**7. 8-Aminoquinolines**

Another big class of antimalarial drugs based on the cinchona alkaloid quinoline moiety is substituted 8-aminoquinolines (**Figure 9**). The 8-aminoquinolines were the first synthetic antimalarial drugs approved by the FDA. The German researchers introduced pamaquine as the first compound in this sequence. Due to its high toxicity and restricted activity, pamaquine was no longer used in clinical trials [31]. In 1950, primaquine was introduced as a pamaquine analogue. It was the only approved treatment for removing the Plasmodium parasite from the liver and preventing malaria relapses caused by *P. ovale* and *P. vivax* until July 2018 [32].

In patients with erythrocytic glucose-6-phosphate dehydrogenase deficiency, all of the 8-aminoquinolines have been reported to cause hemolytic anaemia. This is a common genetic trait in people who live in malaria-endemic areas [33]. Since 4-AQs are active during the blood stages of the parasite life cycle, and the blood stages of *P. falciparum* can be cultured and thus studied relatively easily, the mechanism of action for 8-aminoquinolines (8-AQs) is less well known than for 4-aminoquinolines (4-AQs) [34, 35].

The mechanism of action for the 8-AQs cannot be inhibition of hemozoin formation because liver cells do not produce haemoglobin. Primaquine suggested an autoxidation of the 8-amino group to produce ROS. Augusto et al. [36] suggested the creation of a radical anion at the 8-amino group. Cell-destructive oxidants like hydrogen peroxide, superoxide, and the hydroxyl radical can form as a result, causing oxidative damage to essential cellular components.

The structure–activity relationships in this series display very little variance. The four agents in **Figure 9**, all have the same 6-methoxy moiety as quinine, but the substituent on quinoline are at position 8 rather than carbon-4, as they are on cinchona alkaloids. Between the two nitrogens, all of the agents in this sequence have a four to five carbon alkyl linkage or bridge. The other three 8-aminoquinolines, with the exception of pentaquine, all have one asymmetric carbon. Although there are some variations in the metabolism of each stereoisomer and the form of adverse reaction, there are little differences in antimalarial activity based on the stereochemistry of the compounds. In patients with a glucose-6-phosphate dehydrogenase deficiency, all of the 8-aminoquinolines can cause hemolytic anaemia (G6PD). This is a common genetic trait found in people who live in malaria-prone areas. The key clinical problems associated with primaquine are a short half-life (4–6 hours), which means it must be taken everyday for 14 days to be successful, and hemolysis [37–40].

#### **7.1 Primaquine**

Primaquine (PQ), an 8-aminoquinoline that has been clinically used since 1950, is still the only drug used worldwide to treat relapsing *P. vivax* malaria caused by

**Figure 9.** *Structures of some representative 8-aminoquinolines.*

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

hypnozoites, and it inhibits gametocyte formation. It is not used in the prevention of disease. The only drug available for treating *P. vivax* and *P. ovale* latent hepatic life cycle forms is primaquine [41, 42]. Following the initiation of chloroquine treatment for the erythrocytic stages of infection, primaquine is recommended for the radical cure of these infections. It has one of the narrowest spectrums of activity of any currently used antimalarial drug, as it is only indicated for exoerythrocytic *P. vivax* malaria. Chloroquine or a drug prescribed for chloroquine-resistant *P. vivax* is combined with primaquine to treat endoerythrocytic *P. vivax*. It is also active against the exoerythrocytic stages of *P. ovale* and the main exoerythrocytic stages of *P. falciparum* [43], in addition to its accepted indication.

Primaquine is readily absorbed, widely spread, and cleared mainly by non-renal removal. Carboxyprimaquine is the primary metabolite. Primaquine is successful when administered once daily or even once weekly [44], despite the fact that the medication is quickly removed from the plasma. Except in people with G6PD deficiency, where administration can cause brisk hemolysis, primaquine is typically well tolerated. Prior to starting primaquine therapy, patients should be tested for G6PD deficiency. Regardless of G6PD status, primaquine should never be given to a pregnant woman. Neutropenia, gastrointestinal disturbances, and methemoglobinemia are rare side effects. *P. vivax* relapses after primaquine therapy have been treated with chloroquine and higher doses or longer courses of primaquine [45].

Primaquine is the most effective currently available prophylactic for *P. vivax* malaria and equivalent to such regimens as doxycycline, mefloquine, and atovaquone-proguanil for the prevention of *P. falciparum* malaria, according to a recent meta-analysis and systematic review [46, 47]. NPC1161B, a chiral 8 aminoquinoline derivative developed at the University of Mississippi, was still undergoing preclinical testing in 2014 [48–52].
