4-Aminoquinoline drugs

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 drug resembles very similar to chloroquine mechanistieally and it does not possess any added advantages over the other 4-aminoquinoline drugs. It has been demonstrated amply that the hydroquinone (phenol) amine system rapidly gets oxidized to a eorresponding quinone-imine system, either accomplished via antioxidatively and/or metabolically and the resulting product may be solely responsible for the ensuing amodiaquine toxicity. 

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. 

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. 

Primaquine is the most effective and most toxic drug from the whole series of known 8-aminoquinolines. It is generally used for treating exoerythrocyte forms of malaria caused by P. vivax and P. ovale. It also acts on the sexual forms of the plasmodia, which die in the human body upon using this drug. 

Drugs that may be affected by magnesium salts include aminoquinolines, nitrofurantoin, penicillamine, and tetracyclines. 

Children Children are especially sensitive to 4-aminoquinolines. Safe use of the drug in the treatment of JRA and SLE has not been established. 

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. 

Hydroxychloroquine (Plaquenil), like chloroquine, is a 4-aminoquinoline derivative used for the suppressive and acute treatment of malaria. It also has been used for rheumatoid arthritis and discoid and systemic lupus erythematosus. Hydroxychloroquine has not been proved to be more effective than chloroquine. Adverse reactions associated with its use are similar to those described for chloroquine. The drug should not be used in patients with psoriasis or porphyria, since it may exacerbate these conditions. 

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. 

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

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. 

De, D. Byers, L. D. Krogstad, D. J. Antimalar-ials synthesis of 4-aminoquinolines that circumvent drug resistance in malaria parasites. 

Aminoquinoline derivatives, (III), prepared by Jain (4) have a broad spectrum of activity against blood and tissue stages of human malaria parasites as well as being useful in treating drug-sensitive and multidrug-resistant malaria. 

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 review of certain chemicals is essential. Ethylene glycol is an antifreeze used for gasoline engines and may produce somnolence, imreactive pupils, disc swelling, and kidney failure. Systemic lead poisoning produces headaches, coma, cranial nerve palsies, and papilledema. Wood alcohol, or methanol, may produce severe toxic neuropathy and disc edema. Drugs known to produce toxic optic neuropathy include amiodarone (an antiar-rhythmic), quinine, aminoquinolines, ibuprofen, ethambutol, isoniazid, and chloramphenicol. 

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