Quinine

Most fascinating old chiral drug, from historical point of view, is Quinine. It is known that by early 1600s quinine was being used by South American natives, in Peru, Ecuador, as a crude preparation from the bark of the Cinchona tree for the treatment of malaria.

Cinchona tree

Chirality and biological activity

Quinine contains two major fused ring systems: aromatic quinoline and bicyclic quiniclidine. The molecule contains four stereogenic carbon centers at C-3, C-4, C-8 and C-9, respectively  and can exist in 16 stereoisomeric forms (24 = 16 stereoisomers). Among the 16 stereoisomers the natural product with the antimalarial activity is the levorotatory unichiral compound with the configuration (3R,4S,8S,9R). (In the structure below stereogenic carbons are numbered in red font and configuration assigned in brackets.)

Natural product with antimalarial activity

Stereoselective synthesis of quinine was successfully done in 2001, 181 years after compound was first isolated. The need for effective antimalarial drugs continued over nearly two centuries since quinine was first isolated. Structural modifications of quinine molecule have resulted in many useful antimalarial agents including chiral drugs quinacrine, primaquine and chloroquine.

Nomenclature

(8S,9R)-6′-Methoxycinchonan-9-ol

Therapeutic category

Anti-malarial

Exercise

Construct molecular model (ball and stick) of (-)-quinine molecule and learn to assign absolute configuration to the stereogenic centers.

References

Joseph Gal in Chirality in drug research. Edited by Eric Francotte, W. Lindner. Weinheim: Wiley-VCH. ISBN 978-3-527-60943-7. Page 3-25, 2006.

Wainer, l. W., & Drayer, D. E., Eds. Drug stereochemistry and Pharmacology: Marcel-Dekker, New York,1988.

Francotte, Eric; Lindner, Wolfgang . Chirality in drug research. Eric Francotte, W. Lindner. Weinheim: Wiley-VCH. ISBN 978-3-527-60943-7,  Page 3-25, 2006.

The handed world“, https://chiralpedia.com/blog/the-handed-world/.

Chiral twins – Identical? … But not really!”,  https://chiralpedia.com/blog/ chiral-twins-identical-but-not-really/.

Harkishan Singh and V.K. Kapoor. Medicinal chemistry and pharmaceutical chemistry, Vallabh Prakashan, New Delhi, Page 513-15, 2012.

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