly active crude
extracts with parasite inhibition $ 80%. Of these plants, five were toxic to mice or the toxicity
was not documented, reducing the list to Terminalia albida (Combretaceae), Annickia polycarpa
(Annonaceae), Vernonia amygdalina (Asteraceae), Carica papaya (Caricaceae), Ficus thonningii
(Moraceae), Quassia amara (Simaroubaceae), and Triumfetta cordifolia (Tiliaceae). Unfortunately,
none of these plants achieved complete inhibition of parasitemia in the model used.
In vitro and in vivo evaluation of antimalarial compounds
In Table 8.3, molecules isolated from plant extracts were tested for their antiplasmodial
or antimalarial activity. The most interesting molecules presenting with IC
50
values
# 1 μM were the cryptolepine analog (from Cryptolepis sanguinolenta, Periplocaceae), dio-
conpeltine A, habropetaline A, and dioncophylline A and C (from plants of the
273Plant extracts and plant compounds validated by in vitro and/or in vivo approach
Medicinal Plants as Anti-infectives