Received: 27 October 2019 Revised: 14 December 2019 Accepted: 14 January 2020

DOI: 10.1002/ptr.6628

REVIEW

Medicinal plants used in the treatment of Malaria:

A key emphasis to Artemisia, Cinchona, Cryptolepis,
and Tabebuia genera

Samin Mohammadi1,2 | Behzad Jafari3 | Parina Asgharian1,4 | Miquel Martorell5,6 |

7
Javad Sharifi-Rad

1
Faculty of Pharmacy, Tabriz University of
Medical Sciences, Tabriz, Iran Malaria is one of the life-threatening parasitic diseases that is endemic in tropical
2
Student Research Committee, Tabriz areas. The increased prevalence of malaria due to drug resistance leads to a high
University of Medical Sciences, Tabriz, Iran
3
incidence of mortality. Drug discovery based on natural products and secondary
Department of Medicinal Chemistry, Faculty
of Pharmacy, Urmia University of Medical metabolites is considered as alternative approaches for antimalarial therapy. Herbal
Sciences, Urmia, Iran
medicines have advantages over modern medicines, including fewer side effects,
4
Drug Applied Research Center, Tabriz
University of Medical Sciences, Tabriz, Iran
cost-effectiveness, and affordability encouraging the herbal-based drug discovery.
5
Department of Nutrition and Dietetics, Several naturally occurring, semisynthetic, and synthetic antimalarial medications
Faculty of Pharmacy, University of are on the market. For example, chloroquine is a synthetic medication for antimalar-
Concepcion, Chile
6 ial therapy derived from quinine. Moreover, artemisinin, and its derivative,
Unidad de Desarrollo Tecnológico (UDT),
Universidad de Concepción, Chile artesunate with sesquiterpene lactone backbone, is an antimalarial agent originated
7
Phytochemistry Research Center, Shahid from Artemisia annua L. A. annua traditionally has been used to detoxify blood and
Beheshti University of Medical Sciences,
Tehran, Iran eliminate fever in China. Although the artemisinin-based combination therapy
against malaria has shown exceptional responses, the limited medicinal options
Correspondence
Parina Asgharian, Faculty of Pharmacy, Tabriz demand novel therapeutics. Furthermore, drug resistance is the cause in most
University of Medical Sciences, Tabriz, Iran. cases, and new medications are proposed to overcome the resistance. In addition
Email: parina.asgharian@gmail.com
to conventional therapeutics, this review covers some important genera in this area,
Miquel Martorell, Department of Nutrition and including Artemisia, Cinchona, Cryptolepis, and Tabebuia, whose antimalarial activi-
Dietetics, Faculty of Pharmacy, University of
Concepcion, Concepcion, Chile. ties are finely verified.
Email: martorellpons@gmail.com
KEYWORDS
Javad Sharifi-Rad, Phytochemistry Research
antimalarial therapy, Artemisia, drug discovery, malaria, medicinal plants
Center, Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
Email: javad.sharifirad@gmail.com

Funding information
CONICYT PIA/APOYO CCTE, Grant/Award
Number: AFB170007

1 | I N T RO DU CT I O N phases: In the first phase, the pharmacophore or the core structure,

In recent years, despite the advances in treatment strategies, there
are still challenges to discover and develop new therapeutics in order
to improve the quality of life and increase the survival rate (Pan et al.,
2010). Drug discovery and development can be divided into two main
which gives the pharmacological activity, will be identified; in the sec-
ond phase, the identified lead compound will be evolved to a novel
medicine (Giang & Otsuka, 2018). Designing drugs with the highest
selectivity to the target molecule is one of the main concepts of drug
discovery (Gertsch, 2011). In this regard, medicinal plants are among

Phytotherapy Research. 2020;1–14. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons, Ltd. 1
2 MOHAMMADI ET AL.
the key sources to produce new pharmaceuticals with high selectivity
(Balunas & Kinghorn, 2005).
Herbal medicines have advantages over modern medicines,
including fewer side effects, cost-effectiveness, and affordability,
encouraging herbal-based drug discovery (Chakraborty, 2018;
M. Sharifi-Rad et al., 2018). Plants have always had therapeutic appli-
cations. Some of these applications have come to us orally or through
herbal books (Balunas & Kinghorn, 2005; Salehi, Fokou, et al., 2019;
Salehi, Venditti, et al., 2019; J. Sharifi-Rad et al., 2018).
Plants produce several types of metabolites. The secondary
metabolites of plants, such as phenolic compounds and alkaloids syn-
thesized for various reasons such as fighting against pathogens, can
be used for therapeutic purposes (Chakraborty, 2018; Salehi et al.,
2018). Natural compounds can also be useful in identifying the func-
tional pathways of receptors; for example, the acetylcholine receptors
were classified into two distinct categories according to the stimula-
tion of the receptors with muscarine and nicotine isolated from Ama-
nita muscaria fungi and Nicotiana tabacum L., respectively (Gertsch,
2011; Otvos, Still, Somsen, Smit, & Kool, 2019). The isolation of the
materials with pharmacological functions from different parts of
plants was first performed in 1803 where morphine was extracted
from opium. Later, digoxin and quinine were derived from Digitalis
and Cinchona genus, respectively (Balunas & Kinghorn, 2005).
Which plant to start with? The idea to screen the large herbarium
for a specific effect without any clue is not rational, however in some
cases, it is necessary to do this. Another strategy is investigation of
some species of plants which formerly indicated valuable medicinal
applications. Moreover, traditional medicines are the best source to
begin the discovery with (Lemma et al., 2017); for instance, Egyptian
traditional medical books mentioned the application of plant mixtures
in their prescriptions.Additionally, Chinese herbal formulations, which
developed over thousands of years, were evaluated for their thera-
peutic potentials (Gertsch, 2011; Zhou, Li, Chang, & Ben-
soussan, 2019).
Malaria is one of the life-threatening parasitic diseases. The
increased prevalence of malaria due to drug resistance leads to a high
incidence of mortality (Heshmati Afshar et al., 2018). The use of natu-
ral compounds originated from plants is one of the strategies to dis-
cover novel antimalarial agents (Willcox, 2011). Artemisinin was firstly
isolated from Artemisia annua L. in 1972; this molecule and semisyn-
thetic derivates such as artemether, arteether, artesunic acid, and
dihydroartemisinin are quite effective against multidrug-resistant
malaria strains (Dharmendra Kumar et al., 2014; Gaur et al., 2015;
Qidwai, Yadav, Khan, Dhawan, & Bhakuni, 2012; Tiwari, Yadav, &
Chaudhary, 2019). This review introduces some important plants such
as Artemisia spp., Cinchona spp., Cryptolepis sanguinolenta (Lindl.)
Schltr., and Handroanthus impetiginosus (Mart. ex DC.) Mattos (syno-
nym Tabebuia avellanedae Lorentz ex Griseb.), which are frequently
assessed for their antimalarial activities in the literature.
Malaria is a prevalent disease in the tropics and a critical factor in
increased morbidity and mortality in these regions. Parasites of the
Plasmodium genus, including Plasmodium falciparum, Plasmodium vivax,
Plasmodium ovale, and Plasmodium malariae, cause malaria in humans.
According to different drug sensitivity of various species and the
probability of mixed infections, primary diagnosis is essential (Mueller,
Zimmerman, & Reeder, 2007). The detection of malaria infection in
the bloodstream is based on light microscopy, which is suitable for dif-
ferential diagnosis of various Plasmodium species, highly accurate, and
cost-effective (World Health Organization [WHO], 2015). Infected
red blood cells (RBCs) have different appearances depending on the
pathogen that can lead to identifying the type of the parasite (Table 1;
Centers for Disease Control and Prevention, 2019).
According to the World Health Organization report, there were
219 million malaria infection cases worldwide in 2017, which showed
a reduction compared with 2010 (239 million infections). Moreover,
92% of infected cases in 2017 have been reported from African conti-
nent, in which most of the patients were infected by P. falciparum par-
asites. In 2016, malaria caused 451,000 deaths worldwide, whereas
in 2017, this number decreased to 435,000 deaths. Understanding
the malaria parasites' life cycle can lead to a useful treatment discov-
ery. The proliferation and transmission cycles of these parasites were
shown in Figure 1 and explained in the following paragraphs
(WHO, 2018).
Following the infected female Anopheles mosquito bite, sporozo-
ites enter the bloodstream and attack hepatocytes. Sporozoites prolif-
erate in the liver and convert to schizonts, and then schizonts rupture
and release merozoites into the bloodstream (exoerythrocytic cycle).
Merozoites enter the erythrocytes, and the asexual proliferation cycle
begins. Inside the erythrocytes, trophozoites become schizonts, which
then rupture and release merozoites. Some merozoites released from
infected erythrocytes turn into gametocytes, which enter peripheral
blood. Following the mosquito bite, the matured gametocytes were
then transmitted to Anopheles. Each gametocyte forms a macroga-
mete or eight microgametes in the mosquito's midgut, and then
female and male gametes fuse and become an ookinete while passing
the midgut wall. In the next phase, ookinete is converted to an oocyst
and gradually enlarged. Finally, it bursts and releases sporozoites. The
sporozoites, which migrated to mosquito's salivary glands, start the
next cycle of infection through mosquito's bite to humans (sporogonic
cycle; Bousema & Drakeley, 2011; Miller, Good, & Milon, 1994).
Female Anopheles nourish from blood in order to produce eggs.
Parasites do not cause severe problems in the mosquito, unlike
human. More than 30 Anopheles species are malaria vectors.
T A B L E 1 Infected RBCs characteristics (Centers for Disease
Control and Prevention, 2019)
Infected Infected RBC Schüffner's
Parasite RBC size shape dots
Plasmodium Normal Crescent No
falciparum
Plasmodium vivax >>Normal Ameboid Yes
Plasmodium ovale >Normal Fimbriation Yes
and elongated
Plasmodium malariae <Normal, Normal — No
Abbreviation: RBCs, red blood cells.
MOHAMMADI ET AL.
F I G U R E 1 Malaria pathogenesis:
Sporozoites are transmitted to humans
through infected Anopheles bite and invade
liver cells. In the hepatocytes, sporozoites
mature into schizont form, and then the
infected liver cells rupture and release
merozoites. Merozoites enter RBCs and first
convert to trophozoites and then to schizonts.
Infected RBCs rupture and release
merozoites. Moreover, some trophozoites
turn into gametocytes. Ingestion of
gametocytes leads to the infection in
Anopheles mosquitoes. A macrogamete and a
microgamete fuse in the mosquito gut and
eventually create oocysts, which release
sporozoites after maturation
Anopheles gambiae and Anopheles funestus are the main species
responsible for malaria transmission. These species are mostly
anthropophilic (prefer to bite humans than other animals). Mature
female mosquito lives more than 10 days in the tropical regions;
therefore, they have enough time for transmitting parasites. Using
insecticide-treated nets, long-lasting insecticidal nets, and indoor
residual spraying can reduce the incidence of disease. Pyrethroids are
used for insecticide-treated nets, and all four classes of insecticides,
including pyrethroids, organophosphates, carbamates, and organo-
chlorines, can be used for indoor residual spraying.
Therefore, given that Anopheles mosquitoes multiply several times
throughout the year, they can develop resistance to insecticide agents
quickly. In this case, the insecticide class should be changed (Centers
for Disease Control and Prevention, 2018; Malaria Consortium, 2011).
2 | ANTIMALARIAL AGENTS WITH THE
HERBAL ORIGIN
For many decades, chloroquine was the first choice of malaria treat-
ment; the quinine derivative originated from the Cinchona tree was
an active drug until chloroquine resistance arose due to incorrect
usage and monotherapy. Currently, chloroquine indication is limited
for the treatment of malaria caused by P. vivax and is no longer used
for P. falciparum (Skrzypek & Callaghan, 2017). To overcome the drug
resistance, a large number of antipyretic herbs in Chinese traditional
3
medicine were screened for their antimalarial activity (AMA), which
finally resulted in introducing artemisinin as a novel antimalarial agent
(Muangphrom, Seki, Fukushima, & Muranaka, 2016). Yadav, Kumar,
Teli, Yadav, and Chaudhary (2019) proposed the following targets to
develop new antimalarial drugs: membrane biosynthesis, mitochon-
drial system, apicoplasts, parasite transporters, shikimate pathway,
hematin crystals, parasite proteases, glycolysis, isoprenoid synthesis,
cell cycle control/cycline dependent kinase, redox system, nucleic acid
metabolism, methionine cycle and the polyamines, folate metabolism,
the helicases, erythrocyte G-protein, and farnesyl transferases.
According to the World Health Organization guidelines on
chloroquine-resistant malaria, artemisinin-based combination ther-
apies (ACTs) were recommended as the first line of treatment.
Table 2 shows the antimalarial therapeutic programs involving one
of the artemisinin derivatives, such as artemether, artesunate, and
dihydroartemisinin (WHO, 2015). Artemisinin has a short half-life;
therefore, to prevent drug resistance and preserve the adequate
blood concentration of antimalarial agents, the secondary medicine
was added to the therapeutic regimen (Smithuis et al., 2010). For
example, lumefantrin was introduced as the secondary agent into
the ACT regimen. Lumefantrin was first synthesized during the
Vietnam War in China to prevent death of soldiers from malaria
(Cui & Su, 2009). In addition to lumefantrin, pyrimethamine/
sulfadoxine, the synthetic pyrimidine derivatives, are among the
antimalarial agents administered along with artesunate (Burrows,
Rosowsky, & Modest, 1967; Kapoor, 1988). Previously, several
4 MOHAMMADI ET AL.

TABLE 2 Recommended medications for malaria therapy based on the WHO guidelines (WHO, 2015)

Recommended medication based on the WHO

Clinical situation
Uncomplicated Plasmodium falciparum
malaria
Uncomplicated Plasmodium vivax,
Plasmodium ovale, Plasmodium malariae,
or Plasmodium knowlesi
Relapse prevention of Plasmodium vivax
and Plasmodium ovale malaria
Severe malaria
Pre-referral treatment of severe malaria
Statement
Children and adult
First trimester of pregnancy
Chloroquine susceptible areas
Chloroquine-resistant areas
Children and adult
Pregnant and breastfeeding women
Children and adult (including pregnant and
breastfeeding women)
Low transmission areas
When artesunate is not available
Children and adult
When artesunate is not available
malaria guidelines
Artemisinin-based combination therapies (ACTs):
1. Artemether and lumefantrine
2. Artesunate and amodiaquine
3. Artesunate and mefloquine
4. Dihydroartemisinin and piperaquine
5. Artesunate and sulfadoxine and pyrimethamine
Quinine and clindamycin
An ACT or chloroquine
An ACT
Primaquine
Chloroquine (until delivery and breastfeeding are
completed), then primaquine
Artesunate (parenteral, for at least 24 hr), then an
ACT (oral, for 3 days)
Artesunate (parenteral, for at least 24 hr), then
primaquine (oral, single dose)
Artemether (parenteral), or quinine (parenteral). In
this case, artemether has priority over quinine.
Artesunate (single dose intramuscular)
Artemether (intramuscular) or quinine
(intramuscular); Artesunate (single dose rectal, for
children <6)

Abbreviation: WHO, World Health Organization.

studies reported the resistance to artemisinin derivatives and other
ACTs, indicating the necessity of new antimalarial agents (Ashley &
Phyo, 2018).
3 | ADVANTAGES AND DISADVANTAGES
OF ACTs VERSUS CHLOROQUINE
After a therapeutic course and elimination of parasites from periph-
eral blood, there is a significant possibility of disease recurrence due
to the presence of hypnozoites in the liver stage. Reinfection is also
possible in the case of patients living in endemic regions. On the
other hand, postponing disease recurrence and reinfection is an
important issue that provides a great chance for the hematologic
recovery of patients and prevention of anemia (Price & Douglas,
2009; White, 2018). Artemisinin derivatives cause a more significant
parasitemia reduction compared to chloroquine; however, due to
their short half-lives, another antimalarial agent is usually added to
the ACT regimens to prevent disease recurrence and drug resistance.
This includes piperaquine with eliminating half-life of 23 to 28 days
(Mutabingwa, 2005).
Nonetheless, ACTs can treat fever and lower gametocytes in the
bloodstream more efficiently than chloroquine, and in turn, the inci-
dence of parasite transmission from humans to the mosquito vector is
reduced. On the contrary, chloroquine has an extended half-life of
1–2 months, and in turn, the possibility of malaria relapses is less than
artemisinin derivatives. Although the cost of conventional antimalarial
medications is lower than ACTs, in the case of chloroquine-resistant
infections, ACTs are the best therapeutic choices (Douglas, Anstey,
Angus, Nosten, & Price, 2010). The extensive application of antimalar-
ial agents on the one hand and the resilience of Plasmodium parasites
on the other hand leads to short-term efficacy of quinine-based medi-
cations. A proof of the concept to the stated fact is the major rise of
malaria incidence after a significant reduction in the 1950s through
using chloroquine (Price & Douglas, 2009). Artemisinin derivatives
and chloroquine are almost safe medications. However, clinical trial
documents are not sufficient to approve the safety of artemisinin
derivatives. There are controversial reports about the neurotoxicity of
artemisinin derivatives following high dose administration in animals
and human studies.
Moreover, the indication of artemisinin derivatives during preg-
nancy is a challenging issue; however, available data reported mini-
mal teratogenic effects for artemisinin derivatives (Mutabingwa,
2005). Further studies showed minimal side effects followed by
taking chloroquine in comparison with other antimalarial agents
such as mefloquine, which causes central nervous system, gastroin-
testinal and skin disorders, as well as tinnitus and myalgia. Diarrhea,
dizziness, arrhythmia, and hepatitis are rare adverse effects of chlo-
roquine (Braga et al., 2015; Petersen, Rønne, Rønn, Bygbjerg, &
Larsen, 2000).
Dihydroartemisinin–piperaquine (DHA-PQ) and artemether–
lumefantrine (AL) are the most common ACT regimens formulated as
MOHAMMADI ET AL.
T A B L E 3 Advantages and disadvantages of antimalarial medicinal plants in comparison with fully synthetic drugs (Karamati, Hassanzadazar,
Bahmani, & Rafieian-Kopaei, 2014; Wells, 2011; Willcox et al., 2011)
Advantages
1. The most effective agents for the treatment of malaria, even in
resistant cases.
2. Due to the compatibility with human physiology, they cause less
serious side effects.
3. Patients have higher compliance.
4. Novel antimalarial pharmacophores can be designed based on
natural products.
5. Because medicinal plants are commonly used by local populations,
by monitoring these patients, more clinical information can be
achieved even before going to be used in clinical practice.
polypills and have shown considerable efficacy in several studies
(Bassat et al., 2009; Dama et al., 2018). The multidrug form of the
medication has some obvious results; patients are adherent to admin-
istered medication, and there are fewer concerns about drug misuse
(Price & Douglas, 2009). DHA-PQ is suitable for regions with a high
transmission probability due to its long half-life, whereas AL is more
effective than DHA-PQ in reducing the bloodstream gametocytes.
This is the main reason for the physicians to consider AL as a notable
option in nonendemic areas to reduce parasite transmission to mos-
quitoes (Okell et al., 2014). The incidence of the side effects is the
same in both multidrug forms (DHA-PQ and AL). It is worth to say that
gastrointestinal side effects are the most common adverse effects of
these medications. Additionally, dermatitis, hypersensitivity, and
altered alanine aminotransferase levels have been reported as rare
side effects (Bassat et al., 2009). The advantages and disadvantages of
antimalarial medicinal plants in comparison with fully synthetic drugs
are summarized in Table 3.
4 | PHYTOCHEMICALS WITH AMA
From a structural viewpoint, artemisinin is a sesquiterpene lactone
(Figure 2). Artemisinin and all of its derivatives have a peroxide bridge.
Reduction of this bridge with Fe2+ ion causes the production of radical
compounds, which subsequently alkylate proteins and kill parasites in
the blood stage of malaria (Tilley, Straimer, Gnädig, Ralph, & Fidock,
2016; Van Agtmael, Eggelte, & van Boxtel, 1999). Several derivatives
were produced by simple chemical reactions on the artemisinin struc-
ture; dihydroartemisinin, a water-soluble derivative, was produced by
reducing the carbonyl group in artemisinin. Artesunate is the steric
form of dihydroartemisinin, and artemether is obtained by adding a
methyl group to the artemisinin's carbonyl group (Figure 2; Loo, Lam,
Yu, Su, & Lu, 2017).
Quinoline is the basic structure for a number of antimalarial
agents such as quinine, chloroquine, piperaquine, amodiaquine, and
5
Disadvantages
1. The higher cost of production for some herbal medicines, such as
artemisinin from herbal sources, leads to synthetic endoperoxides
production to be in priority.
2. Herbal sources may not be available in all countries, unlike
nonherbal drugs.
3. In some herbal medications, patients should take more than a
single dose per day due to short drug half-lives and probable drug
resistances, unless in multidrug forms.
4. Generally, the application of medicinal plants does not have any
limitations; therefore, their safety and usage restrictions can be
neglected, and in turn, misuses and abuses can arise.
5. Lack of high-level clinical studies and validation methods for
antimalarial medicinal plants.
mefloquine (Leverrier, Bero, Frederich, Quetin-Leclercq, & Palermo,
2013; Parhizgar & Tahghighi, 2017). Chloroquine and primaquine are
quinine derivatives with 4- and 8-aminoquinoline backbone, respec-
tively. Quinacrine is a synthetic 9-aminoacridine demonstrating an
inadequate therapeutic profile (i.e., minor AMA with higher drug side
effects) as an antimalarial agent (Figure 2; Foye, 2008). Piperaquine,
compared with other quinine derivatives, has a complex structure
consisting of two quinoline units and two piperazine rings. The bulky
bisquinoline structure reduces the efflux (the main reason for chloro-
quine resistance). Therefore, piperaquine can be administered in drug-
resistant cases (Davis, Hung, Sim, Karunajeewa, & Ilett, 2005).
Malaria parasites form acidic vacuoles inside the erythrocytes in
order to breakdown and convert hemoglobin into toxic heme and
then inert hemozoin (Coronado, Nadovich, & Spadafora, 2014). The
uncharged nature of chloroquine facilitates the entrance into the vac-
uoles, which then is protonated and accumulated in acidic locale of
vacuoles. Chloroquine prevents the heme conversion to hemozoin.
Some parasites can remove chloroquine from their vacuoles, which
the drug does not accumulate there consequently, resulting in chloro-
quine resistance (Bray et al., 2005).
5 | I M P O R T A NT GE N U S E V A L U A T ED F O R
THEIR ANTIMALARIAL PROPERTIES
5.1 | Artemisia spp.
Table 4 shows the selected commercially available artemisinin deriva-
tives dispensed for malaria therapy. Artemisinin was first separated
from A. annua (Figure 3b). Artemisinin is also found in other species of
Artemisia, including Artemisia apiacea. Generally, extraction of Artemi-
sia's dried leaves was performed using nonpolar solvents such as
petroleum ether or hexane followed by the separation and purification
of the compound by column chromatography or high performance
liquid chromatography (Stringham, Moore, Teager, & Yue, 2018; Tian
6 MOHAMMADI ET AL.

F I G U R E 2 Chemical structures of some antimalarial agents, including artemisinin-based compounds, an indoloquinoline named cryptolepine,
an iridoid obtained from Scrophularia lepidota, artemisinin like arteflene, which possess better anti-Plasmodium effects in comparison with the
original compound (yingzhaosu), a naphthoquinone known as lapachol and its derivative, atovaquone with further oral bioavailability, and
quinoline-based antimalarial drugs

et al., 2012). In addition to sesquiterpenes, Artemisia genus contains other (Czechowski et al., 2019; Rasoanaivo, Wright, Willcox, & Gilbert, 2011;
compounds, including flavonoids such as artemetin, chrysosplenetin, and Tan, Zheng, & Tang, 1998).
cirsilineol, which also have beneficial effects on malaria; therefore, these The essential oil of A. annua has been investigated for its antimicrobial
compounds may synergistically increase AMA along with artemisinin activity (Bilia, Santomauro, Sacco, Bergonzi, & Donato, 2014). Although
MOHAMMADI ET AL. 7

TABLE 4 Examples of artemisinin's commercial derivatives (Drugs.com, 2018)

Artemisinin's commercial derivatives Brand name Manufacturer Pharmaceutical dosage form

Artemether Artenam Arenco Pharmaceutical (Belgium) Ampoule
Artem Hilton (Pakistan) Ampoule
Larither IPCA (India) Ampoule
Paluther Sanofi Aventis (Bangladesh) Ampoule
Artemether plus lumefantrine Coartem Novartis (Bangladesh, United States, etc.) Tablet
Lifart-L Iscon Life Sciences (India) Oral suspension and tablet
Lumartem Cipla (India) Tablet
Riamet Novartis (Belgium, Bulgaria, etc.) Dispersible tablet
Artesunate Artesun Guilin Pharmaceutical (Shanghai) Vial for injection
Asunate Adley (India) Vial for injection
Falcigo Zydus Cadila (India) Vial for injection
Plasmotrim Acino Switzerland (Myanmar) Rectal capsule
Artesunate plus amodiaquine Co-Artesun Guilin Pharmaceutical (Shanghai) Tablet
Artesunate plus mefloquine Artequin Acino Switzerland (Myanmar) Tablet
Falcigo plus Zydus Cadila (India) Tablet
Dihydroartemisinin Alaxin GVS Labs (Kenya) Tablet
Dihydroartemisinin plus piperaquine Eurartesim Sigma-tau (Germany, France, etc.) Tablet
P-Alaxin Bliss GVS Pharma (India) Oral suspension and tablet

F I G U R E 3 Images of Cinchona
calisaya Wedd. (a) and Artemisia annua
L. (b). The figures are obtained from
“African plants - A Photo Guide” by
getting the required permissions
(Latham, 2014)

the essential oil contains different percentages of components according
to the plant's growing site (China, India, Iran, etc.), the major components
of the essential oil are common such as camphor, germacrene D, artemisia
ketone, and 1,8-cineole. Recent studies have indicated the significant anti-
microbial activity of monoterpene- and sesquiterpene-rich essential oil of
A. annua, regardless of the growing site, against Gram-positive and Gram-
negative bacteria and fungi (Bilia et al., 2014).
The discovery of artemisinin from A. annua has a substantial
impact on malaria therapy, which in turn boosted the research on the
Artemisia genus. Table 5 summarizes some clinical trials that studied
the efficacy and safety of artemisinin derivatives. Bamunuarachchi,
Ratnasooriya, Premakumara, and Udagama (2013) evaluated the in
vivo AMA of the ethanolic extract of Artemisia vulgaris leaves con-
taining alkaloids and coumarins based on preliminary phytochemical
screening results on infected mice. Various doses of A. vulgaris extract
were administered orally in mice, and the data showed that the
extract reduced the amount of Plasmodium berghei parasites in the
bloodstream in a dose-dependent manner by 80%; however, the drug
 8

TABLE 5 Some completed randomized controlled trials reported ACTs efficacy and safety in malaria

Trial title Enrollment Treatment Reported outcomes NCT identifier

Artemisinin-resistant malaria in Cambodia 561 • Dihydroartemisinin–piperaquine Infection relapse percent differs from a minimum of 2% up to NCT01736319
a maximum of 46% in various regions of Cambodia.
Treatment efficacy and malaria transmission after 219 • Dihydroartemisinin–piperaquine In 31.8% of Kenyan children (6 months–10 years) with NCT01939886
artemisinin combination therapy 2 (TRANSACT2) • Artemether–lumefantrine Plasmodium falciparum infection, residual parasitemia was
detected on Day 3 of ACT therapy.
In addition, after Day 42 of treatment, recurrent infection risk
is higher in children treated with AL regimen than patients
treated with DP regimen, but transmission risk is lower by
using AL.
Safe and efficacious artemisinin-based combination 3,428 • Dihydroartemisinin–piperaquine According to the results, DP was the most effective and safe NCT00852423
treatments for African pregnant women with malaria • Artesunate–mefloquine regimen in pregnant women with Plasmodium falciparum
(PREGACT) • Artesunate–amodiaquine mono-infection; however, regimens were not that much
• Artesunate–amodiaquine different in adverse effects on fetus.
Evaluation of 4 artemisinin-based combinations for treating 4,112 • Dihydroartemisinin–piperaquine This study carried out in different regions of sub-Saharan NCT00393679
uncomplicated malaria in African children • Amodiaquine–artesunate countries on 6- to 59-month-old children with Plasmodium
• Artemether–lumefantrine falciparum infection. Pairwise comparison of regimens was
• Chlorproguanil–dapsone–artesunate conducted. DP indicated the lowest relapsing rate followed
by AA.
Artemisinin resistance in Cambodia II (ARC II) 143 • Artesunate Even in ACT-resistant regions, increasing the usual artesunate NCT00722150
daily dose (4 mg/kg) was not beneficial in lowering residual
parasitemia evaluated on Day 3 of treatment, but it could
predispose patients to neutropenia. Therefore, the
administration of artesunate along with another potent
antimalarial agent could be a better solution in this situation.
Artemisinin resistance in Bangladesh 126 • Artesunate The results did not confirm resistance to artesunate in NCT00639873
• Quinine–doxycycline Bangladesh.
Clinical investigation of in-vivo susceptibility of P. falciparum 40 • Artesunate Resistant Plasmodium falciparum was detected in Cambodia NCT00493363
to artesunate in western Cambodia • Artesunate–mefloquine through prolonged parasitemia in comparison with patients
in Thailand.
Artemisinin resistance in Cambodia 94 • Artesunate Three percent of patients treated with artesunate indicated NCT00479206
• Quinine–tetracycline drug resistance. Prolonged parasitemia and increased IC50
are resistance criteria.
Efficacy and safety of a single low-dose primaquine for the 220 • Artemether–lumefantrine Followed by adding a single dose of primaquine to the AL NCT02090036
clearance of gametocytes • Artemether–lumefantrine–primaquine regimen, the results did not show any significant effect.
Artemisinin-based antimalarial combinations and clinical 720 • Artesunate–amodiaquine AA, DP, and AL regimens were administered to three groups NCT01845701
response in Cameroon • Dihydroartemisinin–piperaquine of children from 6 months old to 6 years old in Cameroon;
• Artemether–lumefantrine the results did not show significant difference in efficacy
and adverse effects between these groups.
600 • Trimethoprim–sulfamethoxazole SP and DP regimens administered to infants monthly and TS NCT00948896
• Sulfadoxine–pyrimethamine administered daily as prophylaxis. The therapy was
(Continues)
MOHAMMADI ET AL.
 MOHAMMADI ET AL. 9

dose could not be increased significantly due to the possible adverse

NCT01775592
NCT identifier effects such as hematotoxicity and hepatotoxicity (Bamunuarachchi
et al., 2013). In another study, Artemisia afra was investigated for

Abbreviations: AA, amodiaquine–artesunate; ACT, artemisinin-based combination therapies; AL, artemether–lumefantrine; DP, dihydroartemisinin–piperaquine; NCT, National Clinical Trial Identifier; SP,
potential antimalarial function. Although the infusion of A. afra has
been used to treat malaria in southern Africa, the results of the study
indicated that A. afra's infusion did not have antimalarial effects in
continued until 24 months of age. The results indicated 58%

respectively. Adverse effects were not significantly different

This study was conducted in Vietnam (Quang Nam Province).

Although DP regimen was still effective, some cases with a vitro.

observed. The results indicated the importance of novel

prolonged parasitemia (>72 h) and increased IC50 were On the contrary, the nonpolar extract of A. afra's different parts
protection for DP and 28% and 7% for TS and SP,

such as roots and leaves were effective in vitro against chloroquine-

sensitive P. falciparum parasites. In a study conducted by Liu et al.
(2010), the AMA of the chloroform extracts was assessed by estimat-
ing the Plasmodium lactate dehydrogenase activity, and the results
indicated the effectiveness of the extracts. In one recent study, Arte-
misia herba-alba Asso has been studied for insecticidal activity (Aziz
antimalarial drug discovery.

et al., 2018). The results indicated adequate insecticidal effects for

in the mentioned groups.

this plant. The A. herba-alba extract eliminated Anopheles stephensi

Reported outcomes

with an LC50 value of 9.86 μg/ml when used in a nanoparticulated

form. Nanoparticles of this extract can also be effective against other
insects such as Aedes aegypti being responsible for yellow fever
spread (Aziz et al., 2018). Recently, the AMA of Artemisia armeniaca
Lam., Artemisia aucheri Boiss., Artemisia scoparia Waldst. & Kitam., and
Artemisia spicigera K.Koch were studied using β-hematin formation in
vitro assay, and the results showed that the dichloromethane extracts
of the Artemisia genus have the capability of inhibiting the conversion
• Dihydroartemisinin–piperaquine

• Dihydroartemisinin–piperaquine

of heme to hemozoin at high concentrations (Afshar et al., 2011;

Mojarrab, Shiravand, Delazar, & Heshmati Afshar, 2014). β-Hematin is
used to assess the antimalarial potential of novel compounds so that
β-hematin has a regular crystalline structure similar to that of
hemozoin, and it can be produced in vitro under a special chemical
reaction in acidic acetate solution. Giving a brief description of
Treatment

β-hematin formation assay, various concentrations of the extracts, as

well as positive and negative controls, are incubated with hematin,
oleic acid, hydrochloric acid, and sodium acetate buffer. Then, centri-
fugation is performed, and the formed β-hematin pellets are attained
Enrollment

and then washed. Finally, the absorbance of samples at 400 nm is

read, and the results are calculated compared with the negative con-
95

trol as percentages of crystallization inhibition (Afshar et al., 2011;

sulfadoxine–pyrimethamine; TS, trimethoprim–sulfamethoxazole.

Tekwani & Walker, 2005).

Chemopreventive therapy for malaria in Ugandan children
(PROMOTE-Chemop) Chemopreventive therapy for

Plasmodium falciparum artemisinin resistance Vietnam

malaria in Ugandan children (PROMOTE-Chemop)

5.2 | Cinchona spp.

The bitter-tasted Cinchona bark was used for beverage manufacturing.

Additionally, bitters have been used as medicines for recurrent fevers
as well as tonics; the effect of Cinchona bark on periodic and relapsing
fever treatment and prophylaxis has been proved in the early 18th
(Continued)

century. Quinine is the main alkaloid of Cinchona bark mainly

extracted from Cinchona pubescens Vahl. and Cinchona calisaya Wedd.
(Figure 3a) for antimalarial therapy (Cosenza, Somavilla, Fagg, &
Brandao, 2013). Several factors influenced the considerable indication
TABLE 5

Trial title

of quinine as an antimalarial agent, including short half-life, bitter

taste, and numerous side effects such as headache, dizziness, nausea,
vomiting, and hemolysis. Furthermore, the encountered resistance to
10
medicine limited effective malaria treatment (Shanks, 2016). Recently,
various novel antimalarial therapies with quinine scaffold have been
synthesized such as hydroxyethylapoquinine, to reduce side effects
and prevent drug resistance (Sanders, Meyers, & Sullivan, 2014).
5.3 | Cryptolepis sanguinolenta (Lindl.) Schltr
For a long time, roots and leaves of C. sanguinolenta (Lindl.) Schltr.
have been extensively used in Traditional West African medicine in
the treatment of malaria. Cryptolepine has an indoloquinoline basis
and performs its antimalarial effect by connecting to the column
chromatography sequences and preventing DNA synthesis
(Lisgarten, Coll, Portugal, Wright, & Aymami, 2001; Osafo,
Mensah, & Yeboah, 2017). Cryptolepine was first derived from the
roots of C. sanguinolenta. Grellier et al. (1996) provided the root
extract of C. sanguinolenta and examined its AMA. The results indi-
cated that the extract and cryptolepine, the main alkaloid in the
plant roots (Figure 2), have significant antimalarial effects by
inhibiting the sensitive and even resistant species of Plasmodium
parasites (Osafo et al., 2017). An in vitro assay, based on calculated
IC50 values, showed a greater potency for cryptolepine in killing
P. falciparum parasites compared with isocryptolepine, the other
alkaloid existing in the C. sanguinolenta extract. Therefore, crypt-
olepine antiparasitic activities were evaluated by additional in vivo
experiments in the infected mice against P. berghei and Plasmodium
vinckei petteri using the classical 4-day suppressive test, and the
results indicated higher suppression percentage against P. vinckei
petteri (Grellier et al., 1996). In this method, a quantified number of
parasitized RBCs were intraperitoneally injected into the model
mice, followed by the administration of various concentrations of
cryptolepine saline solution through intraperitoneal injection for
3 days. In the next step, growth inhibition percentages by increas-
ing concentrations of cryptolepine were calculated compared with
the control group (Grellier et al., 1996; Peters, 1965). In a clinical
trial, the plant's root powder was formulated as tea bags and pre-
scribed to 44 patients. The results showed at least 50% reduction
in parasitemia rate in all the patients after 7 days; however, two
cases of recurrence have been reported after 25 days (Bugyei,
Boye, & Addy, 2010). The essential constituent of C. sanguinolenta
has several other effects, including antibacterial and cytotoxic
actions. Moreover, recent studies have revealed the importance of
C. sanguinolenta as an anticancer, antihypertensive, and antipyretic
agent (Osafo et al., 2017).
5.4 | Handroanthus impetiginosus (Mart. ex DC.)
Mattos
H. impetiginosus contains a naphthoquinone known as lapachol. Inter-
rupting the parasite's electron transport chain is the mechanism of
lapachol's AMA. Atovaquone with better oral bioavailability was
developed by applying changes to the structure of lapachol to be used
MOHAMMADI ET AL.
as a prophylaxis for malaria (Figure 2; Cruz, Spangenberg, Lacerda, &
Wells, 2013). In addition to atovaquone, other derivatives were devel-
oped from lapachol, and their antimalarial effects were assessed. de
Souza et al. (2014) synthesized some quinone-based compounds
and their activities were evaluated against chloroquine-resistant
malaria by determining histidine-rich protein 2 (HRP-2) secretion
level from P. falciparum-infected erythrocytes. Among them, two
compounds with 2-hydroxy-3-methylamino naphthoquinone deriv-
atives showed IC50 values less than 5 μM. in vivo studies revealed
that the developed compounds could reduce parasitemia by 63% in
mice with chloroquine-sensitive P. berghei (de Souza et al., 2014).
HRP-2 seems to play an important role in the conversion of heme
to hemozoin in P. falciparum parasites present in all strains of the
parasite. In the anti-HRP-2 test, samples and controls were poured
into a 96-well plate. Then, the parasites were added to the plate as
samples with 1.5% hematocrit and 0.05% parasitemia. After incuba-
tion, the cells were lysed through freeze–defreeze cycles, and a
certain number of the lysed cells from each well were added to
another plate, coated with anti-HRP-2 antibody. The secondary
antibody was added to the plate after blocking and washing steps.
Eventually, tetramethylbenzidine was added to the wells, and then
the absorbance amounts were measured at 450 nm, and AMA of
the samples was calculated according to the results of negative and
positive controls (de Souza et al., 2014; Noedl, Wernsdorfer,
Miller, & Wongsrichanalai, 2002).
5.5 | Artabotrys hexapetalus (L.f.) Bhandari
Yingzhaosu is a natural and also synthetic antimalarial herbal com-
pound originated from A. hexapetalus (L.f.) Bhandari and is structur-
ally related to artemisinin. From a structural viewpoint, yingzhaosu
is a nonalkaloidal antimalarial agent with an endoperoxide group,
as well as artemisinin and its derivatives (Zhou & Xu, 1994).
Arteflene is a synthetic peroxide-containing compound derived
from yingzhaosu (Figure 2). An in vivo study conducted in mice
showed fourfold to fivefold higher antimalarial potency for paren-
teral injection than orally administered arteflene, which was associ-
ated with the rapid metabolism of the drug to a weaker compound
in the stomach (Girometta, Jauch, Ponelle, Guenzi, & Wiegand-
Chou, 1994). In one clinical trial conducted on 23 patients with mild
malaria, the results indicated that 48 hr after a single dose adminis-
tration of arteflene, P. falciparum parasites were completely cleared
from the bloodstream in 53% of the patients (Salako et al., 1994).
There were also failed outcomes in the application of arteflene in
malaria treatment. In one clinical trial, the efficacy of arteflene was
assessed in comparison with mefloquine for the treatment of chil-
dren with uncomplicated P. falciparum. Following a single oral dose
administration of arteflene, drug resistance occurred in eight out of
21 patients, whereas there was no drug resistance to mefloquine.
Moreover, after 28 days, only one patient who received arteflene
was completely cured, whereas all the patients were cured in the
case of mefloquine (Radloff et al., 1996).
MOHAMMADI ET AL.
6 | OTHER HERBS WITH ANTIMALARIAL
POTENCY
In addition to the previously discussed plants and their antimalarial
constituents, other herbs were also studied in terms of AMA. In this
section, we intend to highlight a number of these studies.
6.1 | Syzygium cordatum Hochst. ex Krauss
S. cordatum Hochst. ex Krauss is a highly important medicinal herb in
southern and eastern Africa regarding its antimalarial and antibacterial
effects. In addition, the plant's fruits have nutritional value. A number
of traditional medical applications have been reported for S. cordatum,
including antibacterial, antidiarrhea, and wound healing boosting
effects.
Furthermore, in Tanzania and Zambia, decoction of bark and
leaves of this herb is consumed to treat malaria, and recent studies
have confirmed the effectiveness of the method (Maroyi, 2018).
Nondo et al. (2015) investigated the antimalarial efficiency of the
ethanolic extract of S. cordatum bark using the Plasmodium lactate
dehydrogenase assay. The results showed that the percentage of
growth inhibition by the extract against chloroquine-resistant
P. falciparum parasites was approximately 55% (Nondo et al., 2015).
In another study, the AMA of the dichloromethane extract of
S. cordatum's leaves was assessed through [3H] hypoxanthine incor-
poration method. The results also indicated that the leaves extract
could inhibit the chloroquine-sensitive P. falciparum parasites with
IC50 of 6.2 μg/ml (Bapela, Meyer, & Kaiser, 2014). Hypoxanthine is
usually one of the most important members of P. falciparum culture
because P. falciparum parasites require a hypoxanthine source for
nucleic acid synthesis.
For this reason, to assess growth of parasites, [3H] hypoxanthine
radioisotope is added to their microculture. In the mentioned study,
the parasites were cultured in RPMI medium, and RBCs were used
as the host cells. Then, the samples and a standard medication like
chloroquine were added to the plate. After incubation under a cer-
tain condition, [3H] hypoxanthine was added to the wells. In the
next step, harvesting was performed after further incubation.
Finally, the erythrocytes were filtered, and the parasitized RBCs
were detected and counted (Bapela et al., 2014; Chulay, Haynes, &
Diggs, 1983).
6.2 | Scrophularia umbrosa Dumort
The dichloromethane rhizome extract of S. umbrosa Dumort was eval-
uated by β-hematin formation assay and showed moderate anti-Plas-
modium activity (IC50 = 27.12 mg/ml) in comparison with chloroquine
(IC50 = 0.014 mg/ml), as a positive control. The extract of aerial parts
showed minimum antimalarial effects (Nikkhah, Heshmati Afshar,
Babaei, Asgharian, & Delazar, 2018; Nikkhah, Heshmati Afshar,
Babaei, Delazar, & Asgharian, 2018).
11
6.3 | Astrodaucus persicus (Boiss.) Drude
Goodarzi et al. (2017) assessed the anti-Plasmodium activity of the
various extracts of A. persicus (Boiss.) Drude using in vivo tests in
mice. The results indicated significant differences on the fourth day of
therapy between the negative control group and the test group.
Root's hexane extract and fruit's ethyl acetate extract showed approx-
imately 73% and 72% of parasitemia suppression, respectively
(Goodarzi et al., 2017).
6.4 | Eremostachys molucelloides Bunge
E. molucelloides Bunge was investigated for antimalarial effects in an
in vitro study. The dichloromethane extract of plant rhizomes has
been found to have stronger AMA than the other extracts of
E. molucelloides (IC50 = 0.324 ± 0.039 mg/ml). However, the antimalar-
ial effect of the extract was less than control (i.e., chloroquine
IC50 = 0.014 ± 0.003 mg/ml). Moreover, in this study, IC50 value for
the 6:4 ethyl acetate/n-hexane fraction of dichloromethane rhizome
extract was 0.047 ± 0.0003 mg/ml (Asnaashari, Heshmati Afshar,
Ebrahimi, Bamdad Moghadam, & Delazar, 2015).
7 | CONC LU SION
Nature has always inspired scientists in many fields; drug designing is
not an exception. The great portion of the medications available in
the market either is natural or originated from natural products. Drug
resistance always rises, and new medications are proposed to over-
come the resistance. High throughput drug screening to find second-
ary function for the available drugs is considered as an efficient
method to develop a lead compound to fight against diseases. Malaria
treatment is based on herbals; nevertheless, the impact of modern
medicines should not be overlooked. This review provided some
important herbals with AMA and introduced some others with poten-
tial AMA. The important thing here is that the traditional medication
for malaria therapy is a gold mine, and it is reasonable to see more of
these medications in the market in the near future.
AC KNOWLEDG EME NT
This work was partially supported by CONICYT PIA/APOYO CCTE
AFB170007.
CONFLIC T OF INT ER E ST
The authors declare no conflict of interest.
OR CID
Javad Sharifi-Rad https://orcid.org/0000-0002-7301-8151
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How to cite this article: Mohammadi S, Jafari B, Asgharian P,
Martorell M, Sharifi-Rad J. Medicinal plants used in the
treatment of Malaria: A key emphasis to Artemisia, Cinchona,
Cryptolepis, and Tabebuia genera. Phytotherapy Research. 2020;
1–14. https://doi.org/10.1002/ptr.6628