**5. Cinchona alkaloids**

The medicinal use of the bark of the cinchona tree, which is native to South America, is the starting point for the discovery and synthesis of quinine and synthetic quinoline-containing antimalarial drugs. The quinoline derivatives quinine, quinidine, cinchonidine, and cinchonine are the four most abundant biologically active alkaloids found in the bark (**Figure 2**). The bark also includes quinoline derivatives such as quinicine (also known as quinotoxine) and indole-containing alkaloids including cinchonamine [6].

#### **5.1 Quinine and quinidine**

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Quinine is the first example of a pure chemotherapeutic agent to be produced on an industrial scale and it was the only drug available for the treatment of malaria

**Figure 2.**

*Structures of the four major and two minor quinoline containing alkaloids obtained from the bark of the cinchona tree.*

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

until the 1930s. Quinine has been used for "fevers" in South America since the 1600s. It is one of the major alkaloids was first used to treat malaria as early as the beginning of the 17th century, and became the standard therapy for malaria from the mid-19th century to the 1940s. The extraction of QN is still more economically viable than its synthetic production [6]. The pure alkaloids, quinine, and cinchonine were isolated in 1820. The stereoisomer, quinidine, is a more potent antimalarial, but it is also more toxic (less selectively toxic). Quinine is lethal for all *Plasmodium* schizonts and the gametocites from *P. vivax* and *P. malariae*, but not for *P. falciparum*. Today, quinine's spectrum of activity is considered too narrow for prophylactic use relative to the synthetic agents [7].

The emergence of resistant strains of *P. falciparum* was first reported in the 1980s [8] and as of 2006, quinine is no longer used as a front-line treatment for malaria but is still on the WHO's Model List of Essential Medicines (MLEM) [9] for the treatment of severe malaria in cases where artemisinins are not available. The mechanism of resistance to quinine is poorly understood and varies with the susceptibility of the parasite to other aminoquinoline antimalarial drugs. Quinine is the only treatment recommended for pregnant women in the first trimester3 and, until recently, it was the only clinical option for the treatment of severe malaria because it can be formulated for safe intravenous administration. However, intravenous artesunate is now preferred when available [10].

QN in clinical uses most often combined with a second agent to shorten the duration of therapy and thus minimise the adverse effects [11]. A toxic syndrome is referred to as cinchonism. Symptoms start with tinnitus, headache, nausea, and disturbed vision. If administration is not stopped, cinchonism can proceed to involvement of the gastrointestinal tract, nervous and cardiovascular system, and the skin. The stereoisomer, quinidine, is a schizonticide, but its primary indication is cardiac arrhythmias. It is a good example where stereochemistry is important because it provides a significantly different pharmacological spectrum [12].
