8- Aminoquinolines

Amodiaquine, a Mannich base 4-aminoquinoline, eliminates blood stage parasites. Its mode of action is similar to that of chloroquine (see below) and there is some cross-resistance. 

The formation of 0-seryl or 0-prolyl esters (Figure 1) of certain N-hydroxy arylamines has been inferred from the observations that highly reactive intermediates can be generated in vitro by incubation with ATP, serine or proline, and the corresponding aminoacyl tRNA synthetases (11,12,119). For example, activation of N-hydroxy-4-aminoquinoline-l-oxide (119,120), N-hydroxy-4-aminoazobenzene (11) and N-hydroxy-Trp-P-2 (121) to nucleic acid-bound products was demonstrated using seryl-tRNA synthetase from yeast or rat ascites hepatoma cells. More recently, hepatic cytosolic prolyl-, but not seryl-, tRNA synthetase was shown to activate N-hydroxy-Trp-P-2 (12) however, no activation was detectable for the N-hydroxy metabolites of AF, 3,2 -dimethyl-4-aminobiphenyl, or N -acetylbenzidine (122). 

The identification of C8-guanyl and N6-adenyl adducts of 4-aminoquinoline-l-oxide (102,103) in DNA modified by the metaboli-cally-generated 0-seryl ester and the similarity of the adduct profile with that obtained on reaction of DNA with N-acetoxy-4-araino-quinoline-l-oxide suggest an electrophilic reaction mechanism similar to that for the N-acetoxy or N-sulfonyloxy arylamines (Figures 4 and 5). However, N-seryloxy or N-prolyloxy arylamines have not been synthesized and the decomposition products of the esters generated in vitro have not yet been studied. 

The answer is c. (Hardman, pp 970-972.) Chloroquine is a 4-aminoquinoline derivative that selectively concentrates in parasitized red blood cells. It is a weak base, and its alkalinizing effect on the acid vesicle of the parasite effectively destroys the viability of the parasite. 

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). 

Aminoquinolines (69) did not react with EMME in chloroform, but the reactions took place readily in refluxing xylene. At higher temperature, however, side-product (70) formation accompanied the condensation (58JCS828). 

GEP3628356 4-Aminoquinolines 50JOC1224 58JCS828, 70JMC230 86EUP174832... 

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... 

Both 2-aminoquinoline and 4-aminoquinoline pro-tonate first on the ring nitrogen, with 4-aminoquinoline being the more basic, the conjugate acid benefiting from increased charge distribution through... 

Sawada Y, Kayakiri H, Abe Y, et al. A new class of nonpeptide bradykinin B2 receptor ligands, incorporating a 4-aminoquinoline framework. Identification of a key pharmacophore to determine species difference and agonist/antagonist profile. 7 Med Chem 2004 47 2667-77. 

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

Retinal or visual field changes attributable to any 4-aminoquinoline compound hypersensitivity to 4-aminoquinoline compounds long-term therapy in children. 

Ophthalmic effects Irreversible retinal damage has been observed in some patients who had received long-term or high-dosage 4-aminoquinoline therapy for discoid and SLE or RA. When prolonged therapy is contemplated, perform initial (baseline) and periodic (every 3 months) ophthalmologic examinations (including visual acuity, expert slit-lamp, funduscopic, and visual field tests). 

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

Mefloquine is also a 4-aminoquinoline. It is a blood schizonticide active against the asexual stages of all malaria parasites. Mefloquine is currently the prophylactic agent of choice for short-term travellers. Resistance of P. falciparum against mefloquine has occurred in South-East Asia. Only an oral... 

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. 

Every patient with malaria should be examined for simultaneous infection with more than one species of Plasmodium. Infections with both P. falciparum and P. vivax are among the most commonly encountered mixed infections. In patients with falciparum malaria, attacks of P. vivax malaria may later develop it is important not to misinterpret this delayed P vivax form as a relapse of P. falciparum infection. If a mixed infection is identified, a combination of 4-aminoquinoline and primaquine should be administered, since the primaquine helps to eliminate any persisting tissue forms of P. vivax. 

In a Chichibabin-type reaction (see Section 2.4.2), quinoline reacts with potassamide (KNH2) in liquid ammonia at -70 °C to give 2-amino-1,2-dihydroquinoline and this is oxidized by potassium permanganate [manganate(VII)] at the same temperature to yield 2-aminoquinoline (Scheme 3.6). If the temperature is allowed to increase to -45 °C the adduct rearranges into 4-amino-1,4-dihydroquinoline, and upon oxidation this product gives 4-aminoquinoline. 

These compounds exist as the amino tautomers and normally the imino forms are not observed. All react with acids at the heterocyclic nitrogen atom, giving salts. The protonated forms of both 2- and 4-aminoquino-lines are resonance hybrids (Scheme 3.10), but 4-aminoquinoline is more basic than 2-aminoquinoline, possibly because the nitrogen atoms that carry the charge between them in the corresponding cation are more widely separated. 

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