8-aminoquinoline derivatives

The inhibition of both enzymes by primaquine and related compounds (8-aminoquinoline derivatives) possesses remarkable clinical implications to be discussed later (cf. Section 2.8.3). 

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... 

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. 

Steinhaus, R.K., Baskin, S.I., Clark, J.H., Kirby, S.D. (1990). Formation of methemoglobin and metmyoglobin using 8-aminoquinoline derivatives or sodium nitrite and subsequent reaction with cyanide. J. Appl. Toxicol. 10 345-51. 

The only reported syntheses of this ring system have utilized 8-aminoquinoline derivatives as intermediates. Two such intermediates have been used 8-amino-6-methoxyquinoline (46) and 8-amino-1,2,3,4-tetrahydroquinoline (51). The latter furnished derivatives described as... 

With Palladium Daugulis s group [95] have been pioneers in this field of catalysis, in 2005 they were the first to report the arylation of secondary C(sp )-H bonds with an 8-aminoquinoline-derived Af,Af-bidentate DMG. This led both the groups of Corey and Baran to apply this methodology in the synthesis of complex natural products [96a, b]. 

By increasing the loading of copper(I) iodide, difluorination could also be achieved for the pyridyl substrate. Notably, the 8-aminoquinoline-derived auxiliary can be cleaved by refluxing NaOH in ethanol for 24 h. 

Pamaquine was synthesized in 1952, this 8-aminoquinoline was the first drug capable of preventing the relapses in Plasmodium vivax malaria. Toxicological concerns led to restrictions in the use of Pamaquine. Primaquine another 8-aminoquinoline derivative has been used since 1950 s for the eradication of liver stages in course of Plasmodium vivax infections. 

Syntheses of some 8-aminoquinoline derivatives were reported by Armer et al. [20]. Novel analogues were screened for both in-vitro and in-vivo anticoccidial activity. Pentyl group at 8 position of quinoline ring showed better anticoccidial activity. Other analogues were less potent in-vitro or in-vivo or both. Also, an exploration of the terminal nitrogen substitution has revealed the tetrahydropyran group to be optimal. 

Reaction of 2-aminoquinoline derivatives with BrCH2C0C02Et gave imidazoquinoline-2-carboxylate 473 which upon hydrolysis with sodium hydroxide gave the corresponding acid which had been tested against the passive cutaneous anaphylaxis (78GEP2802493, 78BEP858605) (Scheme 79). 

One example, however, which involves closure of the central pyrimidine ring is the thermally induced intramolecular condensation of the pyrrolidone-substituted aminoquinoline derivative 246 (Equation 73) <1999JHC755>. 

The generation of a library of 2-aminoquinoline derivatives has been described by Wilson and colleagues (Scheme 6.240) [423]. The process involved microwave irradiation of the secondary amine and aldehyde components to form an enamine (1,2-dichloroethane, 180 °C, 3 min) and subsequent addition of the resulting crude enamine to a 2-azidobenzophenone derivative (0.8 equivalents) and further micro-wave heating for 7 min at the same temperature. 

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. 

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. 

Dabequine is a 4-aminoquinoline derivative, the adverse reaction pattern of which is unknown. The WHO Scientific Group s report concerning this drug dates from 1984 and there seems to be little or no later information on it in humans. 

Tafenoquine is an S-aminoquinoline derivative that is more active than primaquine (SEDA-13, 811). It is active against all human forms of malaria. In animals, tafenoquine is several times more potent than primaquine and is effective against both blood and liver stages of the malaria parasite. It has a half-life of 14 days, which makes it a good candidate for prophylaxis, with the... 

Quinolone ring closure to fused heterocycles is possible as shown in equation 33 for the formation of pyrazoloquinolones, which are potential pharmaceuticals A modification of this kind of ring closure is the replacement of the carboxyl group by a nitrile leading to aminoquinoline derivatives (equation 33). 

The quinoline scaffold and derivatives occur in a large number of natural products and drug-like compounds. A method for microwave-assisted synthesis of 2-aminoquinolines has been described by Wilson et al. [62]. The process involves rapid microwave irradiation of secondary amines and aldehydes to form enamines, then addition of 2-azidobenzophenones with subsequent irradiation to produce the 2-aminoquinoline derivatives (Scheme 10.27). Purification of the products was accomplished in a streamlined manner by using solid-phase extraction techniques to produce the desired compounds in high yields and purity. Direct comparison of the reaction under thermal and microwave conditions, using identical stoichiometry and sealed reaction vessels, showed the latter resulted in improved yield. 

Solomon VR, Haq W, Srivastava K, Puri SK, Katti SB (2007) Synthesis and antimalarial activity of side chain modified 4-aminoquinoline derivatives. J Med Chem 50 394-398... 

From Af-phenyl substituted ketenimines 15 and ynamines the linear 1 1 adducts 16 are formed, which undergo an intramolecular cyclization reaction to give 4-aminoquinoline derivatives 17. 

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