Gametocites In Seeds

& 120-mg lumefantrine; 4-dose regimen over 48 hrs or 6-dose regimen over 3 days Pediatric Tablet: 10-mg artemether & 60-mg lumefantrine; 4-dose regimen over 48 hrs or 6-dose regimen over 3 days

Quinine and Quinidine. Quinine has been used for "fevers" in South America since the 1600s. 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 (site 2 in Fig. 7.1) and the gametocites (site 4) 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. The mechanism of action is discussed in the chloroquine section. The mechanism of resistance to quinine is poorly understood and varies with the susceptibility of the parasite to other aminoquinoline antimalarial drugs. Quinine is still indicated for malaria caused by P. falciparum resistant to other agents including chloroquine. Many times it is administered in combination with pyrimethamine and sulfadoxine, doxycycline, or mefloquine depending the specific form of malaria and geographical location.

Cinchona Alkaloids
Figure 7.2 • Cinchona alkaloids.

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.

Quinine has also been used for nocturnal leg cramps, but pharmacists must remember that the Food and Drug Administration (FDA) ordered a stop to marketing quinine over the counter for this use because of a lack of proper studies proving its efficacy and possible adverse reactions.

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. Quinidine is discussed further in Chapter 19.


The 4-aminoquinolines (Fig. 7.3) are the closest of the antimalarials that are based on the quinine structure. This group is substituted at the same position 4 as quinine and have an asymmetric carbon equivalent to quinine's C-9 position.

Just as with quinine, both isomers are active and the 4-aminoquinoline racemic mixtures are used. For the newest drug in this series, mefloquine, only the ^,^-isomer is marketed. A significant difference from the commercial cinchona alkaloids is replacing the 6'-methoxy on quinine witha 7-chloro substituent on three of the 4-aminoquinolines. Amodiaquine is no longer used in the United States, and sontoquine has fallen into disuse.

Chloroquine and Chloroquine Phosphate. Chloro-quine can be considered the prototypical structure that succeeded quinine and came into use in the mid-1940s. The phosphate salt is used in oral dosage forms (tablets), and the hydrochloride salt is administered parenterally. Until recently, chloroquine has been the main antimalarial drug used for both prophylaxis and treatment. Note that the list of indications for many of the other drugs in this chapter include Plasmodium resistant to chloroquine. It is indicated for P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. Chloroquine belongs to the 4-aminoquinoline series of which hundreds have been evaluated, but only about three to four are still in use.





Hydroxychloroquine ch2 c2h5

ch2 c2h5

Amodiaquine c2h5

ch2 q2h5


ch2 q2h5

Amodiaquine iminoquinone

Amodiaquine iminoquinone

cf3 Mefloquine

Sontoquine ch3

j ch3


Figure 7.3 • 4-Aminoquinolines.

Even though this drug has been used for many years, its mechanism of action is still not known. Its main site of action appears to be the parasite involving the erythrocyte's lysosome. The following actions have been suggested based on experimental evidence. A very complex mechanism is based on ferriprotoporphyrin IX, which is released by Plasmodium containing erythrocytes, acting as a chloroquine receptor. The combination of ferriprotoporphyrin IX and chloroquine causes lysis of the parasite's and/or the erythrocyte's membrane. Finally, there is evidence that chloroquine may interfere with Plasmodium's ability to digest the erythrocyte hemoglobin or the parasite's nucleo-protein synthesis. The mechanism is based on the drug entering the erythrocyte's lysosome, which has an acid environment, where it becomes protonated. The protonated (positively charged) chloroquine is now trapped inside the lysosome because the pore that leads out of the lysosome is also positively charged. This leaves chloroquine bound to the patient's hemoglobin preventing the parasite from processing it properly.24

In general, chloroquine and the other 4-aminoquinolines are not effective against exoerythocytic parasites. Note that each of the mechanisms require that the parasite be inside the erythrocyte. Therefore, chloroquine does not prevent relapses of P. vivax or P. ovale malaria. The drug is also indicated for the treatment of extraintestinal amebiasis.

Effective such as chloroquine has been, it is a poor example of selective toxicity. Adverse reactions include retinopathy, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (same mutation that confers resistance against malaria), muscular weakness, exacerbation of psoriasis and porphyria, and impaired liver function. Further examples of poor selective toxicity include off-label indications that include rheumatoid arthritis, systemic and discoid lupus erythemaosis (possibly as a immunosuppressant), and various dermatological conditions.

The increase in P. falciparum resistant to chloroquine is considered to be one of the main reasons for the increase in both the incidence and deaths from malaria. The key Plasmodium gene that confers resistance appears to be the pfcrt gene that codes for a transporter protein. The result of the changes in the gene is that the pore through which chloroquine might exit the lysosome is no longer positive charged, allowing protonated chloroquine to exit the lysosome.35 There are at least eight mutations that have been identified in the pfcrt gene, and it is postulated that resistance occurs because of an accumulation of these mutations. Chloroquine remains effective when there are fewer mutations in the pfcrt gene. Once the critical number of mutations has occurred, the parasite spreads over a broad geographical area rendering chloroquine ineffective.22-24

Hydroxychloroquine. In most ways, hydroxychloroquine parallels chloroquine. Structurally, it differs solely with a hydroxy moiety on one of the N-ethyl groups. Like chloroquine, it remains in the body for over a month, and prophylactic dosing is once weekly. The other indications, both FDA approved and off-label, are very similar.

Amodiaquine. Amodiaquine is no longer marketed in the United States, but it is available in Africa. Mechanistically, it is very similar to chloroquine and does not have any advantages over the other 4-aminoquinoline drugs. When used for prophylaxis of malaria, it had a higher incidence of hepatitis and agranulocytosis than that was chloroquine. There is evidence that the hydroquinone (phenol) amine system readily oxidizes to a quinone imine (Fig. 7.3) either autoxidatively and/or metabolically, and this product may contribute to amodiaquine's toxicity.

Mefloquine HCl. The newest of the 4-aminoquino-lines, mefloquine, is marketed as the ^,^-isomer. It was developed in the 1960s as part of the U.S. Army's Walter Reed Institute for Medical Research antimalarial research program. It differs significantly from the other agents in this class by having two trifluromethyl moieties at positions 2' and 8' and no electronegative substituents at either positions 6' (quinine) or 7' (chloroquine). Mefloquine also differs from chloroquine and its analogs by being a schi-zonticide (site 2 in Fig. 7.1) acting before the parasite can enter the erythrocyte. There is some evidence that it acts by raising the pH in the parasite's vesicles interfering with its ability to process heme. Mefloquine-resistant strains of P. falciparum have appeared. Relapse can occur with acute P. vivax that has been treated with mefloquine because the drug does not eliminate the hepatic phase of this species, which can reinfect the liver.

Mefloquine is teratogenic in rats, mice, and rabbits. There is an FDA-required warning that this drug can cause exacerbate mental disorders and is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, and other major psychiatric disorders or a history of convulsions.


The other major group of antimalarial drugs based on the cinchona alkaloid quinoline moiety is the substituted 8-aminoquinolines (Fig. 7.4). The first compound introduced in this series was pamaquine. During World War II, pen-taquine, isopentaquine, and primaquine became available. Only primaquine, after being used during the Korean war, is in use today. All of the 8-aminoquinolines can cause hemolytic anemia in erythrocytic glucose-6-phosphate dehy-drogenase-deficient patients. As pointed out in the introduction to this chapter, this is a common genetic trait found in populations living in areas endemic in malaria and provides some resistance to the parasite. Mechanism of action and spectrum of activity will be found in the primaquine section.

Figure 7.4 • 8-Aminoquinolines.

Isopentaquine HsC CHs

Figure 7.4 • 8-Aminoquinolines.

Very little variations are seen in the structure-activity relationships in this series. The four agents in Figure 7.4 all have a 6-methoxy moiety same as quinine, but the sub-stituents are on the quinoline are located at position 8 rather than carbon-4 as found on the cinchona alkaloids. All agents in this series have a four to five carbon alkyl linkage or bridge between the two nitrogens. With the exception of pentaquine, the other three 8-aminoquinolines have one asymmetric carbon. Although some differences may be seen in the metabolism of each stereoisomer and type of adverse response, there is little difference in antimalarial activity based on the compounds stereochemistry.

Primaquine. Primaquine is the only 8-aminoquinoline currently in use for the treatment of malaria. It is not used for prophylaxis. Its spectrum of activity is one of the narrowest of the currently used antimalarial drugs being indicated only for exoerythrocytic P. vivax malaria (site 2 in Fig. 7.1). To treat endoerythrocytic P. vivax, chloroquine or a drug indicated for chloroquine-resistant P. vivax is used with primaquine. In addition to its approved indication, it is also active against the exoerythrocytic stages of P. ovale and primary exoerythrocytic stages of P. falcip-arum. Primaquine also inhibits the gameocyte stage (site 4 in Fig. 7.1) that eliminates the form required to infect the mosquito carrier. In vitro and in vivo studies indicate that the stereochemistry at the asymmetric is not important for antimalarial activity. There appears to be less toxicity with the levorotatory isomer, but this is dose dependent and may not be that important at the doses used to treat exoerythrocytic P. vivax malaria.

Although structurally related to the cinchona alkaloids, the 8-aminoquinolines act by a different mechanism of action. Primaquine appears to disrupt the parasite's mitochondria. The result is disruption of several processes including maturation into the subsequent forms. An advantage is destroying exoerythrocytic forms before the parasite can infect erythrocytes. It is the latter step in the infectious process that makes malaria so debilitating.

Polycyclic Antimalarial Drugs

There are three antimalarial drugs that have, in common, polycyclic ring systems (Fig.7.5). The first is the common tetracycline antibiotic, doxycycline. The second is halo-fantrine, and the third is the discontinued agent that was used in the South Pacific, quinacrine.

Doxycycline. Like the other tetracyclines, doxycycline (see Chapter 8) inhibits the pathogen's protein synthesis by reversibly inhibiting the 30S ribosomal subunit. Bacteria and Plasmodium ribosomal subunits differ significantly from mammalian ribosomes such that this group of antibiotics do not readily bind to mammalian ribosomes and, therefore, show good selective toxicity. Although doxycycline is a good antibacterial, its use for malaria is limited to prophylaxis against strains of P. falciparumn resistant to chloroquine and sulfadoxine-pyrimethamine. This use normally should not exceed 4 months. Because the tetracyclines chelate calcium, they can interfere with development of the permanent teeth in children. Therefore, their use in children definitely should be short term. Also,

Lumefantrine Figure 7.5 • Polycyclic antimalarial drugs.

Antimalarial Drugs Classification

Artemether (oil soluble) R = CH3 Artesunate (water soluble)

Artemotil (oil soluble) R = CH2CH3


Simplified Aryltrioxanes R = -F or -COOH

tetracycline photosensitivity must be kept in mind, particularly because areas where malaria is endemic are also the areas with the greatest sunlight.

Halofantrine. Structurally, halofantrine differs from all other antimalarial drugs. It is a good example of drug design that incorporates bioisosteric principles as evidenced by the trifluromethyl moiety. Halofantrine is a schizonticide (sites 1 and 2 in Fig. 7.1) and has no affect on the sporozoite, game-tocyte, or hepatic stages. Both the parent compound and N-desbutyl metabolite are equally active in vitro. Halfantrine's specific mechanism of action against the parasite is not known. There is contradictory evidence that its mechanism ranges from requiring heme to disrupting the mitochondria. There is a prominent warning that halfantrine can affect nerve conduction in cardiac tissue.

Lumefantrine. Lumefantrine was developed in China. Its mechanism of action is poorly understood. There is some evidence that it inhibits the formation of jS-hematin by forming a complex with hemin. Lumefantrine is very lipophilic and is

Figure 7.6 • Artemisinin and artemisinin-derived compounds.

marketed in combination with the lipophilic artemesinin-derived artemether (Fig. 7.6).

Quinacrine HCl. Qunacrine is no longer available in the United States. It can be considered one of the most toxic of the antimalarial drugs even though, at one time, it was commonly used. It acts at many sites within the cell including intercalation of DNA strands, succinic dehydrogenase and mitochondrial electron transport, and cholinesterase. It may be tumorgenic and mutagenic and has been used as a scle-rosing agent. Because it is an acridine dye, quinacrine can cause yellow discoloration of the skin and urine.


The artemisinin series (Fig. 7.6) are the newest of the anti-malarial drugs and are structurally unique when compared with the compounds previously and currently used. The parent compound, artemisinin, is a natural product extracted from the dry leaves of Artemisia Annua (sweet wormwood). The plant has to be grown each year from seed because mature plants may lack the active drug. The

Pyrimethamine Figure 7.7 • Sulfadoxine and pyrimethamine.

growing conditions are critical to maximize artemisinin yield. Thus far, the best yields have been obtained from plants grown in North Vietnam, Chongqing province in China, and Tanzania.25

All of the structures in Figure 7.6 are active against the Plasmodium genera that cause malaria. The key structure characteristic appears to be a "trioxane" consisting of the endoperoxide and dioxepin oxygens. This is shown by the somewhat simpler series of 3-aryltrioxanes at the bottom of Figure 7.6, which are active against the parasite. Note that the stereochemistry at position 12 is not critical.26 Although in the victim's erythrocyte, the malaria parasite consumes the hemoglobin consisting of ferrous (Fe+2) iron converting it to toxic hematin containing ferric (Fe+3) and then reduced to heme with its ferrous iron. The heme iron reacts with the trioxane moiety releasing reactive oxygen and carbon radicals and the highly reactive FeIV = O species. The latter is postulated to be lethal to the parasite.27,28

With the reduction of artemisinin to dihydroartemisinin, an asymmetic carbon forms and it is possible to form oil soluble and water soluble prodrugs. Both stereoisomers are active just as is seen in the simpler aryltrioxanes. The chemistry forming each of the artemisinin prodrugs results in the predominance of one isomer. The ^-isomer predominates when producing the nonpolar methyl and ethyl ethers, whereas the a-isomer is the predominate product when forming the water-soluble hemisuccinate ester. The latter can be administered as 10-mg rectal capsules for patents who cannot take medication orally and parenteral treatment is not available.

Fixed Combinations

Because resistance is a frequent problem in the prophylaxis and treatment of malaria, combination therapies that use two distinctly different mechanisms have been developed. One combination inhibits folic acid biosynthesis and dihydrofo-late reductase, and another combination acts on the parasite's mitochondria and its dihydrofolate reductase. Both drugs in the third combination act on hematin, but by two different mechanisms.

Sulfadoxine and Pyrimethamine. This combination (Fig. 7.7) uses a drug from the sulfonamide antibacterial group and a pyrimidinediamine similar to trimethoprim (see Chapter 8). The combination is considered to a schizonto-cide (site 2 in Fig. 7.1). The sulfonamide, sulfadoxine, interferes with the parasite's ability to synthesize folic acid, and the pyrimidinediamine, pyrimethamine, inhibits the reduction of folic acid to its active tetrahydrofolate coenzyme form. Sulfonamides block the incorporation of p-aminoben-zoic acid (PABA) forming dihydropteroic acid. Note the structures of dihydrofolic acid and tetrahydrofolic acid and how PABA is the central part of the folate structure (see Chapter 28). Normally, sulfonamides exhibit excellent selective toxicity because humans do not synthesize the vitamin folic acid. Nevertheless, there are warnings of severe to fatal occurrences of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and serum-sickness syndromes attributed to the sulfadoxine.

Pyrimethamine, developed in the 1950s, inhibits the reduction of folic acid and dihydrofolic acid to the active tetrahydrofolate coenzyme form. Although the latter is required for many fundamental reactions involving pyrimi-dine biosynthesis, the focus in the parasite is regeneration of N5,N10-methylene tetrahydrofolate from dihydrofolate. The synthesis of thymidine 5'-monophosphate from de-oxyuridine 5'-monophosphate is a universal reaction in all cells forming DNA. There are enough differences in this enzyme and dihydrofolate reductase found in mammalian, bacterial, and Plasmodium cells that folate reduc-tase inhibitors can be developed that show reasonable selective toxicity. In the case of the malaria parasite, the intimate relationship between thymidylate synthase and


Figure 7.8 • Atovaquone and proguanil.

dihydrofolate reductase is such that pyrimethamine inhibits both enzymes.

This combination is indicated for prophylaxis and treatment of chloroquine resistance P. falciparum and may be used in combination with quinine. Although indicated only for P. falciparum, the combination is active against all the asexual erythocytic forms. It has no activity against the sexual gametocyte form. The fixed combination contains 500-mg sulfadoxine and 25-mg pyrimethamine. There is a wide number of sulfonamides that could be used in combination with pyrimethamine. The usual approach is to use a sulfonamide that has similar pharmacokinetic properties with the dihydrofolate reductase inhibitor. For this combination, the peak plasma sulfadoxine occurs in 2.5 to 6 hours and pyrimethamine 1.5 to 8 hours. Resistance has developed with much of it involving mutations in either or both of the genes coding for dihydrofolate reductase and thymidylate synthase.

Atovaquone and Proguanil HCl. Atovaquone and proguanil HCl (Fig. 7.8) are administered in combination in the ratio of 2.5 atovaquone to 1 proguanil HCl measured in mg (not mmoles). Proguanil, developed in 1945, is an early example of a prodrug. It is metabolized to cycloguanil

(Fig. 7.9), primarily by CYP2C19. The polymorphic nature of this hepatic enzyme explains why certain subpopulations do not respond to proguanil. These groups cannot convert proguanil to the active cycloguanil.

The basis for this combination is two distinct and unrelated mechanisms of action against the parasite. Atovaquone is a selective inhibitor of the Plasmodium's mitochondrial electron transport system, and cycloguanil is a dihydrofolate reductase inhibitor. Atovaquone's chemistry is based on its being a naphthoquinone and participating in oxidation-reduction reactions as part of its quinone-hydroquinone system. It is patterned after Coenzyme Q found in the mitochondrial electron transport chains. The drug selectively interferes with mitochondrial electron transport, particularly at the parasite's cytochrome bc1 site. This deprives the cell of needed ATP and could cause the cell to become anaerobic. Resistance to this drug comes from a mutation in the parasite's cytochrome.

Cycloguanil (Proguanil) interferes with deoxythymidylate synthesis by inhibiting dihydrofolate reductase. Resistance to proguanil/cycloguanil is attibuted to amino acid changes near the dihydrofolate reductase binding site. Its elimination half-life (48-72 hour) is much shorter than the other anti-malarial dihydrofolate reductase, pyrimethamine (mean h-n h

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  • brad
    How does stereochemistry of quinine affects the pharmacological activities of quinoline alkaloid?
    6 years ago

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