Atebrine, Mepacrine

Dissatisfaction with the performance of pamaquine as a synthetic substitute for quinine led to further synthetic work in the acridine series, and ultimately to the discovery of the antimalarial properties of quinacrine (Atebrin, Mepacrine, 12). Other acridines to find clinical use are acriquine (13), aminoacrichin (14), and azacrin (15), the latter being designed to combine the features of a 4-aminoquinoline and an 8-aminoquinoline. Quinacrine was much less active than pamaquine in early tests against avian malaria, but it was four times as potent against P. berghei in mice [79], It was widely used to treat Allied troops during World War II, but has now been wholly superseded by other compounds such as chloroquine. Nevertheless, it is... 

Interest in the new drugs was considerable at ICI, in keeping with its new-found interest in diversified research. In 1936, ICI had created a Medicinals Chemicals Division as a subsection of its dyestuffs research department. The division drew on expertise in coal tar dye chemistry, as did sulphonamide studies, since the reactions used to produce dye intermediates were almost the same as those used to prepare many pharmaceutical products. This enabled ICI to make substantial contributions during World War II, again drawing on earlier German discoveries, notably the antimalarials Atebrin (Mepacrine), and Plasmoquin," ... 

Quinacrine [Atebrine, Mepacrine, 3-chloro-9(4-diethylamino-l-methyl)butylamino-7-methoxy)-acridine] dihydrochloride. [69-05-6] M 472.9, m 248-250°(dec), pKi -6.49 (aq H2SO4), pK 7.73 (ring... 

Initially approved in the 1930s as antimalarial drug, quinacrine (2) became one of the first potential substitutes to quinine. The total synthesis of quinacrine would be achieved in 1931 by German scientists at Bayer,and it would be subsequently marketed as Mepacrine or Atebrine. However, quinacrine would soon be replaced by another synthetic and more efficient antimalarial drug, chloroquine (3). 

It is now recognized that DNA is also the target for the many other kinds of drugs that act by intercalation. These include the anti-cancer drugs dauno-rubicin, doxorubicin (adriamycin), actinomycin D, anthramycin, amsacrine, and ellipticine the anti-malarials mepacrine (quinacrine, atebrin) and chloro-quine and the anti-trypanosomal drugs ethidium and quinapyramine (more about these drugs in Section 10.3.5). 

Acridines become strongly anti-malarial if substituted with a basic side-chain in the 9-position, but are inactive if quaternized. Mepacrine 10.30) (quin-acrine, Atebrin ) was the first anti-malarial acridine, and the first synthetic anti-malarial to achieve widespread use. For further information, on connections between structure and action in the acridine anti-malarials, see Albert (1966). 

N -((5- Chloro-2-methoxy-9-acridinyl)-lA, N -diethyl- 1,4-pentane diamine, 9CI. 6-Chloro-N-(4-diethylamino-1-methylbutyl)-2-methoxy-9-acridinamine. Mepacrine, INN. Acrichine. Atabrine. Atebrin. Numerous proprietary... 

Schulemann et aLy 1932), and mepacrine (6.9) ( Atebrin ) (Kikuth, 1932 Mauss and Mietzsch, I933)- They were inspired by the weak antimalarial action that Guttmann and Ehrlich (1891) had found in methylene blue (6.70), but systematic work had to await discovery of a test object, and Roehl found this in malaria-infected finches. 

FIG. 10.8 Mepacrine ( Atebrin quinacrine) showing distance between nitrogens of side-chain (from centre to centre of the atoms). 

---