**Abstract**

Malaria is a public health challenge that requires prompt treatment for those infected to make a full recovery. Treatment of malaria infection is to be started as soon as a diagnosis is confirmed. Antimalarial medications are administered to prevent and also to treat malaria. The type of medication used and the duration of therapy is dependent on the type of malaria-causing *plasmodium species*, the severity of the symptoms, geographical area where malaria infection occurred and the medication used to prevent malaria and whether there is pregnancy. Treatment of malaria from public health perspective is to reduce transmission of the infection to others, by reducing the infectious reservoir and to prevent the emergence and spread of resistance to antimalarial medicines. Medications used in the treatment of malaria infection come from the following five groups of chemical compounds: quinolines and aryl amino alcohols, antifolate, artemisinin derivatives, hydroxynaphthoquinones and antibacterial agents. The treatment of malaria is not initiated until the diagnosis has been established through laboratory testing. Artemisinin-based Combination Therapy (ACTs) has been used for the treatment of uncomplicated malaria. ACTs are also to enhance treatment and protect against the development of drug resistance. IV artesunate is used in the treatment of severe malaria, regardless of infecting species.

**Keywords:** Malaria, treatment, drug resistance, ACTs, drugs and plasmodium specie

#### **1. Introduction**

*Plasmodium* species are protozoan parasites that cause malaria, a life-threatening infectious ailment in humans. Five different species of *Plasmodium* are known to infect man: *P. falciparum, P. malariae, P. ovale, P. vivax* and *P. knowlesi. Plasmodium falciparum* is the commonest malaria-causing parasite in the World Health Organization (WHO) African Region, accounting for 99.7% of estimated malaria cases in 2018, as well as in the WHO Eastern Mediterranean Region (71%), the WHO Western Pacific Region (65%), and WHO South-East Asia Region (50%).

*Plasmodium falciparum* causes a serious form of malaria infection. *Plasmodium falciparum* parasite is known to be responsible for the vast majority of malaria morbidity and mortality in Africa [1].

*Plasmodium vivax*, causes most of the malaria infections in the Americas (75%). Also, about 53% of the malaria cases found in Southeast Asiais caused by *P. vivax*.

In addition, *P. vivax* presents some challenges as compared to *Plasmodium falciparum* which includes; shortage of accurate diagnostics and its ability to remain dormant in a person's liver among others [2].

Plasmodium malariae is found worldwide and causes a mild form of malaria. It is not as harmful as that caused by *P. falciparum or P. vivax*. Clinical signs associated with P. malariae include fevers that reoccur just about three-day intervals (a quartan fever) and longer than the two-day (tertian) intervals of the other malarial parasites [3]. *Plasmodium malariae* gives rise to a chronic infection that in some cases can last for a long period. The *P. malariae* parasite has diverse variations between it and the other Plasmodium parasites, one being that maximum parasite counts are normally low as compared to those in patients infected with *P. falciparum* or *P. vivax* [4].

*Plasmodium ovale* causes tertian malaria in humans. It is rare compared to *P. falciparum* and *P. ovale* and substantially less dangerous than *P. falciparum. P. ovale* has recently been shown by genetic methods to consist of two subspecies, *P. ovale curtisi* and *P. ovale wallikeri* [5]. *P. ovale* can infect persons who are negative for the Duffy blood group. This is common in many residents of sub-Saharan.

Africa. This accounts for the significant prevalence of *P. ovale* in most of Africa rather than *P. vivax* [6].

*Plasmodium knowlesi* causes malaria in humans and other primates. The natural warm-blooded hosts of *P. knowlesi* are various monkeys and humans can be infected by *P. knowlesi*. It closely resembles *Plasmodium vivax* as well as other *Plasmodium* species that infect primates other than humans. Individuals with *P. knowlesi* infection can develop uncomplicated or severe malaria comparable to that brought about by *Plasmodium falciparum*. Diagnosis of *P. knowlesi* infection is burdensome as *P. knowlesi* very closely looks like other species that infect humans [7].

## **2. Treatment of malaria and drug resistance**

Malaria is an entirely preventable and treatable ailment. The choice of therapy is dependent mainly on the infecting species, the severity of infection, age of the patient, and susceptibility of parasites to antimalarial therapies, the cost and availability of medicines. The aim of malaria treatment is to ensure rapid and total elimination of the *Plasmodium* parasites from the patient's blood to help prevent the progression of uncomplicated malaria to complicated illness that leads to malaria-related anemia and death. From a public health perspective, treatment is meant to reduce transmission of the infection to others, by reducing the infectious reservoir and preventing the emergence and spread of resistance to antimalarial medicines [8, 9].

Drugs used in the treatment of malaria infection come from the following five groups of chemical compounds: quinolines and aryl amino alcohols, antifolate, artemisinin derivatives, the hydroxynaphthoquinones and antibacterial agents [10].

i.**Quinolines** include 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), 8-aminoquinolines (e.g., primaquine and pamaquine) belong to the quinolines. **Chloroquine** (**Figure 1**), a 4-aminoquinoline manifests its antimalarial activity mostly on the mature trophozoites stage of the parasite by causing inhibition of the hemozoin (Hz) formation from hemoglobin digestion. Free heme causes lysis of membrane and parasite death. The side-effects of chloroquine include pruritus, skin-rashes, cephalgia, gastrointestinal disturbances and rarely bone marrow suppression, alopecia and convulsions [11]. Chloroquine was withdrawn from use because of a

*Treatment of Malaria Infection and Drug Resistance DOI: http://dx.doi.org/10.5772/intechopen.98373*

**Figure 1.** *Chemical structures of some synthetic compounds used as antimalarial.*

decline in effectiveness resulting from resistant strains of the plasmodium parasite and fatal side effects [12]. *Plasmodium* parasite resistance against chloroquine and treatment failure is associated with multiple mutations in *Plasmodium falciparum* chloroquine-resistant transporter (PfCRT), a protein that probably functions as a transporter in the parasite's digestive vacuole membrane which results in reduced intracellular drug concentrations [13]. Chloroquine is currently on the Model List of Essential Medicines (MLEM) for the treatment of *P. vivax* infection in regions where resistance has not developed [14]. **Amodiaquine [2]**, also a Mannich base 4-aminoquinoline and its mechanism of action involve the suppression of the breakdown of hemoglobin. The drug also suppresses the glutathione-dependent destruction of ferriprotoporphyrin IX in the malaria parasite, leading to the accumulation of this peptide, which is unsafe to the survival of the parasite. Amodiaquine is therapeutically potent as compared to chloroquine in treating chloroquine-resistant *Plasmodium falciparum* malaria infections. These two drugs were widely used in the past for both prophylaxis and treatment of malaria. However, amodiaquine has serious adverse effects of hepatitis and agranulocytosis associated with its long-term use and therefore not generally recommended in malaria treatment [15]. Resistance to amodiaquine by plasmodium parasite has been associated with single nucleotide polymorphism (SNP) alleles *pfcrt* 76 T, *pfmdr1* 86Y, 184Y and 1246Y (c). Also, PfCRT, has been found to contribute to resistance to amodiaquine [16].

**Primaquine [3]** is a member of the 8-aminoquinoline range of antimalarials that includes tafenoquine and pamaquine. Primaquine is mainly used in the treatment of *P. vivax* or *P. ovale* malaria, specifically to get rid of the inactive liver forms of these parasites (hypnozoites). To achieve this, a 14-day course of primaquine is required [17]. The usual adverse effects associated with the administration of primaquine include nausea, vomiting, and stomach cramps. The most dangerous adverse effect of primaquine is haemolysis in patients who are deficient in Glucose-6-phosphate dehydrogenase (G6PD) enzyme, Africans or Caucasians of Mediterranean descent. Primaquine is the only antimalarial currently recommended as a therapy in *P vivax* malaria [18]. Resistance to primaquine is known to occur due to CYP-4502D6 mutation, which affects its metabolism and activation [19].

**Piperaquine** is a bisquinoline compound which was first synthesized in the 1960s and was widely used in China and Southeast Asia (Indochina) as a preventive agent for treatment purposes for over 20 years. Due to resistant strains of *P. falciparum* and the introduction of artemisinin-based antimalarial products, the usage of piperaquine declined [20]. Currently, piperaquine is used in combination with dihydroartemisinin to treat malaria [21]. Piperaquine resistance has been reported and the genetic markers plasmepsin 2 (*pfpm2*), exonuclease (*pfexo*) and chloroquine resistance transporter (*pfcrt*) genes are implicated for the resistance [22].

**Mefloquine [4]** is a quinoline methanol compound that resembles quinine and it is active against the asexual stages of malaria; however, its precise mode of action is not known. Mefloquine is therapeutically potent as a preventive agent against malaria and is extensively used in therapy against chloroquine-resistant *P. falciparum* malaria infection. Mefloquine is effective against all five strains of malaria parasites known to affect humans [23]. Frequent treatment using mefloquine is associated with asymptomatic, transient serum enzyme elevations in up to 18 per cent of patients. Adverse reactions such as skin-rash and autoantibody formation are also rare. Reported side effects of mefloquine include nausea, vomiting, abdominal pains, dizziness, neurotoxic effects and chronic neuropsychiatric adverse effects [24, 25]. Mefloquine is currently not widely used due to the perception of central nervous system toxicity [23]. Resistance to mefloquine result from increased amplification in *pfmdr1* in falciparum malaria [26].

ii.**Arylaminoalcohols.** Quinine, quinidine, mefloquine, lumefantrine and halofantrine, belong to the arylamino alcohols**. Quinine** is a drug obtained from the stem bark of the cinchona tree and was the first therapy used for malaria [27]*.* The most common adverse effects of quinine involve a group of symptoms called cinchonism; headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and interference in color perception. Quinine is a common cause of drug-induced disorders, including thrombocytopenia and thrombotic microangiopathy [28]. Quinine can also have severe adverse effects involving multiple organ systems, among which are immune system effects and fever, hypotension, haemolytic anemia, acute kidney injury, liver toxicity, and blindness. Quinine excites the secretion of insulin and may lead to hyperglycaemia which is a risk in pregnancy [29]. The mode of action of quinine is not clear but it is believed to interfere with the parasite's ability to breakdown hemoglobin leading to the inhibition of self-generated formation of betahaematin (haemozoin or malaria pigment) which is a poisonous product of the breakdown of hemoglobin by the parasite [10]. Quinine is currently not used as front-line therapy for malaria due to the high-quality evidence

of the efficacy superiority of artesunate over quinine in adults and children with severe malaria [21]. There is currently inadequate data on resistance to quinine in malaria therapy [30, 31].

	- Artesunate+Amodiaquine (AS-AQ )
	- Artemether+Lumefantrine (A-L)

Artemisinin-based Combination Therapy (ACTs) has been used since the year 2004 for the treatment of uncomplicated malaria. This initiative was important because the malaria parasite became resistant to Chloroquine and other monotherapies. Artemisinin is administered in combination with a second, long-acting antimalarial to enhance treatment and protect against the development of drug resistance [33]. Quite recently the malaria parasite has developed resistance to artemisinin. Reasons for artemisinin resistance include uncontrolled use of artemisinin-based combination therapy (ACT), mobile populations and migrants, artemisinin monotherapy, the use of subtherapeutic levels of artemisinin, substandard and counterfeit drugs, high treatment cost, and co-use of artemisinin derivates as prophylactic agents [41].

## **2.1 New product under development**

**DDD107498** is a compound with the chemical name 6-Fluoro-2-[4-(4 morpholinylmethyl) phenyl]-N-[2-(1-pyrrolidinyl) ethyl]-4-quinolinecarboxamide. It is a novel chemical compound developed based on a 2, 6-disubstituted quinoline-4-carboxamide scaffold against the blood stage of the multi-drug-sensitive *Plasmodium falciparum* 3D7 strain. The compound has a powerful and wide spectrum of antimalarial activity against varied life-cycle phases of the *Plasmodium* parasite, with better pharmacokinetic activities and a satisfactory safety profile. DDD107498 has sub-micromolar efficacy against parasites. The compound has shown marked activity against 3D7 strain parasites. DDD107498 averted the development of trophozoites and schizonts. It is also effective against several drugresistant strains. It is more effective as compared to artesunate in (*ex vivo)* assays against a range of clinical isolates of both *P. falciparum* and *P. vivax* and is not toxic to human cells [42–44]. DDD107498 which is now called M5717 entered the first stages of human clinical trials in 2017 (**Figure 1**).
