Chloroquine preparations

Nalidixic acid, the prototype of this family of drugs, was synthesized as the result of the discovery that an impurity, isolated during the preparation of the antimalarial chloroquine, had significant antibacterial activity. It was... 

Halofantrine, a 9-phenanthrenemethanol derivative, is a blood schizonticide and is active against Plasmodium vivax and chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum. As no parenteral preparation is available it cannot be used for severely ill patients. Oral absorption is slow and incomplete and is increased by a fatty meal. 

Fluoroquinolones The story of fluoroquinolones began in the 1950s with the discovery of the antibacterial properties of 7-chloroquinolone, a side product of the preparation of chloroquin and glafenin. Further research led to the... 

A rapid semiautomated microdilution method for the microbiological assay of the chloroquine has been developed by Desgardins (26). Antimalarial activity of chloroquine may be studied against cultured Plasmodium falciparum, microplates are used to prepare serial dilution of the drug. Parasites obtained from continuous stock cultures are subcultured in the micro-plates for 42 h. Inhibition of uptake of a radio labeled nucleic acid precursor by parasites serves as the indicator of antimicrobial activity. 

Chemosensitizing agents prepared by Lin (6) consisting of phenothiazine derivatives, (V), were effective against chloroquine-resistant Plasmodium falciparum. 

In a further effort to develop better antimalarials by changing the substitution at the 4-amino function of chloroquine led to the discovery of hydroxychloroquine (5) with high antimalarial activity [11,12]. The search for newer 4-aminoquinoline drugs received a new dimension when Burckhalter et al. [13] discovered the antimalarial activity with some a-dialkylamino-o-cresols of the type 6 and 7. Consequently these authors prepared a large variety of Mannich bases attached to the 7-chloroquinolin-4-... 

The key intermediate for synthesizing chloroquine, amodiquine and other 4-aminoquinoline drugs is 4,7-dichloroquinolihe (91), which can be prepared by reacting m-chloroaniline (83) with diethyl oxaloacetate (EtO-CO-CH2-CO-COOEt) or ethoxy methylene malonic ester [EtO-CH=C(CCXDEt)2] as shown in scheme 1 [8,128-133]. 

The synthesis of various 4-aminoquinoline antimalarials may be achieved by nucleophilic reaction of 91 with desired amines. Scheme 2 outlines the preparation of chloroquine (3) and amodiaquine (8) starting from 4,7-dichloroquinoline (91) [134-136]. 

Another method to prepare chloroquine (3) involves reaction of 83 with methyl acrylate to get via 98 and 99 the adduct 100, which is converted into 7-chloro-l,2,3,4-tetrahydroquinoline-4-one (103). Reaction of 103 with novaldiamine (92) under dehydrogenating conditions gives chloroquine in about 25% overall yield [133] (Scheme 3). 

In our typical preparation, we get approx 140 pg of chloroquine/pmol of lipid P. 

It is important to check the status of chloroquine in liposomized preparation before injecting into the animals. No leakage of the chloroquine from the liposomes is detected under these conditions. 

Fitch, C. D., and Chevli, R. (1981). Sequestration of the chloroquine receptor in cell-free preparations of erythrocytes infected with Plasmodium berghei. Antimicrob. Agents Chemother. 19,589-592. 

Emetine (Fig. 7-9) in the form of the crude drug obtained from the roots and rhizomes of Ipecac (Cephaelis ipecacuanha) has been in use since the seventeenth century. The alkaloid, as the hydrochloride, has been used parenterally to treat amebic dysentery. It is also effective in hepatic infestation, but not against amebic cysts. Because of its cardiac toxicity and emetogenic properties, it has been superseded by metronidazole and chloroquine, but it is still used as an alternative. The amebicidal mechanism of emetine is protein synthesis inhibition by interference of peptidyl-RNA translocation. Since this action is general to eukaryotic cells, its relative selectivity in the presence of mammalian cells is not well understood. Unrelated uses of Ipecac (presumably due to its alkaloid content) are as an expectorant in cough preparations and an emergency emetic (Syrup of Ipecac). 

Sulfadoxine/pyrimethamine is an antimalarial preparation. The two components sequentially block two enzymes involved in the biosynthesis of folinic acid within the parasites. It is indicated in the treatment of Plasmodium falciparum malaria for those patients in whom chloroquine resistance is suspected and as prophylaxis of malaria for travelers to areas where chloroquine-resistant P. falciparum malaria is endemic. 

Ethers, esters and carbonates of dihydroartemisinin have been prepared to obtain novel and more active derivatives [45]. After examination of the ethers, including the epimers at position 10, artemether (31 2, R = CH3) and arteether (31 3, R = CH2CH3), they were found to be about twice as active as artemisinin, but less active than dihydroartemisinin. Artemether has been isolated as a natural constituent of A. annua. Arteether was found to be 34 times more active than chloroquine against the W-2 (Indochina) clone of P. falciparum (normally resistant to chloroquine) and three times less active against the D-6 (Sierra Leone) clone (normally resistant to mefloquine). Artemether was two times more active and eight times more active than mefloquine against the W-2 and D-6 clones, respectively. Both artemether and arteether are more oil soluble than artemisinin and are currently in clinical trials. 

R.F. Davis, Process for Preparing 6-Halo-2-Chloroquin-oxaline, U.S. Patent 1987 4,636,562. 

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