Natural Products as Sources of Antimalarial Drugs: Ethnobotanical and Ethnopharmacological Studies

Materials and Methods For this study, relevant information was procured from the inhabitants via a structured questionnaire to procure the general knowledge of antimalarial medicinal plants. Results and Discussion. A total of 90 interviewees (44 men and 46 women) were involved in this survey. A total of 59 medicinal species were identified, which were dispersed in 33 families (Asteraceae (6), Apocynaceae (5), Anacardiaceae, Annonaceae, Fabaceae, Malvaceae, Meliaceae, Poaceae, and Rubiaceae (3 each), Phyllanthaceae (2)) totaling 49% of the cited species. The most cited plants are Azadirachta indica (42), Mangifera indica (38), Carica papaya (28), Cymbopogon citratus (27), Cassia fistula (15), Morinda lucida (14), Anacardium occidentale and Vernonia amygdalina (13 each), Helianthus annuus (11), Enantia chlorantha (10), and Moringa oleifera (9) A total of 105 citations were recorded for the plant parts used (leaf (46), bark (17), fruits (9), root (9), latex (11), stem (11), and inflorescence (2)) while decoction (59%), maceration (25%), infusion (9%), and exudation (7%) were the methods of preparation. Use Values (UVs) of 0.47 to 0.11 were recorded for the frequently used antimalarial plants. The Efficiency Levels (ELs) of 11 different medicinal plants stated by the respondents were Azadirachta indica, Cassia fistula and Morinda lucida (12), Chromolaena odorata (10), Mangifera indica, Enantia chlorantha and Helianthus annuus (8), Cymbopogon citratus (7), Gossypium arboretum (4), Landolphia dulcis (3), and Aloe vera (2) Cocos nucifera, Curcuma longa, Forkia biglobosa, and Musa acuminate are mentioned for the first time in the study area with little or no reported antiplasmodial activities. Conclusion The study appraised the commonly used antimalarial plants in the study areas. Therefore, commitment to scientifically explore the bioactive compounds, antimalarial potential and toxicological profile of these plants is inevitable as they could lead to novel natural products for effective malaria therapy.


Introduction
Malaria is one of the communal diseases of man contributing to stern sociocultural, economic, and health influences in humid, middle-income nations, sub-Saharan Africa, Southeast Asia, and South America [1,2]. It is instigated by Plasmodium ovale, P. malariae, P. falciparum, P. vivax, and P. knowlesi [3]. e outburst of malarial infections in Africa, the Caribbean, Asia, and South American is symptomatic of P. falciparum, the most lethal malaria parasite. e parasite could accumulate in the brain capillaries [4,5]. Malarial infections in India, Central American, and East Mediterranean could be concomitant to P. vivax while P. ovale and P. malariae are prevalent in Papua New Guinea and sub-Saharan Africa [6].
Malaria epidemic has been enormously high in low socioeconomic empowered regions. In Africa, nearly 19 million cases of malaria infections have been reported accounting to 89% of the global cases and almost 17 million deaths have been published [7]. Also, about 450 thousand African children's deaths have been reported and one-tenth of pregnancy deaths have been concomitant to malaria infections [2,8]. It affected the morbidity and mortality rate owing to pathogenic resistance to conventional drugs, vector control agents, and human migration [9]. Several factors have been analysed and reported to control malaria infections in Africa. ese are climate suitability, dams or reservoirs, migration, and vegetation. According to the report published by e World malaria in 2018, malarial cases have tremendously reduced in relation to the report of 2010. Despite this, between 2015 and 2017, no significant progress was achieved in curbing malaria cases [10]. is trend could be indicative of the widely spread of drug-resistant malaria and the intricacy of parasites' life cycle [11].
Quinoline (QN) derivatives are undoubtedly the commonest antimalarial drugs in Africa. Examples of quinoline antimalarial drugs are quinine, amodiaquine, piperaquine, primaquine, pyronaridine, ferroguine, isoquine, amopyroquine, tertbutylisoquine, mefloquine, tafenoquine, and chloroquine. 4-Aminoquinoline is the most accessible antimalarial pharmacophore used in the last century. In recent times, QN derivatives have been integral component of Artemisinin-based Combination erapy (ACT) [12]. e discovery of ACT could be considered as the most noteworthy achievement of ethnopharmacological research in the 20th century [13][14][15], enthused by the use of Artemisia annua L. (Asteraceae). e drug was found effective against all the malarial parasites and led to regulations against quinine-based drugs in Africa. However, despite the predominant achievements of ACT, concerns about the future efficacy of artemisinin have recently been on the rise due to the building-up of resistance by the parasite [7]. is event instigates the unrelenting search for promising antimalarial drugs that are cost-effective, handy, acceptable, and scientifically proven.
Human has used medicinal plants for malaria, cholera, yellow fever, and diabetes treatment [16]. In most African countries, medicinal herbs are viewed as alternative therapies. Medicinal plants have effectively helped in primary health care for the therapy of acute and chronic diseases [17,18]. ey have contributed to the discovery of novel therapeutic agents via isolation, identification, and characterization of secondary metabolites [19]. Secondary metabolites such as flavonoids, stilbenes, coumarins, lignin, tannins, terpenoids, and steroids have been reported as antimalarial compounds [20].
Tropical plants are identified to contain high proportions of natural chemical compounds and a greater diversity than plants from any other biome. us, they are potential sources of new medicines [21]. e increased number of drug-resistant strains makes the development of novel antimalarial urgent. e high cost of malaria treatment has left the poor masses of Nigeria heavily reliant on traditional practitioners and medicinal plants for the treatment of the disease. It seems logical to encourage studies on plants from these regions, especially since the major proportions of malaria attributable deaths occur in sub-Saharan African regions. Although several compounds had achieved success at treating malaria diseases, the emerging threats of drug resistance by some plasmodium species call for the development of new molecules with novel bioactive features. e study explores the ethnobotanical and ethnopharmacological appraisal of antimalarial plants used by people of Omu Aran, Ogbomoso, Ado Ekiti, and Sagamu communities in Nigeria. Hence, the search for novel natural antimalarial molecules in selected plant sources via ethnobotanical and ethnopharmacological investigation is clearly justified.

Typical Vegetation of the Study Area. Ado Ekiti and
Sagamu fall in the rain forest region, characterized by temperature of 21°to 28°C, high humidity, and two distinct seasons, rainy season from April to October and dry season from November to March with mean annual rainfall of 1320 mm. Ogbomoso and Omu Aran fall in the savanna region, characterized by temperature of 21°to 33°C with heavy rainfall between April and October. e humidity is high (51.1%) with mean annual rainfall of 1885 mm. e study sites are opulently rich in evergreen floras and this promotes the use of local herbs for diseases prevention and cure.

Selection of the Informants.
For this study, relevant information and data were procured from selected people in the study area via interview using structured questionnaire to procure relevant knowledge of antimalarial plants used in the vicinity. e questions were structured in a simple way and interpreted to selected respondents selected by nomination method after verbal authorization and approval by the chiefs in the study areas. In a particular study area, the leaders suggested prominent people with vast experience in herbal medicines or practitioners of herbal medicines. For reliability and reproducibility, respondents that accepted to be interviewed were briefed on the significance and objectives of the study. A disclaimer was presented to the interviewees that the views, ideas, and opinions expressed belong solely to the interviewers, and not necessarily to any committee or individual. While conducting the research, researchers were honest but not too detailed in briefing the respondents what he or she needed to do. Conducting the survey involved series of activities.
ese include establishing cordial relationship with respondents, selecting easy ways of interacting, observation, and recording the findings.
Respondents selected must meet the following criteria: (1) they should be indigenous people of Yoruba; (2) they are sound and knowledgeable in phytotherapy; (3) they are accessible to medicinal plants; (4) they must have used herbs for treating malaria; (5) they are approachable and organized.

Structured Questionnaire.
e structured questionnaire was designed according to the technique of Olorunnisola et al. [22] and Sarquis et al. [23] with slight modification. e moderated questionnaire entails information on respondent biodata, commonly used antimalarial medicinal plants, plant parts frequently used, the most effective herbs from the respondents list, mode of preparation, and common side effects of antimalarial plants.

Data Collection.
e study was piloted for 6 months, from March to August 2019. e mode of data collection was through one-on-one interviews, public discussion, and observation. e interviews were conducted mostly in Yoruba (native) language. e respondents gave the native names of plants and showed the interviewers the available plant samples. Information on the questionnaires was supplied on the spot of interview, and several observations and discussions were conducted prior to completing and cross-checking of the information provided.

Data Analysis.
e antimalarial medicinal plants itemized by the respondents were structured according to the scientific, common, and local names, family, plant part used, and mode of preparation. e malarial diseases' symptoms and probable health effects or body reactions were reported. Data were statistically analysed in percentages using Graphpad Prism software (version 6.0) e comparative significance of a plant species for its ethnopharmacological activity was evaluated with the Index of Use Value (UV) and efficiency level (EL).

Use Value (UV).
It is a quantifiable catalogue that denotes the therapeutic importance of each medicinal plant species. It is calculated by UV � ΣUi/n, where Ui is the total number of times plant species is cited and n is the total number of respondents interviewed. UV element helps evaluate plant species frequently mentioned for antimalaria. A high UV denotes plant mentioned mostly by respondents and low for sparingly mentioned [23].

Efficiency Level (EL).
It is a qualitative index that signifies the efficacy of a single plant species from the list of plants given as a response by the interviewees. EL is calculated by CL � Ui, where Ui is the total number of times a particular plant species is mentioned as the most effective from the list of plant species level. EL indicates plant species showing the most effective therapeutic potentials. A high EL denotes the most efficacious plant.  Table 1. e respective age distribution and the level of education of the respondents are shown in Figure 2.

e Effectiveness of the Medicinal Plants.
In this study, 57 respondents (63%) strongly agreed and 26 respondents (29%) agreed that malaria is curable using medicinal herbs while 7 respondents (8%) were neutral. is denotes the local belief in phytotherapy of malaria. e study site has rich vegetation diversity ranging from creeping plant to shrubs and trees. A large number of these plants are used by the inhabitants in malaria therapy due to persistent spread of malaria in these regions.

Indigenous Notion of the Study Area on Malaria.
e common symptoms of malaria and side effects of antimalarial plants according to the native knowledge of Ado Ekiti, Ogbomoso, Omu Aran, and Sagamu people are detailed in Table 2. Yoruba people identify malaria as "iba" and presumed malaria as a common and seasonal disease. From one-on-one interview and observations, malaria prevalence is significantly high during the rainy season in the study areas. According to the respondents, malaria is caused by long-time exposure to rain, cold, hot sun, stress, and mosquito. ey believed that these could disrupt the temperature balance in the body.
Likewise, the respondents were screened to procure knowledge of malaria via the common symptoms they experienced ( Figure 3) Fever, body pain, fatigue, and headache are the common symptoms in the study area and are related to temperature balance of the body system. e local people believed that it could be caused by excessive heat and longtime exposure to cold environment which forces the body to produce excessive heat. Moreover, they explained that fever Scientifica could lead to other symptoms such as headache, fatigue, body pain, and sweating. According to the respondents, probable ways of preventing malaria include reduction in exposure to rain (cold areas) or sun (hot areas), avoidance of mosquito bites, reduction in workload (stress), constant use of antimalarial herbal drugs, and burning of aromatic antimalarial plants which could pose threats to mosquitoes. Medicinal plants are universally reported to produce uncharacteristic effects ranging from simple to intricate. e respondents were screened to procure information on common health effects associated with antimalarial herbal drugs. Several reports were obtained, grouped as dizziness, sweating, weakness, frequent urination, itching, and no side effects ( Figure 4) However, 15 (27), Cassia fistula (15), Morinda lucida (14), Anacardium occidentale and Vernonia amagdalina (13 each), Helianthus annuus (11), Enantia chlorantha (10), Moringa oleifera (9), Chromolaena odorata, and Psidium guajava (7 each) e efficacy of a plant species is evidenced in its number of citations, thus, becoming spotlight in pharmacological research leading to the discovery of novel antimalarial drugs. However, we cannot rule out the possibility of cultural factors unrelated to efficacy as having impacted the citation rate.

Used Medicinal Plant Parts.
e commonest used parts cited are leaf (46), bark (17), fruits (9), root (9), latex (11), stem (11), and inflorescence (2) ( Figure 5) Many antimalarial herbal drugs are commonly prepared from a single plant part, although they could be prepared from the assortment of two or more plant parts. In this survey, leaf and bark were the most cited plant parts contributing to 255 and 101 of the 480 plant parts cited by the respondents. Leaves are the most commonly used plant parts in Nigeria [24,25]. is could be due to the simplicity of the collection, site of synthesizing majority of plant secondary metabolites, and diverse bioactive compounds appraised by preliminary phytochemical investigations of leaves [26][27][28]. Systematic harvest of leaves has little or no influence on plants survival. is explains the frequent utilization of leaves in herbal recipes [29,30].

Assessment of the Different
About four plant species are mentioned for the first time as antimalarial medicinal plant. ese plants have a low UV indicating that there is little awareness on these plants in the region. e plants are Cocos nucifera (0.01), Curcuma longa (0.01), Forkia biglobosa (0.01), and Musa acuminate (0.01).

Antimalarial Assays of Medicinal Plants.
Herbal plants are essential part of biodiversity which have proven to ease and remediate several diseases and infections. In tropical African countries, herbal medicine has been an undisputable therapeutic medium as alternative to conventional medicine [52]. In view of this, therapeutic potentials of medicinal      Cymbopogon citratus. Lemongrass (Poaceae) is a perennial grass, evenly distributed in the tropic region, South and Central America, and has an outstanding profile in the folk medicine [17]. e antimalarial potential of aqueous leaf extracts of C. citratus assessed on twenty-five Swiss albino mice demonstrated significant prophylactic and chemotherapeutic potency against mice infected with 0.2 ml O + human parasitized blood of P. falciparum after 72 h. Significant inhibition was observed in parasitaemia level of blood of infected mice [55]. A larvicidal test of geranial, an essential oil in C. citratus, was evaluated against Anopheles funestus (mature larvae) and P. falciparum according to the WHO standard procedure. Prominent activities were recorded at LD 50 (35.5 ppm and 34.6 ppm) after 6 h. Geranial also displayed significant antiplasmodial activity with IC 50   (4.2 ± 0.5l g/mL) when assessed by the radioisotopic method. Geranial could serve as effective natural biocides for combating the larvae of malaria vectors [61]. e antiplasmodial activity of aqueous leaf and root extracts of C. citratus (200, 400, and 800 mg/kg) and chloroquine (5 mg/kg) was examined against P. berghei in mice using 4-day suppressive test model at P < 0.05. A dose-dependent suppressive pattern was observed with chloroquine and 800 mg/kg (aqueous root extract) [67]. C. citratus plant displayed significant antimalarial activity than herbal concoction or chloroquine (3200 mg/kg) (control) when used as a prophylactic treatment against CBA/Ca mice with patent P. berghei ANKA or P. chabaudi AS at doses of 1600 and 3200 mg/kg. In addition, the synergetic activity of chloroquine and C. citratus plant exhibited high activity than chloroquine alone against P. berghei. e antimalarial activity of entire C. citratus plant aids inevitable efforts to developing whole plant remedies for the treatment of malaria [65]. Morinda lucida. e antimalarial investigation of partly purified cysteine-stabilised peptide extracts of M. lucida leaf was assessed in vitro against P. falciparum W2 and its activities on certain liver and erythrocyte antioxidant parameters in P. berghei NK65-infected mice. Low activities were observed in P. falciparum W2 (IC50: >50 μg/ml); however, in vivo activity against P. berghei led to 51.52% reduction in parasitaemia on 96 h after inoculation and considerably decreased (P < 0.05) malondialdehyde concentrations in the liver and erythrocyte at high doses in contrast to untreated controls [60]. N-Hexane and chloroform fractions of M. lucida leaf extract conducted using standard techniques showed significant activities at 0.6 mg/ ml [64]. e antimalarial activities of M. lucida investigated in P. berghei-infected mice exhibited dose-dependent chemosuppression of 39.8-90.5 which show pronounced activities than quinine [58].
Enantia chlorantha. Enantia chlorantha Oliver (or Annickia chlorantha) belongs to Annonaceae family, socalled Awopa, Osu pupa or Dokita igbo, Eru meru, Kakerim, and Erenba-vbogo in Nigeria. It is dense and widely distributed in Nigeria, Angola, Gabon, Cameroon, and Congo [77]. Oral administration of aqueous extract of E. chlorantha inhibited Plasmodium yoelii in mice at 0.2 to 150 mg/ml while ethanolic extract inhibited the parasite at dose of 0.05 to 0.5 mg/g. e ethanolic and aqueous extracts have ED 50 values of 0·34 mg·g −1 and 6·9 mg·g −1 which are schizonticidal in the mode of action. e activities could be linked to the presence of saponins, tannins, simple sugars, and alkaloids [78]. Synergic reactions of E. chlorantha with N. latifolia and A. altilis were reported to display significant antimalarial and prophylactic activities. is justifies the ethnomedical practice of combination of antimalarial herbal therapies in combating acute or chronic malaria [63].
Carica papaya. e antimalarial property of Carica papaya leaf extracts was screened against P. falciparum 3D7 and Dd2 strains using bioassay-guided fractions and dichloromethane extract. e petroleum ether and chloroform fractions of C. papaya fruit and root assessed in vivo for antimalarial activity against early P. berghei infection in mice displayed pronounced chemosuppressive effect at P < 0.001. Significant activities were observed in petroleum ether fractions (61.78%) compared to 48.11% of chloroform fraction [71]. e synergistic effects displayed by the administration of C. papaya and V. amygdalina in ameliorating plasmodium infection in mice showed significant result at P < 0.05. e oral administration significantly surged the RBC and PCV renaissance when compared to the disease control. is underlined the importance of plants in conventional therapy of malaria infection [68]. Ethanolic leaf extract of C. papaya was appraised on chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. e extracts significantly inhibited the activities of both plasmodium strains with IC 50 � 40.75%, 36.54%, 25.30%, and 18.0% for chloroquine-sensitive and IC 50 � 50.23%, 32.50%, 21.45%, and 23.12% for chloroquine-resistance plasmodium strains [81].
Azadirachta indica. Azadirachta indica extract is appraised to contain bioactive compounds which dictate its potencies against P. vivax and P. falcifarum [82]. Ethanolic leaf extracts assessed in vivo absolutely inhibited P. berghei growth, at azadirachtin dosage of 50 mg/kg mouse body    10 Scientifica  12 Scientifica  14 Scientifica  16 Scientifica weight [83]. e in vivo antiplasmodial potency of aqueous and ethanolic leaf extracts was examined in P. berghei-infected BALB/c mice at dosage of 50 to 200 mg/kg/day. Both extracts exhibited significant antiplasmodial potency in a dose-dependent technique which could be due to the active antiplasmodial compounds screened [56].

Conclusion and Future Prospects
Malaria is a universal civic health peril, and recent drug resistance of the parasite is a persistent concern. is study shows that a highly diverse set of native medicinal herbs is currently used for the management of malaria in Nigeria. Based on the results, there is substantial indication that the traditional use of antimalarial medicinal plants by Yoruba ethnics (studied areas) is driven by important therapeutic agents, which could be elucidated structurally and further established by in vitro or in vivo investigations. In recent times, the growing interest in phytoremediation of malaria led to the isolation and characterization of bioactive compounds in medicinal plants (Table 5) e isolation, characterization, and quantification of these compounds were appraised via chromatographic and spectrophotometric methods. Likewise, different assays such as susceptibility microassay technique [95], four day suppressive test [96], 96-well microtiter plate format SYBR green florescence assay [97], and LDH method [98] are used to appraise the antiplasmodial potential of plant extracts (Table 4). Several modes of preparation, usage factors, health risks, and countermeasures on the use of antimalarial herbal drugs should be systematically examined through advanced scientific approaches. is will aid in the identification and authentication of therapeutic potency of antimalarial compounds isolated from medicinal herbs, thereby promoting its global relevance as efficacious and safe antimalarial plants in primary health care. Individuals, societies, sociogroups, and governmental and nongovernmental organizations should devise plans which could assist in the conservation of these medicinal plants in order to prevent their extermination and exploitation of indigenous populations, as well as considerations for cultural disruptions should one or more of these plant species become a valuable resource. In the meantime, the outcomes of this study serve as a platform of appraisal for indigenous claims of medicinal plants as effective antimalarial drugs in Nigeria and the world as a whole.
Data Availability e datasets used and/or analysed during the current study are available in the manuscript and others not included are available from the corresponding author upon request.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the submission and publication of this article.

Authors' Contributions
All authors designed the experiment, administered the questionnaires, and analysed and discussed the data obtained. 18 Scientifica