Antimalarial drugs 8-aminoquinolines

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

Ibrahim et al. [30] described a fluorimetric method for the determination primaquine and two other aminoquinoline antimalarial drugs using eosin. Powdered tablets or ampule contents containing the equivalent of 50 mg of the drug was extracted with or dissolved in water (100 mL). A 10 mL aliquot was mixed with 10 mL of aqueous ammonia, 1 mL of 0.001% eosin (C.I. acid red 87) in dichloro-ethane, and dichloroethane was added to volume. Primaquine was determined fluorimetrically at 450 nm (excitation at 368 nm). Calibration graphs were rectilinear for 0.1-5 pg/mL of primaquine. Recoveries were quantitative. The method could be readily adapted for determination of the drug in biological fluids. 

Hydroxychloroquine Plaquenil) and chloroquine Ara-len) are 4-aminoquinoline antimalarial drugs that possess modest DMARD activity. They are indicated for the treatment of rheumatoid arthritis and systemic lupus erythematosus their use as antimalarials is detailed in Chapter 53. The onset of action of these drugs is longer than that of other DMARDs, and their side effects are relatively mild. Because of this, these agents show promise as ingredients of combination therapies for rheumatoid arthritis. 

Quinacrine is no longer used extensively as an antimalarial drug and has been largely replaced by the 4-aminoquinolines. 

Vlakhov R, Parushev S, Vlakhov I, Nickel P, Snatzke G (1990) Synthesis of some new quinoline derivatives - potential antimalarial drugs. Pure Appl Chem 62 1303-1306 Madrid PB, Sherrill J, Liou AP, Weisman JL, DeRisi JL, Kipling GR (2005) Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities. Bioorg Med Chem Lett 15 1015-1018... 

A synthesis of 7,8-dioxygenated isoquinolines (found in cularine alkaloids) requires o-metallation of the Af-protected -phenylethylamine. The primary amine is protected by reaction with two equivalents of trimethylsilyl chloride. Phenylhydroxylamine and the allenic nitrile (53.7) react in boiling ethanol over 48 h to give a high yield of 4-aminoquinoline—an important intermediate for the synthesis of some antimalarial drugs. 

El-Ashry et al. [36] studied the complex formation between the bromophenol blue, primaquine, and other important aminoquinoline antimalarials. The colorimetric method used was described as simple and rapid and is based on the interaction of the drug base with bromophenol blue to give a stable ion-pair complex. The spectra of the complex show maxima at 415 420 nm with high apparent molar absorptivities. Beer s law was obeyed in the concentration range 1-8,2-10, and 2-12 pg/mL for amodiaquine hydrochloride, primaquine phosphate, and chloroquine phosphate, respectively. The method was applied to the determination of these drugs in certain formulations and the results were favorably comparable to the official methods. 

Amodiaquine (Camoquin) is another 4-aminoquinoline derivative whose antimalarial spectrum and adverse reactions are similar to those of chloroquine, although chloroquine-resistant parasites may not be amodi-aquine-resistant to the same degree. Prolonged treatment with amodiaquine may result in pigmentation of the palate, nail beds, and skin. There is a 1 2000 risk of agranulocytosis and hepatocellular dysfunction when the drug is used prophylactically. 

Primaquine phosphate is a synthetic 8-aminoquinoline (Figure 52-2). The drug is well absorbed orally, reaching peak plasma levels in 1-2 hours. The plasma half-life is 3-8 hours. Primaquine is widely distributed to the tissues, but only a small amount is bound there. It is rapidly metabolized and excreted in the urine. Its three major metabolites appear to have less antimalarial activity but more potential for inducing hemolysis than the parent compound. 

The development of 4-aminoquinoline antimalarials owes its origin to World War II when the Allies were deprived of the supply of quinine (1) as a consequence of the Japanese occupation of Java, where cinchona was grown widely to produce quinine. To overcome this problem, a synthetic alternative, quinacrine (2) was developed, which was extensively used during the war to treat malaria in man. Neverthless, the need for a more effective and safer antimalarial was pressing. Examination of the structural frame-work of quinine (1) and quinacrine (2) revealed that the common feature in the two drugs is the presence of a 4-substituted quino-... 

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-... 

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