Antimalarial 8-aminoquinolines

Jannie P. J. Marais studied at the University of the Free State, Bloemfontein, South Africa where he obtained his Ph.D. in organic chemistry in 2002. His research focused on characterization of the free phenolic profile of South African red wine, and the stereoselective synthesis of flavonoids, for example, flavan-3,4-diols and flavanones. He joined the National Center for Natural Products Research at the University of Mississippi as a postdoctoral associate in July of 2002, where he worked with Dr. Ferreira on the stereoselective synthesis of flavonoid precursors, the semi-synthesis of proanthocyanidin oligomers, characterization of proanthocyanidin profiles of selected transgenic plants, and the synthesis of radioactive antimalarial 8-aminoquinolines. He was promoted to associate research scientist in 2005, where his main area of research still remains the synthesis of A- and B-type proanthocyanidins, starting at the monomeric level and continuing through the tri- and tetra-meric, to the deca-mer level. 

The pioneering work carried out in Germany in the 1920s showed that appropriately substituted aminoquinolines and amino-acridines afforded a series of synthetic compounds that exhibited antimalarial activity.The exigencies of the Second World War led to a massive program aimed at the same goal in this country. This work led to the development of two distinct structural classes of quinoline antimalarials the 4-amino-7-chloroquino-... 

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. 

Among the aminomethylenemalonates, the A-aryl and A-hetaryl derivatives and their cyclization products are of great importance in organic chemistry, as some of them are key intermediates in the synthesis of different 4-aminoquinoline antimalarials (Scheme 1), in the preparation of anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates (Scheme 2), and in the production of antibacterial agents of the nalidixic acid type (Scheme 3). 

Toxicity by metabolism is not confined to the liver since oxidative systems occur in many organs and cells. Amodiaquine is a 4-aminoquinoline antimalarial that has been associated with hepatitis and agranulocytosis. Both side-effects are probably triggered by reactive metabolites produced in the liver or in other sites of the body. For instance polymorphonuclear leucocytes can oxidize amodiaquine. It appears that amodiaquine is metabolized to a quinone imine by the same pathway as that seen in... 

VI.a.2.1. AminoquinoUnes. The aminoquinolines currently used as antimalarials include the 4-amino-quinolines chloroquine and mefloquine and the 8-aminoquinoline primaquine. 

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. 

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 is the least toxic and most effective of the 8-aminoquinoline antimalarial compounds. The mechanism by which 8-aminoquinolines exert their antimalarial effects is thought to be through a quinoline-quinone metabolite that inhibits the coenzyme Q-mediated respiratory chain of the exoerythrocytic parasite. 

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

Chloroquine is a 4-aminoquinoline antimalarial agent used for the suppression and clinical cure of malaria. It is an excellent erythrocytic schizontocide. It does not prevent relapse in P. vivax and P. ovale malaria. It has no effect on pre and exoerythrocytic phase of the parasite. It also... 

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 major antimalarial agents are the 4-aminoquinoline derivative (e.g., chloroquine), 8-aminoquinoline derivative (e.g., primaquine), folic acid antagonist (e.g., pyrimethamine), and... 

In parallel, extensive studies on P. falciparum field isolates in Gabon [140-142], Senegal [143], Cambodia [118, 119, 144], and the Thailand Burmese border [145] corroborated the efficacy of FQ on the parasite whatever its resistance level to chloroquine or to other commonly used antimalarials mefloquine, quinine, halofantrine, and artemisinin derivatives [146, 147]. The cross reactivity observed in some studies with CQ was limited and it was demonstrated that it was caused by differences in initial parasitemia among isolates at the start of the assays [141]. Independance of susceptibility of P. falciparum with phenotypic variation of pfcrt gene, responsible for CQ resistance, could be suspected from these results, but this was demonstrated at the molecular level on Cambodia isolates [148] and extended further on other genes currently involved in resistance to aminoquinoline antimalarials [89, 90]. 

N-Aryl and N-heteroaryl derivatives of aminomethylene malonates are also very useful and fruitful synthons for formation of 4-aminoquinolines used as antimalarials (equation 215), of the anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates and of antibacterial nalidixic acid derivatives (equation 216). Each of these is an important group of pharmaceuticals, developed in the last twenty years. Because of its medicinal interest this route is widely used for synthesis of quinolines and pyridinofused heterocycles. The chemistry has been comprehensively reviewed in a recent monograph292. Hence, no further details are given here. 

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... 

Manohar S, Khan SI, Rawat DS (2010) Synthesis, antimalarial activity and cytotoxicity of 4-aminoquinoline-triazine conjugates. Bioorg Med Chem Fett 20 322-325... 

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