**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 *Cinchona calisaya* bark [65] and was used as first-line monotherapy. However, this antimalarial drug was exploited in the synthesis of a number of derivatives including 8-aminoquinoline (primaquine) and 4-aminoquinoline (chloroquine) [65, 66]. These derivatives of quinine were shown to eliminate malaria parasites through preventing biotransformation of heme, into nontoxic pigment granules, and therefore allowing heme to accumulate and promote cell lysis as well as Plasmodia auto-digestion [66]. Though quinine was an effective APD-API, development of resistance among *P. falciparum* strains and high toxicity has significantly contributed to its limited use. Additionally, this alkaloid (quinine) has a fairly short pharmacological half-life [66, 67]. However, use of quinine combined with other antimalarial drugs (in order to improve therapeutic efficacy) against malaria has been reported [12, 64].

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

#### *Co-Crystallization of Plant-Derived Antimalarial Drugs: An Alternate Technique for Improved… DOI: http://dx.doi.org/10.5772/intechopen.106200*

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 *P. falciparum* strains, which are chloroquine-resistant [36]. Other quinine derivatives used as first-line monotherapies and are linked to several adverse effects and emergence of resistance include pyronaridine and mefloquine [69]. Although chloroquine significantly reduced malaria-related mortality and morbidity, its prolonged use has resulted in spread of resistance. For instance, cases of chloroquine resistance were reported in countries including Brazil, Thailand, and Vietnam by 1964 [70, 71]. Furthermore, according WHO reports of 1979 and 1981, chloroquine resistance was reported to have covered most parts of North-East India, South America, and Southeast Asia by 1980 [71].

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 [71–73]. This prompted the use of artemisinin, an antimalarial drug, which was discovered from an important plant, *Artemisia annua* in the year 1972 [74]. Artemisinin is an APD-API classified under terpenoids and is specifically a sesquiterpene lactone [75]. This APD-API has been identified to be effective against blood as well as *P. falciparum* gametocyte stages [76].

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 *P. falciparum* strains, which are resistant to artemisinin [77]. Apart from reports of resistance of *P. falciparum* strains to artemisinin, artemisinin is inherently linked to solubility and bioavailability challenges [78, 79]. This, therefore, has resulted in the synthesis of quite a number of artemisinin derivatives with varying degrees of solubilities in oil and water [78–80]. The most common synthetic artemisinin derivatives include artemether, dihydroartemisinin, artesunate, and arteether. Based on their solubilities in water and oil, they are administered into the patient using different routes, for instance, artemether and dihydroartemisinin, which are oil- and water-soluble, are intramuscularly and administered orally administered, respectively [78]. In the face of this improvement, artemisinin derivatives are quickly absorbed, distributed, and metabolized.

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 *P. falciparum* as described in nations including western Cambodia, Myanmar, Viet Nam, and Thailand [5, 78, 81]. Additionally, reports of decreased sensitivity to artemisinin of *P. falciparum* isolates have been made in Nigeria and Madagascar [82]. A number of malaria patients from countries such as Sierra Leone, India, and western Thailand took time to respond to artemisinin derivatives including artesunate and artemether [78, 83, 84]. Furthermore, the use of these antimalarial drugs as first-line monotherapy is associated with maintenance of an effective drug concentration for a short period after drug administration. In addition to this, short oral treatment courses have contributed to increased rates of

recrudescence [66, 71, 85]. An increase in the number days of days of treatment to 7 has significantly reduced recurrent parasitemia, when artemisinin or its derivatives are utilized as monotherapy [74, 77, 85]. Generally, insensitivity to conventional antimalarial monotherapy including artemisinin as well as artemisinin-derived drugs has contributed significantly to antimalarial monotherapies being overlooked and disregarded [86]. Thus, a number of techniques are being explored globally to enhance potency of antimalarial drugs especially plant-derived ones and significantly interrupt parasite resistance to these drugs.
