**8. Artemisinin and its derivatives**

Artemisinin (ART), a sesquiterpene lactone<sup>1</sup> , was discovered in 1971 by Tu Youyou, a Chinese scientist, in the plant *Artemisia annua* (a herbaceous plant in the Asteraceae family), which is widely used in Chinese traditional medicine [55]. Youyou shared the Nobel Prize in Physiology or Medicine in 2015 for "her findings concerning a novel therapy against malaria" [56], owing to the significant positive effect of ART in the fight against malaria.

Artemisinins are successful not only against multi-resistant strains of *Plasmodium falciparum*, but they also have strong stage specificity against the Plasmodium life cycle, including activity during the asexual blood stages [57] as well as the sexual gametocyte stages, which may help to minimise disease spread in lowtransmission areas [58]. Artemisinin resistance was first recorded in western Cambodia in 2008 [59]. ART and its derivatives have been used as first-line drugs in the treatment of malaria since their antimalarial activity was discovered.

Since chemical synthesis of ART is considered to be costly, the key commercial sources of ART are field-grown leaves and flowering tops of *A. annua*. Since mature plants will lack the active drug, the plant must be grown from seed every year. To

<sup>1</sup> Sesquiterpene lactones (SLs) are a type of sesquiterpene with a lactone ring; a sesquiterpene has three isoprene (2-methyl-1,3-butadiene) units. Lactones are cyclic carboxylic esters with a 1-oxacycloalkan-2 one structure (C(=O)O); sesquiterpene lactones (SLs) are present primarily in Asteraceae plants (daisies, asters). Umbelliferae (celery, parsley, carrots) and Magnoliaceae (magnolias) are two other plant families with SLs [53, 54].

maximise artemisinin yield, the increasing conditions must be perfect. Plants grown in North Vietnam, China's Chongqing province, and Tanzania have recorded the highest yields so far [60].

As compared to other compounds historically and currently used, the artemisinin sequence is structurally distinct. The endoperoxide (C–O–O–C) and dioxepin oxygens tend to form a "trioxane," which appears to be the most significant structural element. Artemisinine, a sesquiterpene trioxane lactone with an endoperoxide bridge that is necessary for antimalarial activity, does indeed represent a new chemical class of antimalarial agents. It distinguishes artemisinins from other antimalarial drugs by limiting cross-resistance. Artemisinin derivatives such as artemether, artesunate, and arteether are the most common. These semisynthetic derivatives are prodrugs that are converted to dihydroartemisinin, the active metabolite. Unlike quinine, artemisinin derivatives destroy young circulating parasites until they sequester in the deep microvasculature [61–65] (**Figure 10**).

Following oral administration, the artemisinins are rapidly absorbed, with maximum plasma concentrations occurring in 2 to 3 hours for artemisinin and artemether, and less than 1 hour for artesunate [66, 67]. Artemisinin is transformed to inactive metabolites in the liver, such as deoxyartemisinin, deoxydihydroartemisinin, and others, where the endoperoxide group is lost and the metabolites become ineffective. CYP2B6 is the enzyme that catalyses the reaction. Different artemisinin derivatives are metabolised. They're converted to dihydroartemisinin first (DHA). DHA is a potent antimalarial molecule that lasts for two to three hours in the bloodstream. Artesunate's antimalarial operation is mediated exclusively by DHA. (Direct antimalarials include artemisinin, arteether, artemether, and others.) Within a minute of absorption, artesunate is converted to DHA. DHA is converted to inactive metabolites in the liver by the cytochrome P450 enzyme system (which includes CYP2A6, CYP3A4, and CYP3A5). Both metabolites are glucuronidated before being excreted in the urine or faeces. Artemisinins are relatively safe drugs due to their quick metabolism [68–70].

Artesunate is a water-soluble semisynthetic form of artemisinin that can be taken orally or injected intravenously or intramuscularly. Artesunate is superior to artemisinin and other oil-based derivatives [71] due to its chemical property and pharmacokinetic profile, as it is almost instantly converted into dihydroartemisinin after ingestion, which accounts for the antimalarial activity. The endoperoxide pharmacophore alone has stimulated the production of many different groups of totally synthetic endoperoxides, including the trioxolane OZ277 [72] and the tetraoxane 3 [73], despite the fact that the exact mechanism of action is still highly debated [72] (**Figure 11**).

Although the exact mechanism of artemisinin is unknown, it is thought to be triggered by haem, which produces free radicals, which damage parasite survival proteins [74, 75]. The initial formation of highly reactive oxygen-centered radicals

**Figure 10.** *Structural units of artemisinine family of compounds.*

*Molecular Approaches for Malaria Therapy DOI: http://dx.doi.org/10.5772/intechopen.98396*

**Figure 11.**

*Pharmacophoric structures of ART derivatives.*

by iron(II)-catalysed homolytic cleavage of the peroxide bond is thought to result in rapid intramolecular rearrangement to give cytotoxic carbon-centered radical organisms, which then cause widespread damage to parasite biomolecules by alkylation or by initiating peroxidation (**Figure 12**).
