Antiplasmodial compounds with high selectivity isolated from plants.
Nearly 3.3 billion people globally are at risk of malaria, with 1.2 billion being at high risk. Children under 5 years of age and pregnant women in sub-Saharan Africa still account for a higher percentage of malaria-related mortalities, despite recent reports of decline in malaria mortalities in Africa. Majority of these deaths are caused by Plasmodium falciparum, a lethal malaria parasite which has developed resistance to different classes of antimalarial drugs and is responsible for complicated, severe disease. To forestall the debilitating impact of the disease and provide safe and effective alternative therapies, medicinal plants have been explored as a source of new antimalarials. The isolation of quinine and artemisinin from plants present medicinal plants as a robust source of effective antimalarials. In this chapter, we review the different approaches employed in antimalarial discovery from plants, different classes of plant antimalarial compounds and their proposed mechanisms of action. Compounds that show potential for further development based on their high efficacy and selectivity are also highlighted. Common obstacles encountered in the process of antimalarial drug discovery from plant sources are identified and prospects for the identification of new, effective antimalarial components from plant sources are also discussed.
- Antiplasmodial screening
- Medicinal plants
- Plasmodium falciparum
Malaria has remained a leading cause of mortality in close to 100 countries where nearly 2.4 billion people reside, almost half of whom are located in sub-Saharan Africa. With continuous malaria transmission all year round and increasing rates of human movement in disease-endemic areas, a high burden of antimalarial use in these areas has contributed to global malaria burden . Exposure of parasites to suboptimal antimalarial drug concentrations favors the selection of parasites with traits that enable them to survive in the presence of the drug . Over time, the most lethal strain of the malaria parasite,
In order to fast-track the development of effective, alternative medicines from medicinal plants, appropriate pre-clinical studies that confirm their safety and efficacy are required to provide sound experimental data that establish an evidence base. The development of effective medicines from plants is not without its challenges and efforts should be made to address these especially with novel approaches to preclinical screening and clinical testing. Conventional drug development is very time dependent and cost dependent but is rarely rewarding eventually; as the number of approvals for new drugs has declined in recent years . Hence, we also explore the revisited “reverse pharmacology” paradigm to address this problem and secure the future of antimalarial drug discovery.
1.1. Current status of drug discovery from plant sources
Many medicines used against different diseases including cancer, diabetes, hypertension, neurodegenerative disorders and infectious diseases have been sourced from a plant or designed based on scaffolds of compounds isolated from plants. The latest of these include artemether (antimalarial), galantamine (for Alzheimer’s disease), nitisinone (for tyrosine-associated metabolic disorder) and tiotropium (anticholinergic), which have all recently been introduced in the United States or are currently involved in late-phase clinical trials . Drug discovery from medicinal plants involves a multi-thronged approach that includes, but is not limited to traditional medicine practitioners, botanists, medicinal chemists, pharmacologists and molecular biologists. Conventionally, plants are selected either randomly or based on their claimed historical medicinal relevance and subjected to sequential extraction and purification steps. This can be very tedious and time-consuming and more effective methods for identifying new lead molecules from plants have been explored. These include chemoinformatics and bioinformatics as tools for in silico drug discovery , systems/polypharmacology approach which integrates oral bioavailability tests, druggability, blood-brain barrier permeation, target identification and network analysis owing to the complex composition of medicinal plant extracts and their diverse physiological effects . High throughput pharmacological screens and genetic manipulation have also been applied to discover new drug leads from plants, in which plants extracts are screened against an array of receptors with or without gene manipulation and compared to existing drugs .
2. Approaches in antimalarial drug discovery
Six major approaches to antimalarial drug discovery have been identified and reviewed, including the investigation of natural products . A plant-based approach is particularly useful in resource-poor, malaria-endemic areas where nearly one-fifth of patients rely on herbal remedies to treat malaria and febrile illnesses . The choice of plants for antimalarial drug discovery may be based on both random and empirical methods to explore biodiversity or through studies guided by traditional use of the plant in the treatment of fever. The latter ethnopharmacological approach has been recognized to give higher success rates for finding active compounds, as over 50% of extracts from ethnomedicinal plants were active in vivo and/or in vitro .
2.1. Ethnopharmacology-based plant selection and extraction
Herbal medicines have played a pivotal role in health and disease management for many centuries. Different ancient civilizations, including Mesopotamian, Indian ayurveda, ancient traditional Chinese medicine and Greek unani medicine, show documented evidence for the use of herbs in the treatment of different ailments. In Africa, knowledge of traditional medicine constitutes part of a wholistic system, passed through generations by oral communication and indigenous practices . The scientific exploitation of herbs used ethnomedicinally for pain relief, wound healing and abolishing fevers has resulted in the identification of a wide range of compounds that have been developed as new therapeutics .
The major role of ethnopharmacology is to discover new plant-derived compounds based on the traditional use of medicinal plants. The knowledge on the use of plants for fevers and other symptoms of malaria is used to guide the selection of plants to be subjected to antimalarial screening and isolation of active constituents. This is a favored and conservative approach in drug discovery as historical use of a plant as medicine increases the possibility that safe and pharmacologically active compounds would be isolated from it.
2.2. Preclinical efficacy studies
2.2.1. In vitro assays
In vitro cultures of asexual forms of
Detection of parasite growth in in vitro assays generally involves the examination of Giemsa-stained smears for viable parasites. This method is very time-consuming, lacks precision and limits rapid, large-scale screening of compounds. Colorimetric determination of parasite lactate dehydrogenase in the presence of nitro blue tetrazolium which is reduced to a formazan derivative has been developed and used successfully . Other methods have been developed which rely on incorporation of radiolabeled metabolic precursors, measurement of dye-stained parasite DNA by fluorimetry or flow cytometry and use of luminometry for genetically modified parasites that express luciferase [19–21]. Fluorescence-based assays that employ DNA-binding fluorophores have also been described, for example, the fluorimetric method described by Benoît et al.  in which parasite growth is quantified by stained DNA of viable parasites. Enzyme-linked immunosorbent assays (ELISAs) with monoclonal antibodies which measure
Culture conditions for other human and nonhuman
2.2.2. In vivo assays
Mouse models of malaria infection using rodent parasites are especially useful for studying the pathological effects of interactions between the host and the parasite. These models predict clinical outcomes of infections such as parasitemia, sequestration of parasitized red blood cells, splenomegaly, pulmonary edema and hematological and biochemical phenomena. Laboratory rodent parasites such as
2.2.3. Bioactivity-guided studies, compound isolation and identification
In common practice, traditional herbal remedies are prepared in water, either at room temperature or by boiling to obtain a decoction. Alcoholic solvents are also used as they produce higher extract yield and extract a wider variety of chemical components compared to aqueous extraction . Separation and purification processes for antimalarial plant extracts and fractions involve different chromatographic methods. Frequently, as the extract is separated sequentially, antiplasmodial activity is monitored with a high-throughput in vitro bioassay until the compounds responsible for activity are isolated. This method is based on the assumption that antiplasmodial activity is limited to one or few compounds, whereas when such activity is due to different compounds acting synergistically, it may be lost with further separation . Chromatographic procedures commonly employed include flash column, medium- and high-pressure liquid chromatography and centrifugal countercurrent chromatography. The structure of isolated compounds is determined on the basis of their spectroscopic properties using mass spectrometry, ultraviolet and infrared spectroscopy and complete proton and carbon mapping using one- and two-dimensional nuclear magnetic resonance techniques. It has also been possible to use tandem or hyphenated techniques of these spectroscopies for full stereochemical elucidation of constituents without isolation from extracts . The compound obtained is thereafter subjected to further testing, extending to transmission and radical cure assays. Following the selection of a lead compound, it may be optimized by synthesizing chemical derivatives with the desired bioavailability, potency and selectivity before pre-clinical testing for efficacy and safety, preparatory for phase I clinical testing .
3. Isolated compounds and antiplasmodial activity
Some examples of identified compounds that exhibit good antimalarial activity
where EC50 = effective concentration required to inhibit cellular growth by 50% and IC50 = concentration required to inhibit parasite growth by 50%.
From the compounds shown in Table 1, it is evident that a remarkable diversity of plant-derived compounds exists and they can form good templates for the design of novel antimalarials. One example of such is gedunin, a limonoid extracted from the leaves of
A study of species of
Other compounds have also been investigated and found highly active against hepatic stage
|Compounds||Plant source||Family||Antiplasmodial activity||Source|
|Gedunin||Meliaceae||(Pf D6) 0.039 μg/mL|
(Pf W2) 0.02 μg/mL
|Febrifugine||Hydrangeaceae||(Pf W2) 0.53 ng/mL|
(Pf D6) 0.34 ng/mL
|Ellipticine||Apocynaceae||(Pf K1) 0.81 μM|
(Pf 3D7) 0.35 μM
|Olivacine||Apocynaceae||(Pf K1) 1.4 μM|
(Pf 3D7) 1.2 μM
|Uvaretin||Annonaceae||(Pf K1) 3.49 μg/mL||[37, 38]|
|Bartericin A||Moraceae||(Pf W2) 2.15 μM|||
|Lanaroflavone||Anacardiaceae||(Pf K1) 0.48 μM|||
|Ineupatorolide A||Asteraceae||(Pf D10) 0.019 μM|||
|6α,7β-Diacetoxyvouacapane||Leguminosae||(Pf 3D7) 0.97 μM|||
|Neosergeolide||Simaroubaceae||(Pf K1) 0.002 μM|||
|(+)-Catechin-3-gallate||Fabaceae||(Pf FcB1) 1 μM|||
4. Isolated compound classes and intra-parasitic targets
This group of plant secondary metabolites represents the largest group of plant secondary metabolites with the highest number of compounds displaying potent antiplasmodial activity. They also serve as good templates for synthesis of many quinolone-based antimalarial drugs. Alkaloids displaying potent antiplasmodial activity occur as steroidal alkaloids, bisbenzylisoquinolines, naphthylisoquinolines, indoloquinolines and indolomonoterpenoid alkaloids, among others. Quinoline alkaloids isolated from the bark of
Although the mechanism of action of quinine has not been fully resolved, it has been reported to exhibit inhibitory effects on heme polymerization and heme catalase activity . Following the success of quinine identification and use, natural antiplasmodial alkaloids have been isolated and reviewed by Kaur et al. . Some alkaloids have been reported to inhibit fatty acid biosynthesis in the parasite , while some act as resistance reversers. The monoindole alkaloids strychnobrasiline and malagashanine isolated from
4.2. Flavonoids and chalcones
Flavonoids occur ubiquitously in many higher plants where they act as growth regulators and offer protection against plant pathogens . They have been proposed to act by inhibiting the fatty acid biosynthesis (FAS II) pathway, which is present in the parasite’s apicoplast but absent in human hosts . The flavonoid, luteolin-7-O-β-d-glucopyranoside, was reported as the first natural product that targets plasmodial FAB I enzyme which regulates the FAS II pathway . Some flavonoids have also been shown to inhibit l-glutamine and myoinositol influx into infected erythrocytes or act by interfering with hemin degradation [54, 55]. In addition, chalcones have been proposed to act by inhibiting cyclin-dependent protein kinases and plasmepsin II .
4.3. Terpenes and terpenoids
In recent times, attention has been devoted to this class of compounds especially sesquiterpenoids, following the discovery of the endoperoxide sesquiterpene lactone; artemisinin. These compounds are attractive because some possess intrinsic antiplasmodial activity and offer good starting points for chemical modification into derivatives with desired physicochemical properties and enhanced efficacy. Artemisinin and its derivatives owe their antiplasmodial effects to the presence of an endoperoxide bridge that generates toxic-free radicals when it is broken down (Figure 2). Another example of a highly potent antiplasmodial sesquiterpene is ineupatorolide A (Table 1).
Apart from the major classes of isolated compounds discussed above, other examples such as xanthones, stilbenes, coumarins, lignans, tannins and steroids have also been reported to exhibit potent antiplasmodial effects .
5. Clinical studies
Literature search revealed only few plant-derived extracts or compounds undergoing clinical studies and these are shown in Table 2. Spirotetrahydro β-carbolines (spiroindolones) present a unique group of compounds that share structural similarities with strictosamide, an iridoid indole alkaloid identified in an extract of
6. Reverse pharmacology: from bedside to bench
Conventional drug discovery and development is an energy-, time- and resource-demanding venture; hence, the entire process results in minimal success rates. Millions of compounds are involved during initial screening and identified hits are ranked based on potency, ease of synthesis, known limitations to therapeutic use and novelty to determine a possible lead compound . The lead compound is thereafter subjected to preclinical tests and various optimization processes to confer desired chemical and pharmacokinetic properties on it before final clinical testing. After passing through rigorous Phases I-III trials, it may be accorded statutory approval for clinical use. This is very expensive and time-consuming and many pharmaceutical companies are looking for new approaches in drug discovery that will lead to expedited launch of new, effective and safe drugs.
Reverse pharmacology is a science that integrates well-documented clinical experiences and observations toward lead development, through interdisciplinary studies (preclinical, clinical) for drug development . Here, “safety“ is the starting point as well-documented evidence of traditional use as medicine. This provides an important basis for further scientific testing. Hence, reverse pharmacology adopts a “bedside to bench” approach, compared to conventional “bench to bedside” drug discovery and development.
The use of
An example of antimalarial drug development using the reverse pharmacology approach in recent times is seen in the study of a standardized extract of
It is interesting to note that subsequent to the report on the clinical efficacy of
Naturally occurring antiplasmodial compounds in plants show vast chemical diversity but also exist within a complex mixture of other plant secondary metabolites which in itself constitutes a major challenge to efforts in identifying compounds responsible for biological effects. Other problems with plant-based drug discovery process range from the basic ones like sustainable access to plant material, seasonal and environmental variations and legislative issues concerning plant use, to challenges concerning complex fractionation procedures, small quantity of pure compounds and poor pharmacokinetic/physicochemical properties that negatively affect druggability . With an increasing understanding and use of genomics, it is possible that bioactive molecules can be produced more efficiently using plant-cell cultures and genetically modified microbes . This has already been exploited in the production of artemisinin precursors from genetically modified
Innovative drug discovery through reverse pharmacology or conventional methods especially in resource-constrained remote areas where medicines are urgently needed should be given more attention. There is the need to explore other aspects of the use of plant extracts and compounds as efficacy boosters or drug resistance reversers in combination with conventional therapy . Efficacy screening against the parasite at all stages of development including gametocytes and hypnozoites should be incorporated in preclinical drug testing as they are often overlooked yet useful tools to identify agents that block transmission of resistance and prevent relapse . In the course of literature review, a number of antimalarial compounds reported also displayed significant cytotoxic effects on human cells. Thus, screening for inhibitors against parasite-specific targets in organelles like the apicoplast and pathways such as heme degradation and type II fatty acid biosynthesis would likely identify active leads with highly selective antiplasmodial action.
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