Open access peer-reviewed chapter
Abstract
Malaria is a complex disease associated with a variety of epidemiology and clinical symptoms worldwide. Despite the availability of a variety of antimalarial medications, national policies of many countries advocate for a single-medication first-line therapy for the majority of clinical malaria symptoms. However, the studies revealed that using multiple first-line medicines against malaria works more effectively. In this scenario, single-target monotherapy approaches have difficulties since malaria symptoms are seldom caused by single molecular entities. The current work is based on the critical literature review and primary sources as well as secondary databases. The chapter outline is as follows: (1) main antimalarial plant-derived active pharmaceutical ingredients (APD-APIs), (2) limitations of single APD-APIs and shift to multiple first-line therapies in malaria treatment, (3) techniques in the development and properties of APD-APIs co-crystals. The search for novel plant-derived antimalarial medicines and the development of antimalarial co-crystals are essential in the fight against antimalarial drug resistance.
Keywords
- antimalarial drugs
- mono-therapy
- multiple first-line treatments
- co-crystallization
- plant-derived antimalarial drugs
1. Introduction
Malaria deaths and cases have decreased dramatically in the last 15 years, yet it remains one of the leading tropical diseases in terms of reported deaths [1]. Accordingly, the World Health Organization (WHO) recorded up to 216 million cases of malaria and about 445,000 deaths in 2016 only [1]. Development of antimalarial medicine resistance, as well as dramatically diminished sensitivity to artemisinin combination therapy (ACT), is the primary cause of this trend [2, 3, 4, 5, 6]. Apart from that, the chemotherapeutic choices for treating and preventing malaria are limited [4]. In light of these circumstances, novel antimalarial drug discovery, particularly medicines associated with multiple mode of action and versatility in terms of efficacy against resistant
The search for APD-APIs is motivated by previous studies, which have revealed the existence of two important plant-based antimalarial drugs (1) quinine and (2) artemisinin from
Interestingly, plants are important sources of APIs, which can be utilized in treatment and prevention many human health problems including malaria [17]. Generally, up to 25% of known plant species are exploited in medicine production worldwide and approximately 65% of the global population count on plants for their basic health care [20, 21]. These plants have been identified as rich sources of template compounds for synthesis of other important drugs and in the prevention as well as fight against many infectious diseases including malaria. In the case of malaria, two lead antimalarial drugs, quinine and artemisinin, have been utilized as derivatives of chloroquine and artemether, respectively. Additionally, antimalarial drugs such as primaquine, amodiaquine, and mefloquine are synthesized based on quinine and in antimalarial drugs including arteether, and sodium artesunate, where artemisinin is the lead compound [7, 22]. Plants are associated with potential antimalarial APIs classified into major groups including flavonoids, alkaloids, glycosides, terpenoids, and phenolic acids [23].
Co-crystals are solid compounds that show promise in drug development, particularly in terms of improving physicochemical properties such as drug solubility. Generally, co-crystals are formed due to the interactions between (1) active pharmaceutical ingredients (APIs) and (2) co-crystals forming agents (normally solid under ambient conditions) [24, 25]. Normally, H-bond holds the two components of co-crystals, and this is facilitated by functional groups of APIs, e.g., carboxylic acid functional group. Moreover, APIs are associated with other function groups such as amine and amide groups [26]. Co-crystallization is performed under relatively mild reaction conditions. The techniques for preparing co-crystals are classified into (1) solid-state and (2) solution-based [27, 28, 29, 30].
Despite the various studies that have been conducted on a wide range of pharmacological molecules, plant-derived antimalarial drug molecules appear to have been neglected [10]. Many current antimalarial drugs are becoming ineffective owing to the drug resistance. For instance,
2. Summary of main APD-APIs
According to Ungogo [31], statistics for pharmaceuticals authorized by the U.S Food and Drug Administration (1981–2010) suggested that around 35% of approved new medicines were derived from natural sources, with plants-derived drugs contributing 25%. Phenolics, quinones, alkaloids, saponins, terpenes, and their derivatives are examples of APD-APIs. Notably, these APD-APIs can be utilized as both crude phytomedicines and pure pharmaceuticals. They can, nevertheless, serve as basis for the production of synthetic pharmacologically complex active compounds, models for designing lead molecules, and taxonomic markers for the discovery of novel drugs [31].
2.1 Alkaloids
Alkaloids are a group of diverse plant secondary metabolites characterized by a basic nitrogen associated with a carbon ring [32]. The classification of these APD-APIs is on the basis of the principal C-N skeleton, and in certain instances, classification is according to biological origin. Using the first classification system, alkaloids are classified into 13 classes: pyrroles, pyrrolines, pyrrolidines, pyrrolizidines, indoles, pyridines, pyrimidines, piperidines, quinolones, isoquinolines, quinolizidines, tropanes, and imidazoles [31]. Antimalarial alkaloids have been reported in several studies, for instance, Iwu and keayman [33] isolated alkaloids (which are antimalarial) from
Figure 1.
Some examples of the antimalarial alkaloids.
2.2 Terpenoids
Terpenoids are compounds of plant essential oils and terpene hydrocarbons derivatives, and according to [35], these APD-APIs are classified into eight categories: monoterpenoids, diterpenoids, triterpenoids, tetraterpenoids, hemiterpenoids, sesquiterpenoids, sesterterpenoids, and polyterpenoids. Notably, in several studies, terpenoids were identified in antimalarial plant essential oils [35, 36, 37, 38], and most of the plants from which essential oils are extracted have been exploited as traditional antimalarial and antipyretic medicines [39]. One of the most common antimalarial terpenoids is artemisinin, which is classified as sesquiterpenoid. This sesquiterpenoid (artemisinin) as well as bioactive compounds derived from this antimalarial is highly antimalarial especially against
Figure 2.
Some examples of the antimalarial terpenoids.
2.3 Quinones
Quinones are normally classed on the basis of their molecular structure, and accordingly, they are classified into three major groups: anthraquinones, benzoquinones, naphthoquinones. The three classes of quinones are aromatic ring based where anthraquinones, benzoquinones, and naphthoquinones have linear/angular anthracene ring, benzene ring, and naphthalenic ring, respectively [46]. Benzoquinones were isolated and had a substantial
Figure 3.
Some examples of the antimalarial quinones.
2.4 Phenolics
Phenolic compounds are considered highly abundant group of plant metabolites. These metabolites are classified into three major groups: flavonoids (polyphenolic compounds, which exist as aglycones, methylated derivatives, and glucosides in plants), phenolic acids (e.g., hydroxybenzoic and hydroxycinnamic acids), and polyphenols [55, 56]. Additionally, these APD-APIs are characterized by a hydroxyl group bonded to an aromatic hydrocarbon group, with the most basic being a phenol (C6H5OH). Phenolics include lignins and tannins (polyphenolic compounds with high molecular weight) such as hydrolyzable and condensed tannins. Classification of phenolics is normally based on three methods: (1) number of hydroxylic groups, (2) chemical composition, and (3) number of aromatic rings as well as number of carbon atoms in the side chain [56]. Generally, phenolic compounds are rarely in a free form in plants, and therefore, they exist as glycosylates and polyphenols [55, 56, 57]. Phenolic compounds such as ellagic acid have shown significant degree of activity against malaria parasites, for example, [58] reported antimalarial activity of ellagic acid against
Figure 4.
Structural summary of some of the antimalarial phenolics.
3. Limitations of single APD-APIs and shift to multiple first-line therapies in the treatment of malaria
3.1 Limitations of single APD-APIs in malaria treatment
The treatment of malaria is basically based on natural products, for example, APD-APIs, semisynthetic and synthetic compounds. Effective and safe antimalarial drugs are broadly classified into three main categories: (1) quinoline derivatives, (2) antifolates, and (3) artemisinin derivatives [64]. The first identified and widely used APD-APIs was quinine, an alkaloid. Notably, quinine was extracted from the
The derivative of quinine, 8-aminoquinoline (primaquine), was utilized as a monotherapy against malaria during the first part of the twentieth century. However, it was disregarded due to abnormally elevated toxicity associated with highly reduced activity [64]. The other antimalarial drugs, which were widely exploited as first-monotherapy after abandonment of primaquine, include quinacrine, a derivative of acridine. Another derivative of quinine, a 4-aminoquinoline, chloroquine was later used as a first-line monotherapy against malaria for several years due to its efficacy, low as well as manageable side effects, and low cost [68]. Being the first-line monotherapy for a long period of time, chloroquine has led to
Though not plant-derived, pyrimethamine was widely utilized as an antimalarial monotherapy in early 1950 and late 1960 as a prophylactic and treatment drug. Due to resistance of malarial parasite against pyrimethamine, pyrimethamine was combined with sulfadoxine to produce a more efficient antimalarial drug, sulfadoxine-pyrimethamine (SP) [71]. This antimalarial drug was recommended as a first-line drug in many countries associated with chloroquine inactivity [72, 73]. Although for some time, resistance to pyrimethamine was inhibited by sulfadoxine, inactivity of sulfadoxine to malaria parasites was finally reported in African and Asian countries [71, 72, 73]. This prompted the use of artemisinin, an antimalarial drug, which was discovered from an important plant,
The use of artemisinin as monotherapy has been noted in many regions including western part of Cambodia, and clinical studies in these regions have shown emerging
Artemisinin and its derivatives including artesunate are characterized by being quick-acting and rapid blood parasite reduction. However, this effectiveness is hampered by a rise of artemisinin-resistant
3.2 Shift to multiple first-line therapies in malaria treatment
Shift from monotherapy to multiple first-line therapies in malaria treatment, e.g., use of artemisinin-based combination therapy (ACTs) has been exploited as an intervention to alleviate resistance to several antimalarial monotherapies [87], and according to [88], the adoption of ACTs was as a result of occurrence of resistance to oral artemisinin monotherapies. ACTs are produced by combining artemisinin derivatives with complimentary partner drugs, and the net effects of combining these drugs are: (1) rapid action and short period of treatment due to artemisinin derivatives and (2) prevention of recrudescence due to the partner drug [71, 89, 90]. It is against this background that WHO recommended the use of ACTs in the early 2000s in countries that had prevalence of
4. Techniques in the development and properties of APD-APIs co-crystals
4.1 Techniques for development of co-crystals
Despite the fact that there are several APD-APIs, they lack key pharmacological activities due to poor physicochemical qualities such as low bioavailability, stability, and solubility [97]. Nanoparticles, co-crystallization, liposomal formulations, chemical changes, and changing ADP-APIs into solids such as polymorphs, salts, and hydrates are just a few of the strategies that may be employed to improve physical characteristics of ADP-APIs [98]. Co-crystallization has been praised for its effectiveness in increasing the pharmacological characteristics of APD-APIs. The use of co-crystallization to adjust the physical features of APD-APIs is excellent since co-crystals are not considered as new medications by the US Food and Drug Administration, but rather pro-drugs [99]. Although co-crystallization of APD-APIs improves their biopharmaceutical and physicochemical traits, there is need to screen APD-APIs based co-crystals. The screening of co-crystals efficiency is basically based on emerging techniques including quantitative structure-activity, Hansen solubility parameters calculation, and pKa rule [100, 101].
Co-crystallization involves dissolving APIs and respective coformers in an appropriate solvent at a predetermined stoichiometric ratio and the solvent is then removed to saturate of solutes for co-crystal production [25, 26]. This therefore implies that co-crystallization is based on slow solvent evaporation as well as reaction co-crystallization and slurry and antisolvent diffusion [12, 28]. Basically, co-crystallization is dependent on strong H-bonds between APIs and their respective coformers, thereby facilitating co-crystal formation [27, 29]. Notably, co-crystallization under the solution-based technique can be effectively achieved if the least soluble component is prevented from sole precipitation, and co-crystals’ purity can be improved by selecting APIs and coformers with congruent solubilities [28, 29, 30]. In addition to this, other factors such as solvent systems, stoichiometric ratio, and crystallization temperature influence co-crystallization process [29]. Costa et al. [102] reported that co-crystal structures from APIs and coformers with similar shapes and polarities co-crystallize easily with each other.
In addition to solution-based technique, solid-state grinding can be applied, and this involves homogenizing APIs and coformers in mortar to prepare co-crystals using mechanical techniques [29, 102]. Solid-state grinding techniques (SSGTs) are based on and depend on molecular mobility and existence complementarity between APIs and coformers [26, 27, 28, 29, 30]. Preparation of co-crystals may involve addition of small quantities of solvents before grinding of APIs and coformers, where the solvent facilitates co-crystal formation. This technique is called liquid-assisted method and is highly efficient in the formation of co-crystals [26, 27, 28, 29, 30]. APIs (bioactive compounds) generated from antimalarial plants are essential and have received attention in drug discovery and development. However, due to their poor physicochemical and biological qualities, such as solubility, stability, and dissolution performance, the large proportion of antimalarial plant-derived APIs (APD-APIs), such as alkaloids, flavonoids, phenolic acids, and terpenoids, are disregarded [19, 21, 23]. These PDADs-APIs supply a lot of hydrogen bond donors and acceptors for co-crystal formation, which makes it possible for APD-APIs and coformers to interact [29, 102]. Co-crystallization of these APD-APIs with coformers provides distinct advantages in terms of modulating physicochemical features of these compounds while avoiding covalent interactions that might compromise their therapeutic potential [27, 28, 29]. These PDADs-APIs supply a lot of hydrogen bond donors and acceptors for co-crystal formation, which makes it possible for APD-APIs and coformers to interact [102].
Co-crystallization can be applied to the production of multicomponent solids with more than two APIs. This combination of APIs has recently improved physical properties of individual APIs and reduced the number of doses given to a patient [103, 104]. It has, however, noted that formulation of APIs-APIs combinations is associated with inherent challenges including chemical interactions, instability, and variations in solubility of different APIs [105]. Though APIs-APIs combinations could potentially address the issues around antimalarial resistance, there is dearth of published information on APIs-APIs co-crystals. As indicated for other APIs-APIs co-crystals, APD-APIs- APD-APIs combinations are presumed to have synergistic as well as additive effects and enhanced bioavailability, among other advantages of biopharmaceuticals (Figure 5).
Figure 5.
Theoretical outline of the formation of APD-APIs co-crystals.
4.2 Properties of APD-APIs co-crystals
APD-APIs have poor physicochemical qualities, and their combination with coformers to produce co-crystals considerably improves a variety of attributes including thermal stability, solubility, and hygroscopicity [106]. The alteration of these APD-APIs affects therapeutic action while retaining pharmacological properties [97]. An overview of the key attributes of both APD-APIs and APD-APIs co-crystals is outlined in this section.
4.2.1 Thermal stability
Thermal stability is a critical feature for any APD-API or APD-API co-crystal. However, most APD-APIs have low thermal stability, and modifying these APD-APIs into APD-API co-crystals has demonstrated to enhance overall stability [107]. Notably, APD-APIs that easily sublime at room temperature inevitably result in drug loss during manufacture and storage. According to Lu et al. [108], the conversion of APD-APIs into APD-API co-crystals such as 2,6-dihydroxybenzoic acid has greatly increased thermal stability, as evidenced by results of study using differential scanning calorimetry and the thermogravimetric analysis method. When compared with APD-API, dihydroartemisinin, which sublimes at a relatively low temperature, co-crystals such as 2,6-dihydroxybenzoic acid have a higher sublimation temperature above 100°C, indicating a better degree of thermal stability [108].
4.2.2 Solubility
APD-APIs are often either slightly soluble or insoluble, which limits their application as biopharmaceuticals. The modification of these APD-APIs into co-crystals may be crucial, as several studies have shown that co-crystals can maintain stability while also enhancing solubility [109]. In most circumstances, it has been noted that selecting highly soluble coformers can increase co-crystal solubility. For example, in the production of certain APD-APIs co-crystals, extremely soluble coformers such as succinic acid and benzoic acid have been used [110].
4.2.3 Hygroscopicity
Because of the presence of free functional groups such as hydroxyl groups, most APD-APIs, including phenols, are very unstable at high relative humidity (have high hygroscopicity) [111]. Wong et al. [112], on the other hand, claim that the interaction between APD-API and their respective coformers during crystallization processes increases stability at high relative humidity. Curcumin-resorcinol co-crystals, for example, have been demonstrated to be very stable at high (95%) relative humidity as compared with curcumin, which quickly absorbs moisture at 75% relative humidity [113]. The interaction between the APD-API functional groups and those of the coformers, resulting in intermolecular interactions, is correlated to the stability of APD-API co-crystals at high (95%) relative humidity (low hygroscopicity) [114]. The presence of these intermolecular connections in APD-API co-crystals inhibits the interaction between moisture and APD-API functional groups [111]. This basically means that when the interactions between coformers and APD-APIs increase, the barrier to moisture absorption of APD-API co-crystals falls dramatically.
5. Challenges and opportunities associated with development of co-crystallized antimalarial drugs from APD-APIs
Notably, APD-APIs are divided into two categories: (1) potential compounds for natural medicine production and (2) templates for artificially synthesized pharmaceuticals [115]. The quest for novel plant-derived antimalarial drugs, as well as the development of phytomedicines in general, is, however, inherently associated with two major obstacles, (1) existence of extremely active plant compounds with complicated molecular structures, where no feasible industrial production is envisaged, and (2) presence of APD-APIs with relatively reduced activity yet with relatively simple molecular structures, for which artificial production could be conducted [115, 116]. With notable examples of naturally occurring ADP-APIs, the development of novel antimalarial drugs is without. Although various powerful plant-derived antiplasmodial compounds have been documented, the majority of them have only been assessed in vitro, with few being evaluated for toxicity and even fewer being evaluated in vivo [117, 118]. Furthermore, most of them seem to be present in low quantities in plants and are frequently found as part of complicated composites, making separation and processing extremely costly. Among other factors, scientific evaluation of traditional ADP-APIs is limited by paucity of ethnobotany information [115, 117].
6. Conclusion and outlook
Though co-crystallization is a critical technique of improving therapeutic potential of pharmaceutically poor APD-APIs, there are several changes associated with APD-APIs co-crystal production including identification of suitable coformers and appropriate methods of production. However, like any other co-crystals, APD-APIs co-crystals are presumed to improve physical and pharmaceutical properties of ADP-APIs. APD-APIs such as phenolic acids and terpenoids have been shown to provide important functional groups, which allows for the formation of non-covalent intermolecular associations with a number of coformers during co-crystallization processes. In this chapter, information on pharmaceutical applications of APD-APIs co-crystals is summarized. With more research and clinical studies, co-crystallization of APD-APIs into single and multi-component molecules could provide the basis for malaria treatment.
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