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Springer MRW: [AU:0, IDX:0] P Pharmacology of Antimalarial studies were performed by German scientists just Drugs, Current Anti-malarials before World War II. However, the drug was reported to be too toxic for human use and not Kesara Na-Bangchang1 and Juntra Karbwang2 introduced for general use at that time. By late 1Chulabhorn International College of Medicine, 1944, in the intensive search for an effective anti- Thammasat University, Pathumtanee, Thailand malarial drug during World War II, US workers 2Clinical Product Development, Institute of synthesized 25 different 4-aminoquinoline deriv- Tropical Medicine, Nagasaki, Japan atives, with the objective of discovering more effective and less toxic suppressive agents than quinacrine. Of these compounds, chloroquine Currently available antimalarial drugs can be clas- proved the most promising and later underwent sified into four broad categories according to their extensive clinical studies. Since then, chloroquine chemical structures and modes of action. had been used as the drug of choice for treatment of human malaria all over the world until the 1. Arylamino alcohol compounds: quinine, quin- advent of chloroquine resistance in Plasmodium idine, chloroquine, amodiaquine, mefloquine, falciparum in the early 1960s. Clinical treatment halofantrine, piperaquine, and lumefantrine failures of P. falciparum were first noted in 2. 8-Aminoquinoline: primaquine and Thailand almost at the same time as in South tafenoquine America. Chloroquine-resistant P. falciparum 3. Antifolate compounds: sulfadoxine, pyrimeth- has since then spread relentlessly to virtually all amine, proguanil, chlorproguanil, and areas of the world except Central America, North trimethoprim Africa, and parts of Western Asia. 4. Artemisinin compounds: artemisinin, artesunate, artemether, b-arteether, and dihydroartemisinin Chemistry and Physical Properties 5. Others: atovaquoneand antibacterial drugs Chloroquine [7-chloro-4-(4-diethylamino-1-methy- (tetracycline, doxycycline, and clindamycin) lbutylamino) quinoline: Fig. 1a] is a weakly basic tertiary amine synthetic antimalarial agent which is a 4-aminoquinoline derivative. It has a quinoline ring Arylamino Alcohol Antimalarials with a side chain identical with that of quinacrine. The chlorine atom in the seventh position appears to Chloroquine be crucial to the antimalarial activity of all Chloroquine was first synthesized by Bayer in 4-aminoquinoline antimalarials. The drug is used Germany as early as 1934. The initial clinical © Springer Science+Business Media, LLC, part of Springer Nature 2019 P. G. Kremsner, S. Krishna (eds.), Encyclopedia of Malaria, https://doi.org/10.1007/978-1-4614-8757-9_149-1 2 Pharmacology of Antimalarial Drugs, Current Anti-malarials Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 1 Chemical structures of (a) chloroquine and (b) mono-desethyl chloroquine as a racemic mixture of equal amounts of S(+) and R in vitro, but it is less effective than the parent com- (À) chloroquine. pound against chloroquine-resistant strains. Chloroquine is a white or slightly yellow, odor- The mechanisms of action and resistance of less, crystalline powder with a bitter taste. It is chloroquine have not been fully elucidated. poorly soluble in water, but soluble in diluted Proposed mechanism(s) of action include DNA acid, chloroform, and ether. Chloroquine phos- binding, inhibition of various enzymes (e.g., phate is readily soluble in water at acidic mixed-function oxidase, heme polymerase, phos- pH. Chloroquine sulfate is soluble in a mixture pholipase, and glutathione-S-transferase) and/or of water and methanol but non-soluble in pure transporters, inhibition of protein synthesis, inter- water. The drug is sensitive to light and should ference with digestion of host-derived hemoglobin be protected from light. The molecular weights of in the parasite digestive food vacuole (acid lyso- the base, phosphate, sulfate, and hydrochloride some), and lysosomotropic effect. Interference salts are 320, 516, 436, and 393, respectively. with hemoglobin digestion process and alteration Structure-activity relationship (SAR) studies of of lysosomal pH appear to be important mecha- many derivatives of the 4-aminoquinolines show nisms of chloroquine action. During the process of that halogen substitutions at any position other hemoglobin digestion, the protein moiety of hemo- than seven reduce pharmacologic activity and globin is degraded to related peptides, and heme is toxicity. An aryl rather than an alkyl side chain transformed into hemozoin (HZ), a nontoxic crys- decreases the therapeutic ratio. Increasing alkyl talline polymer. Chloroquine is a weak base with side chain length above five carbons decreases pKa values of 8.1 and 10.2 and the protonation of the therapeutic ratio and increases toxicity. the drug encharged at the neutral pH of the blood. With the acidic pH for parasite food vacuole, chlo- roquine accumulates and binds hematin, a toxic Pharmacological Activities product of hemoglobin degradation, therefore pre- venting its incorporation into the hemozoin crystal. Antimalarial Activity and Mechanism of The free hematin interferes with the parasite detox- Action and Resistance Chloroquine is highly ification processes and thereby damages the Plas- effective and acts rapidly against asexual erythro- modium membranes by lipid peroxidation cytic forms of Plasmodium vivax, Plasmodium mechanism. ovale, Plasmodium malariae, Plasmodium Resistance to chloroquine in P. falciparum knowlesi, and chloroquine-sensitive P. falciparum. involves mainly the mutation in the parasite trans- (À)-Chloroquine is less active than (+)-chloroquine port gene pfcrt (Plasmodium falciparum chloro- enantiomer against chloroquine-resistant strains of quine resistance transporter) along with pfmdr1 P. falciparum. Chloroquine is also active against (Plasmodium falciparum multidrug resistance 1) gametocytes of P. vivax, P. malariae,andP. ovale and pfmrp1 (Plasmodium falciparum multidrug and immature forms of P. falciparum. The drug has resistance-related protein 1). The pfcrt gene is no effect against the exoerythrocytic tissue stages of located on chromosome 7 and encodes a 49 kDa malaria. Its major plasma metabolite mono- protein (PfCRT) localized in parasite’s food vac- desethylchloroquine (Fig. 1b)hassimilarantimalar- uole with ten predicted transmembrane domains. ial activity against chloroquine-susceptible parasites Pharmacology of Antimalarial Drugs, Current Anti-malarials 3 An amino acid substitution at position 76 from Chloroquine has potential for use as an adjunct lysine to threonine (K76 T), located on the first therapy with standard antiretroviral drugs. Syner- transmembrane domain, has been reported to be gistic activities have been demonstrated when directly associated with chloroquine-resistant chloroquine is used in combination with zidovu- P. falciparum isolates in wide geographic areas. dine, didanosine, and the protease inhibitors The pfmdr1 gene is located on chromosome 5 and (indinavir, ritonavir, and saquinavir). Chloroquine encodes a homologue of the mammalian multi- is associated with low levels of HIV RNA in drug resistance gene in P. falciparum, breast milk of the HIV-infected patients. In addi- P-glycoprotein homologue 1 (Pgh-1). Pfmdr1 tion to HIV, inhibitory activity against the repli- can modulate the degree of chloroquine resistance cation of severe acute respiratory syndrome in some parasite strains, suggesting that some (SARS) or coronavirus infections is shown alleles and overexpression of PfMDR1 may in vitro. enhance chloroquine concentration within the Chloroquine also has potential for use as a digestive food vacuole by active transport. The chemosensitizer in cancer in conjunction with pfmrp1 is located on chromosome 1 and encodes some conventional anticancer drugs, through inhi- a 1822 amino acid proteins PfMRP1 which is a bition of the function of membrane-associated transporter member of the ATP-binding cassette proteins belonging to the P-glycoprotein and (ABC) proteins similarly to PfMDR1. It is local- multidrug resistance (MDR) protein families. ized to the parasite plasma membrane. PfMRP1 Chloroquine is a potent autophagic drug that modifies drug responses but is not a major deter- may lead to cellular degradation of hepatocytes in minant of chloroquine resistance. Potential inhib- the liver with the concurrent production of itors of these parasite transport proteins which vacuoles. could effectively reverse chloroquine-resistant Chloroquine has been shown to inhibit glucose P. falciparum in clinical settings are being 6-phosphate dehydrogenase activity in vitro. investigated. Administration of chloroquine to rats also caused alterations in several hepatic and renal antioxidant enzymes, thereby inducing an oxidative stress in Other Pharmacological Activities and Clinical these organs. Uses Apart from malaria, chloroquine is com- monly used in patients with several inflammatory Therapeutic Indications for Malaria conditions, such as rheumatoid arthritis, systemic Chloroquine is one of the most successful and lupus erythematosus (SLE), discoid lupus widely used medications and with obvious health erythematosus, porphyria cutanea tarda, polymor- precautions, saving countless lives from malaria phous light eruptions, solar urticaria, recurrent since the 1940s. The drug was for several decades basal cell carcinoma of the skin, porphyria cutanea the antimalarial of choice because it was effective, tarda, and antiphospholipid antibody syndrome. well tolerable,
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