**6. 4-Aminoquinolines**

4-aminoquinolines (4-AQ), 4-anilinoquinolines, 9-aminoacridines, and azaacridines are all members of this class. These groups are thought to have similar mechanisms of action, are successful on the same stage of the parasite, and may share similar mechanisms of resistance, in addition to their structural similarity (**Figures 3** and **4**).

4-Aminoquinoline is a type of aminoquinoline in which the amino group is located at the quinoline's 4-position. Antimalarial agents derived from 4-aminoquinoline can be used to treat erythrocytic plasmodial infections. Amodiaquine, chloroquine, and hydroxychloroquine are some examples [13].

Malaria is treated with 4-aminoquinolines (4-AQs) during the blood stage of the disease (the merozoites). The unprotonated form of these drugs is a weak base that can cross the food vacuolar membrane of parasites; however, once within the vacuole, both the quinoline nitrogen and the amino group of the side chain of 4-AQs become protonated species that is impermeable to the vacuolar membrane, causing ion-trapping inside the vacuole [14].

#### **6.1 Chloroquine and hydroxychloroquine**

Chloroquine, a 4-aminoquinoline, prevents ferriprotoporphyrin IX polymerisation, causing oxidative membrane damage and parasite death in infected erythrocytes. Because of widespread resistance, it's normally only used to treat malaria

**Figure 3.** *General chemical structure of 4-aminoquinoline.*

**Figure 4.** *Structures of some representative 4-aminoquinolines.*

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

patients in situations where chloroquine susceptibility can be guaranteed. Malaria caused by *P. falciparum* is almost always immune to choloroquine, with the exception of cases acquired in Haiti.

Chloroquine is only effective against the parasite's erythrocytic stages; for the full cure of *P. vivax* and *P. ovale* infections, another agent (primaquine) is needed. Chloroquine has been used in conjunction with dehydroemetine to treat invasive amebiasis that has not responded to other treatments and to treat connective tissue autoimmune disorders that have not responded to other treatments.

Chloroquine is thought to get stuck in the parasite's food vacuole, where it prevents -hematin from crystallising. The acidic nature of the vacuole (pH 4.8–5.2) causes chloroquine to become 'trapped' in its membrane-impermeable doubly protonated shape, which is membrane-impermeable. Chloroquine then forms a complex with free heme, causing heme to accumulate and the parasite to die. *P. falciparum* resistant strains were discovered to have a mutation in the Pfcrt gene, which encodes the chloroquine resistance transporter (Pfcrt) protein [8, 9]. Because of changes in the membrane protein, this transporter protein induces reduced drug concentration inside the food vacuole, allowing chloroquine to disperse away from the vacuole. CQ-resistant parasite strains have a neutral threonine residue at position 76 of the Pfcrt protein in place of the positively charged lysine moiety, allowing chloroquine efflux from the digestive vacuole [15–17].

Within the parasite's food vacuole, the parasite catabolises the protein of the host cell haemoglobin, resulting in peptides, which are further degraded to produce amino acids, which are used by the parasite for survival and development. As a byproduct of haemoglobin degradation, free heme (iron (II) centred porphyrin) is produced, which quickly oxidises to hematin (iron (III) centred species). Heme and hematin are also extremely toxic to parasites. Heme may interfere with the parasite's organelles' various membranous structures, causing irreversible damage and disrupting transport processes and ion homeostasis. Multiple pathways result in parasite death. 25.19 Biomineralisation removes heme and hematin, resulting in hemozoin, a parasite-unfriendly substance. Hloroquine prevents or inhibits the parasite's ability to detoxify heme, resulting in parasite death [18–20].

Chloroquine tablets are bitter in taste and are available in the United States. Chloroquine suspensions are commonly available for paediatric use in other countries and are much more well tolerated. As a malaria chemoprophylactic, chloroquine may be used. Most people tolerate chloroquine well, even when used for long periods of time. Mild gastrointestinal symptoms (which are usually relieved if the medication is taken with food), intermittent headaches, blurred vision, dizziness, weakness, confusion, hair depigmentation, skin eruptions, corneal opacity, weight loss, and myalgias are all potential side effects. Antihistamines are commonly used to treat intense pruritus, which is a common problem among black Africans who take the medication. Patients with psoriasis, retinal disease, or porphyria should avoid chloroquine. In most respects, hydroxychloroquine is similar to chloroquine. The only structural difference is a hydroxy moiety on one of the N-ethyl groups. It stays in the body for over a month, much like chloroquine, and prophylactic dosing is once weekly. Children tolerate hydroxychloroquine better [21–24].

#### **6.2 Amodiaquine**

Amodiaquine was first documented to have antimalarial activity in 1946, but due to its toxicity, it was removed as a prescribed monotherapy in the early 1990s. It acts in a similar way to chloroquine and has some cross-resistance with CQ, but it does not have any advantages over other 4-aminoquinoline drugs [25] (**Figure 5**).

**Figure 5.** *The inter-nitrogen distance in the side chains of amodiaquine and CQ.*

**Figure 6.** *Metabolic activation of amodiaquine to amodiaquine iminoquinone.*

It had a higher rate of extreme hepatitis and agranulocytosis than chloroquine when used for malaria prophylaxis. The toxicity of amodiaquine is thought to be due to P450-mediated and/or autooxidation of the 1, 4-aminophenol group, which produces a quinone imine intermediate [26] (**Figure 6**).

Amodiaquine's efficacy against some chloroquine-resistant *Plasmodium falciparum* strains has led to a resurgence in its use, especially in combination therapy with artesunate. Although amodiaquine resistance in some parts of Africa can restrict the effectiveness of this combination in those areas, the artesunate– amodiaquine combination has proven to be very effective in areas where amodiaquine alone produces responses of more than 80% [27].

#### **6.3 Mefloquine**

The racemic form of mefloquine is the newest of the 4-aminoquinolines. The drug's optical isomers are all active in the same way. The US Army [28] built it in the 1970s. It was initially developed to treat chloroquine-resistant malaria, but it has since been used as a curative and prophylactic medication (travellers coming into regions of malaria) (**Figure 7**).

Mefloquine differs from other 4-aminoquinoline agents in that it has two trifluromethyl moieties at positions 2 and 8, and no electronegative substituents at positions 6 (quinine) or 7 (mefloquine) (chloroquine). Mefloquine is not schizonticidal, which distinguishes it from chloroquine and its analogues. Mefloquine is slowly metabolised to carboxymefloquine, its main inactive metabolite, through CYP3A4 oxidation. The majority of the parent compound is excreted in its natural state in the urine [29] (**Figure 8**).

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

**Figure 7.** *Racemic forms (*RS *&* SR*) of mefloquine.*

**Figure 8.** *Metabolic activation of mefloquine to carboxymefloquine.*

*P. falciparum* mefloquine-resistant strains were first identified in 1986 [23]. In rats, rodents, and rabbits, mefloquine causes teratogenicity. This medication comes with an FDA-mandated warning that it can worsen mental illnesses, and the neuropsychiatric effects can be severe (e.g., suicidal impulses or seizures) or mild (e.g., headaches) (e.g., dizziness, vertigo, ataxia, and headaches). Bradycardia, arrhythmias, and extrasystoles are all possible cardiovascular side effects [30].
