Chemical And Biological Profiles Of Synthetic Antimalarial Molecules Biology Essay

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Malarial has been one of the world's worst killer diseases throughout recorded human history. Despite attempts to eradicate it, it remains one of the worst diseases in terms of deaths annually, and has actually increased in incidence since the 1970s. 1 Malarila is a parasitic endemic in those parts of the world where moisture and warmth permit the disease vector, mosquitoes of the genus Anopheles, to exist and multiply. The transmission of the disease from one person to another is by the Anopheles mosquito. The four different protozoans causing malaria are Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax.1, 2

Malaria is transmitted by female mosquitoes that carry the parasite in their bodies. When the mosquito bites a human, it injects a small amount of its saliva into the human's bloodstream. The saliva contains parasites that travel through the person's bloodstream to his or her liver. There, the parasites reproduce. Eventually, they leave the liver and travel back into the bloodstream. Once in the bloodstream, they begin to cause the symptoms of malaria. 2 Malaria can also be transmitted through blood transfusions. If an infected person donates blood, the blood will contain malaria parasites. If the blood is put into another person's body, the parasites will also flow into his or her bloodstream. For this reason, blood donors are often screened for the malaria parasite before they are allowed to give blood. The incubation period for malaria varies considerably. An incubation period is the time between the mosquito bite and the time symptoms of malaria begin to appear. The incubation period differs depending on the kind of parasite involved. For the most serious form of malaria, the incubation period is eight to twelve days. In some rare forms of malaria, the incubation period can be as long as ten months. 2

A person infected with malaria passes through three stages of very distinctive symptoms. 1 The first stage is characterized by uncontrollable shivering for an hour or two. In the next stage, the patient's temperature rises quickly. It may reach 106°F (41°C) for a period of up to six hours. In the third stage, the patient begins to sweat profusely, and his or her temperature drops rapidly. Other symptoms may accompany these stages. They include fatigue, severe headache, nausea, and vomiting. After the third stage, the patient often falls asleep from exhaustion. The three stages are often repeated the following day, two days later, or at some later time. In many cases, a person experiences a repetition of the stages again and again during their lifetime. Some people go many years before the symptoms repeat. The most serious forms of malaria can result in death in a matter of hours. The parasites attack a person's red blood cells and change their structure. The cells become very sticky and begin to clump together. As they do, they may block blood vessels in vital organs, such as the kidneys and spleen. These organs may no longer be able to function properly, and the patient may fall into a coma and die.

Effective treatment of malaria is dependent on early diagnosis. Since the patient's symptoms are often relatively nonspecific, it is crucial to examine stained blood smears for the presence of parasite. Even this procedure may be inconclusive during the early stages of the infection, since the levels of parasitemia can be quite low. Thus, it is important to repeat blood smear examination several times if malaria is suspected. Drugs used to treat or prevent malaria are called antimalarial drugs. Example of antimalarial drugs use are chloroquine, primaquine, mefloquine and many more. 2, 3


The malarial parasite is a single-cell protozoan (plasmodium). Although there are more than 50 different species of plasmodia have been identified, only four are capable of infecting humans (P. malariae, P. ovale, P. vivax and P. falciparum); the rest attack a variety of animal hosts. Plasmodium falciparum and P. vivax malaria are the two most common forms. 1

Members of the genus Plasmodium have a complex life cycle. A sexual stage occurs in the Anopheles mosquito, while asexual stages take place in an animal host, for example, human. Malaria is actually transmitted from one human to another through the insect vector. 2 Initially, a female mosquito is infected by biting a human with the disease whose blood contains male and female gamete forms of the parasite. Fertilization takes place in the mosquito gut, and after differentiation and multiplication, the mature sporozoite forms migrate to the insect's salivary glands. At the mosquito's next feeding, the sporozoites are injected into the bloodstream of another human to begin the asexual stages. After a relatively brief residence in the systemic circulation, the sporozoites invade liver parenchymal cells, where they divide and develop asexually into multinucleated schizontthes. They are the primary exoerythrocytic tissue forms of the parasite. When this primary stage of development is completed (6-12 days), the schizonts will rupture, releasing merozoites into the blood. These latter forms invade host erythrocytes, where they again grow and divide asexually (erythrocytic schizogony) and become red cell schizonts. Some of the parasites differentiate into sexual (male and female) forms, or gametocytes. If the diseased human is bitten by a mosquito at this time, the gametes will be taken up into the gut to reinitiate the sexual cycle. The gametocytes and the exoerythrocytic liver forms of the plasmodium are not associated with the appearance of clinical symptoms of malaria. 2, 3, 4

The asexual intraerythrocytic parasites, that is, those that do not differentiate into gametocytes, also multiple and grow until they rupture the cells in which they are located; these new merozoites are released into bloodstream. This occurrence not only sets up the subsequent cyclical red blood cell stages of the plasmodium cycle, but also gives rise to the symptoms associated with the malarial infections. 3



5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine

Figure 3.1.1

Pyrimethamine is commonly used as antimalarial drug. It is a synthetic aminopyrimidine - derivative antimalarial agent that is structurally related to trimethoprim. Practically, it occurs as a white, crystalline powder and is practically insoluble in water and slightly soluble in alcohol. 4

The drug is recommended as prophylactic use against all susceptible strains of plasmodia. Often, it is administered with sulfonamides as the combined drugs would give greater effect than any drug acting alone. This could also slow down the process of resistance. However, sulphonamides have little effect on blood stages of P. vivax. 2

Pyrimethamine is a folic acid antagonist and has a mechanism of action similar to that of trimethoprim. The drug binds to and inhibits enzyme dihydrofolate reductase (DHFR). 5 The enzyme is important to catalyse conversion of dihydrofolic acid to tetrahydrofolic acid. Such inhibition prevents the synthesis of folic acid which is important for DNA and RNA synthesis. It works by killing the parasites or preventing the growth.

Resistance frequently occurs in areas where pyrimethamine has been widely used. Protozoa can develop mutation in the malarial gene for dihydrofolate reductase. Also, mutation decreases the binding ability of the drug onto the enzyme due to the loss of hydrogen bonding and steric hindrance. Resistance to pyrimethamine has been reported in P. vivax, P. malaria and P. falciparum.

In terms of pharmacokinetics, the drug is well absorbed from the GI tract. Following oral administration, peak plasma levels occur within 3 to 7 hours and it is rapidly metabolized. There is wide distribution of the drug in the body, mainly to the kidney, lung, and spleen. The rate of renal excretion is slow and the half life is about 4 days. 3, 4

Hypersensitivity is the major problem particularly when pyrimethamine is administered concomitantly with a sulfonamide. In addition, the depletion in folic acid in humans results in hematologic side effects. These include megaloblastic anemia and thrombocytopenia. Besides, other adverse effects may include anorexia, abdominal cramps and seizures.

Concomitant use of antifolic drugs with myelosuppression such as zidovudine and methotrexate, while patient is receiving pyrimethamine treatment, may increase the risk of bone marrow suppression. When folate insufficiency symptoms occur, pyrimethamine should be discontinued. Besides, the drug should not be used in pregnant woman because of teratogenicity. 4


(RS)-N-(6-methoxuqionolin-8-yl)pentane-1,4-diamine )

Figure 3.2.1

Primaquine has the antimicrobial spectrum where it is the only drug which is effective against the liver form (exoerythrocytic) of the malarial parasites. 4 Its antimalarial action is exerted against the hypnozoites which can be found in the liver. Primaquine is more effective against the gametocytes but not the asexual erythrocyte forms of Plasmodium falciparum. Besides, this drug can be given to patients who are recovering from P.falciparum for its gametocytidal properties. 4

The mechanism of action of this drug is unknown. Some strains of P.vivax in South East Asia and New Guinea have found to develop resistance towards this drug. The exoerythrocytic forms of these strains are not terminated by single standard treatment with primaquine and may require repeated therapy with increased doses 3 (katzung). Primaquine is readily absorbed from the gastrointestinal tracts and not bound extensively by tissues. It is actively metabolized and the metabolites are reported to be as active as the parent drug1. Primaquine has peak plasma concentration in 4 to 6 hours after oral administration and is eliminated through renal route. 2

Side effects of primaquine include gastrointestinal distress, nausea, headache, pruritus and leucopenia. Agranulocytosis has also been observed. 1



[(R)-(6-methoxyquinolin-4-yl)((2S,4S,8R)- 8-vinylquinuclidin-2-yl)methanol]

Figure 3.3.1


[(9S)-6'-methoxycinchonan- 9-ol]

Figure 3.3.2

Quinine is used as a first-line therapy drug for the treatment of chloroquine-resistant malaria caused by P. falciparum. Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. 2 The alkaloid quinine was purified from the bark in 1820, and it has been used in the treatment and prevention of malaria since then. It is a levorotatory compound. Like quinine, quinidine is also used as first-line therapy drug for falciparum malaria. Quinidine, the dextrorotatory stereoisomer of quinine is at least as effective as parenteral quinine in the treatment of severe falciparum malaria. 5 After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1-3 hours, and is widely distributed in body tissues. The pharmacokinetics of quinine varies among populations and between uninfected individuals and those with malaria. The half-life of quinine is also higher in those with severe malaria (18hours) than in healthy controls (11hours). Quinidine has a shorter half-life than quinine, mostly as a result of decreased protein binding. Quinine is primarily metabolized in the liver and excreted in the urine. 3, 4

The exact mechanism of antimalarial activity of quinine has not been determined but the drug appears to interfere with the function of plasmodial DNA. Both quinine and quinidine is said to interfere with the heme polymerization. They have similar mode of action as chloroquine, which is, they inhibit the conversion of heme to hemozoin by the parasite, which lead to accumulation of heme and with this, resulted in cell lysis of both the host and the parasite. Resistance to quinine has been reported rarely in P. falciparum malaria. Although cross-resistance has been demonstrated rarely between quinine and 4-aminoquinoline derivatives, quinine may be active against some strains of P. falciparum that are resistant to chloroquine and/or sulfadoxine and pyrimethamine. 1, 2

There are many adverse effects. Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a constellation of symptoms termed cinchonism. Mild symptoms of cinchonism do not warrant the discontinuation of therapy. Hypersensitivity reactions include skin rashes, urticaria, angioedema and bronchospasm. Hematologic abnormalities include hemolysis, leucopenia, agranulocytosis, and thrombocytopenia. 3

There are a few drugs which cannot be used together with quinine. The first drug which is mefloquine can cause drug interactions with quinine. As the cardiac effects may be additive, mefloquine should not be used concomitantly with quinine. Concomitant use of mefloquine and quinine may result in ECG abnormalities or cardiac arrest and may increase the risk of seizures. The second drug like cardiac glycosides should also be used with caution when quinine is used together. Increased plasma concentrations of digoxin and digitoxin have been reported when quinidine was administered concomitantly with these drugs. 3 Quinine appears to increase serum digoxin concentrations and decrease renal clearance of digoxin in a manner that is qualitatively similar but quantitatively less than that of quinidine. Therefore, when these drugs are used with quinine or quinidine, the patients' renal clearance have to be monitored closely.


(R, S)- 2,8-bis(trifluoromethyl)quinolin-4-yl-(2-piperidyl)methanol


Figure 3.4.1

Mefloquine is a 4-quinolinemethanol derivative that is use prophylactically and acutely againts P.falciparum.4 This drug has several similarity in respect to quinine although it does not intercalate with plasmodial DNA. 1 It is ineffective against exoerythrocytic stage of of P.vivax. 4

The detailed mechanism of action of this drug is still unknown. What is known is that mefloquine acts effectively on blood schizont and mature form of the parasite.4 The mechanism of resistance of mefloquine has not been fully elucidated.

In terms of pharmacokinetics, orally administered mefloquine is well absorbed and has an absorption half-life of about 2 hours. Also, the elimination half-life is 2 to 3 weeks. 4

Adverse effects of this drug include nausea, vertigo, vomiting, abdominal pain, diarrhoea and loss of appetite. 4 Moreover, there are also CNS disturbances caused by this drugs which include hallucination, confusion, anxiety and depression. 1 Mefloquine should be avoided in patients who are taking β-blockers and calcium channel blockers as they will cause sinus bradycardia. Patient who is receiving mefloquine are not advised to take quinine as this will potentiate dose-related effects of mefloquine.



Figure: 3.5.1

Chloroquine is an anti-parasitic drug first introduced in 1946 for the treatment and prophylaxis of malaria.7 Chloroquine was developed during World War II in response to the shortage of quinine that resulted from the Japanese occupation of the cinchona plantations in Southeast Asia. It was soon identified as a cheap, safe and very efficacious drug for both radical cure and prophylaxis.8 Due to worldwide massive usage of Chloroquine during the post-war period, development of drug resistance has occurred. Since its first independent appearance in South America and Southeast Asia, resistance was soon spotted in other malarious areas, and current molecular information suggests that resistance developed independently in different geographic regions.8 Nowadays, it is estimated that about 80% of the worldwide parasite population is resistant to the drug.8

The mechanism of action of chloroquine is to prevent the polymerization of hemozoin. Inside red blood cells, the malarial parasite must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism.9 Digestion is carried out in a vacuole of the parasite cell and during this process, the parasite produces the toxic and soluble molecule heme.9 The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP) and to avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a non-toxic molecule, which collects in the digestive vacuole as insoluble crystals.9 Chloroquine act by enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion.9 Chloroquine (CQ) then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic and this causing chloroquine cannot leave by simple diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme accumulation. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-Chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion due to parasite cell drowns in its own metabolic products.10

Resistance of chloroquine was spotted and these problems can be prevent or minimize by combining different antimalarial drugs with different mechanisms of action and ensuring very high cure rates through full adherence to correct dose regimens.11 The effectiveness of chloroquine against the parasite has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-Resistant cells efflux chloroquine at 40 times the rate of Chloroquine-Sensitive cells and the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the pfcrt gene (Plasmodium falciparum Chloroquine Resistance Transporter). 12 The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes and is thought to mediate chloroquine leak from its site of action in the digestive vacuole. 13 Mutations in the pfmdr1 gene (P. falciparum multidrug resistance) of P. falciparum also have been reported to be linked to chloroquine resistance although these mutations are thought to be of secondary importance compared to pfcrt gene.12

In term of pharmacokinetics, chloroquine has a very high volume of distribution, as it is able to diffuse into the body's adipose tissue, erythrocytes, liver, spleen, kidney, lungs, melanin-containing tissues, and also leukocytes.9

Figure: 3.5.2

Chloroquine is also a lysosomotropic agent which it will accumulates preferentially in the lysosomes of cells in the body.14 At neutral to basic pH, small, lipophilic nature of chloroquine enables it readily penetrate the lipid bilayer and once enter the cell it can easily diffuse into acidic subcellular compartments, such as endosomes and lysosomes, where it becomes diprotonated and accumulates by ion trapping (Figure 3.5.2).14 At acidic lysosomal pH, chloroquine becomes diprotonated and assumes a net positive charge, preventing it from exiting the phagolysosome.14 Thus, chloroquine can concentrate within lysosomes up to 10,000-fold higher than its extracellular levels.

The lysosomotropic character of chloroquine is believed to account for much of its anti-malarial activity14 and the drug concentrates in the acidic food vacuole of the parasite will interferes with essential processes.

The adverse effect of choloroquine at the doses used for prevention of malaria include gastrointestinal problems such as stomach ache, itch, headache, and blurred vision.9 When doses are extended over a number of months, it is important to watch out for a slow onset of "changes in moods" (depression, anxiety). These may be more pronounced with higher doses used for treatment. Besides, chloroquine tablets have an unpleasant metallic taste.9

A serious rare toxicity in the eye might occur when chloroquine is use in prolonged therapy with high doses and thus ophthalmologic examination should be routinely performed.9 Besides, chloroquine can cause electrocardiographic changes due to it has a quinidine-like effect.9 Chloroquine also should not administered with phenylbutazone or gold therapy as it can cause severe dermatitis.9

Overuse of Chloroquine treatment has also led to the development of a specific strain of E. coli that is now resistant to the powerful antibiotic Ciprofloxacin 15

3.6 ARTEMISININ (Qinghaosu)


Figure 3.6.1

Artemisinin is used for treatment of multidrug-resistance P.falciparum infection.16 It is effective against blood schizonts of all human malaria parasites but no effect on hepatic stages. Antimalarial activity of artemisinin is the production of free radicals due to decomposition of endoperoxide bridge in the parasite food vacuole.17

Artemisinin is rapidly absorbed orally with peak plasma concentration in 1-2 hours and having half-life of 1-3hours after administration.16 This drug is actively metabolized to active metabolite dihydroartemisinin.

Adverse effects of this drug include the commonly reported ones which are nausea, vomiting and diarrhoea. Artemisinin should be avoided in pregnant women if possible.16


Prompt elimination of parasite is the main objective in the clinical management of patient suffering from an acute malarial attack. Schizontocidal, or repressive drug is particularly effective in this regard. Chloroquine and Pyrimethamine are the drugs that are widely used against plasmodia. Besides, there are many other alternatives such as Primaquine, Quinine and Artemisinin.