Antimalarial alkaloid quinine synthesis

Quinine is the principal alkaloid derived from the bark of the cinchona tree. It has been used for malaria suppression for over 300 years. By 1959 it was superseded by other drugs, especially chloroquine. After widespread resistance to chloroquine became manifest quinine again became an important antimalarial. Its main uses are for the oral treatment of chloroquine-resistant falciparum malaria and for parenteral treatment of severe attacks of falciparum malaria. Quinine is a blood schizonticide with some gametocytocidal activity. It has no exoerythrocytic activity. Its mechanism of action is not well understood. It can interact with DNA, inhibiting strand separation and ultimately protein synthesis. Resistance of quinine has been increasing in South-East Asia. 

P. falciparum strains are reported also to be resistant to quinine (S3). It is noteworthy that quinine can now be made by total synthesis and that analogs of quinine with improved activity or fewer side effects also can be made available (52). In this connection it is important to know that the antimalarial activity of Cinchona alkaloids is not dependent on their absolute configuration the racemates and the unnatural enantiomers were shown to be as active as the natural alkaloids (51). An excellent summary by R. M. Finder of the mode of action of quinine as an antimalarial drug appeared recently in Progress in Medicinal Chemistry where pertinent details can be found (52). 

Cinchona alkaloids comprising quinine, quinidine, cinchonidine, and cinchonine as the major members constitute a unique class of quinoline alkaloids with tremendous impact on human civilization. The odyssey of Cinchona alkaloids began with the discovery of their antimalarial properties followed by the very successful application in stereochemistry and in asymmetric synthesis. Currently, the portfolio of applications of Cinchona alkaloids is much broader, involving chiral stationary phases for enantioselective chromatography, novel biological activities, and several useful transformation converting them into other modular and chiral building blocks, such as, for example, quincorine or quincoridine. Current pressure on a more intense exploration of sustainable products and easy access to diverse molecular architectures make Cinchona alkaloids of primary importance for synthetic catalytic and medicinal chemistry. 

Bucher C, Sparr C, Schweizer WB, Gilmour R., Fluorinated quinine alkaloids synthesis. X-ray structure analysis and antimalarial parasite chemotherapy. Chem. Eur. J. 2009 15 7637-7647. 

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