8 minutes reading time (1653 words)

    Quinine - One of the Great Molecules

    C Ramsden
    Keele University

    Quinine belongs to the molecular elite. If chemical compounds won medals and prizes, quinine would be one of the most decorated molecules in the history of science. For over 300 years it has played a major role in chemistry and medicine and has not been associated with adverse properties such as addiction or toxicity. Because of its rich history and variety of uses in the service of mankind, it probably outranks other distinguished natural product molecules such as morphine and the outstanding synthetic product aspirin (see Box 1). 

    Cinchona bark and mosquito bitesIf you live in Europe or North America you probably never worry about catching malaria, but until the last century the threat of malaria was serious. During the Middle Ages work in whole areas of Europe including England and Scotland came to a standstill during some months because of malarial fever (or 'the ague', as it was known). Oliver Cromwell died of malaria in 1658. Remarkably it was not until 1897 that the link between malaria and mosquitoes was recognised. As a result of controlling mosquitoes, largely by improved drainage, a higher standard of housing and, when necessary, the use of insecticides, malaria is no longer a problem in the UK. Sadly, this is not true in other parts of the world such as Africa and Southeast Asia. It is estimated by the World Health Organisation that up to 500 million people suffer from malaria and that each year two million of these victims die. Half of these deaths occur among children. Forty years ago malaria was in retreat. Widespread use of the synthetic insecticide DDT had effectively reduced the mosquito population. But DDT had harmful effects on the environment and its use was rightly, but unfortunately, stopped before the war against malaria had been won. Now malaria is fighting back in a virulent new form. 'New malaria' has changed the rules and is spreading in the form of a mutant parasite that is resistant to a number of the widely prescribed drugs that are so effective against 'old malaria'. What a dirty trick this is. Chemists must rise to the challenge of finding new weapons to suppress an old enemy. (see Box 2).

     Quinine was the first drug used to treat and prevent old malaria and is still the only really effective drug for cerebral malaria. The history of its discovery and development makes an epic story. (if you are interested in history as well as chemistry read "The Fever Bark Tree", by M.L. Duran-Reynals). Like many natural product drugs, quinine first appeared as a herbal remedy, in this case used by Peruvian Indians for treatment of fever. They had recognised that infusions of the bark of the cinchona tree were effective in treating the symptoms of malaria. The use of this bark attracted the attention of Jesuit missionaries who brought it back to Europe in the early seventeenth century. In spite of the great need for remedies for malaria, the prospects for 'Jesuit's powder' were poor. For example, it had a bitter taste that made it unpalatable. If you think your modern medicine on a nice plastic spoon is bad you should try a tankard of Peruvian bark! Also the trees that produced the most effective bark were rare and difficult to recognise unless you had an experienced Indian guide. It is probable that many batches of the bark were quite useless. No wonder it got a bad name. Expert identification at the point of collection is a vital component of herbal medicine.

    The successful development of cinchona bark as an antimalarial remedy is probably due to the work of one man, Sir Robert Talbor (1642-1681). He worked as an apothecary in East Anglia, where malaria was a particular problem, and experimented with different formulations of the bark. His careful experimentation was rewarded by consistent success in controlling 'the ague' and his work soon came to the attention of King Charles II. Effective treatment of members of European royal families who were malaria victims led to respectability for Talbor's medicine and in due course the bark became the focus of much attention. Cinchona trees were cultivated and chemists became interested in isolating the active ingredient, which was the alkaloid, quinine. The isolation of quinine from cinchona bark is attributed to Pelletier and Caventou in Paris in 1820. Soon it was being produced commercially in both London and Paris and its reputation as an effective antimalarial drug was established.

    The active ingredient
    By 1937 the great German chemist Justus von Liebig had developed methods of combustion analysis that gave reliably accurate measurements of the relative amounts of carbon, hydrogen, nitrogen and oxygen in chemical compounds. Using this approach, which is still used by modern chemists, he was able to show that each molecule of quinine contains the following numbers of atoms of each element: C20H24N2O2. You can confirm this molecular formula by counting the atoms in the structure of quinine in Box 1.

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     The next task was to find out how these atoms (C20H24N2O2) are connected to each other, and this was much more difficult. Before the structure of quinine could be solved many other developments had to take place in chemistry and it was not until 1906 that the structural formula of quinine was finally determined. Like most alkaloids, quinine was found to be a heterocyclic molecule (see Box 3). It contains rings of atoms that include nitrogen as well as carbon.

     Once the structural formula of a natural product is known then attempts to make it in the laboratory can begin. This is called total synthesis. For a moderately large molecule such as quinine, synthesis is a challenging problem. The total synthesis of quinine was achieved by the American chemists Woodward and Doering in 1944. Woodward later received the Nobel Prize in recognition of his outstanding contributions to the total synthesis of natural products. The quinine that Woodward and Doering produced in their laboratory at Harvard University was identical in all respects to that isolated from cinchona bark. The way that the natural quinine is made (Biosynthesis) is, of course, quite different from the laboratory route to synthetic quinine.

     Synthetic quinine is a rare commodity. The routes used to prepare it are too long and uneconomic for commercial production. The quinine that is produced and used by industry is all natural huge plantations of the cinchona tree have been established. At the outbreak of the Second World War, Java (Indonesia) produced over 90% of the world's supply. This resulted in something of a crisis when the Japanese cut off these supplies during the War.

    The Sea Captain's Tale

    New drugs are usually discovered by collaborating chemists and biologists, but occasionally doctors make a useful contribution. In 1914 Karl Wenckebach, a distinguished cardiologist, examined a sea captain who was seeking treatment for a trial fibrillation (irregular and unsynchronised beating of the heart). Wenckebach confessed that there was little that he could do and was surprised to be told by his patient that his attacks were relieved by quinine. He had observed this effect while using the alkaloid as an antimalarial in the tropics and convincingly demonstrated its effectiveness by returning the next day with a normal heart beat. Wenckebach tried quinine on other patients with mixed results. It was soon found that quinidine, which is a stereoisomer of quinine (Box 4) and isolated from the same source, is a much more effective antiarrhythmic drug.

    By the early 1920's the use of quinidine for heart disorders had been widely accepted and it is still in use today.

    Quinidine is a minor component of cinchona bark. Most of the quinidine that is used in medicine is actually made by chemical conversion of natural quinine to its stereoisomer, so it is a semi-synthetic drug.

    Because quinine is readily available and cheap, synthetic chemists are finding it to be a valuable reagent. Since quinine occurs as a single stereoisomer it can be used to influence laboratory reactions that normally give racemic mixtures, so that they produce only a single stereoisomer. This is particularly important in the synthesis of drug molecules where only one of the possible stereoisomers has the desired biological activity.

    Would you like ice with that?
    Have you ever tasted quinine? You probably have. In addition to its role in medicine, quinine is valuable in other ways. One of its major uses is addition to Indian tonic water and bitter lemon, to give them a desirable bitter taste. Have a look at the label. Better still, have a taste, it's a great improvement on Talbor's Peruvian bark!

    About the author
    Chris Ramsden was born in the north of England and educated at Buxton College and Sheffield University. After completing a PhD in heterocyclic chemistry at Sheffield with David Ollis, he held a Robert R. Welch Post-doctoral fellowship for two years at the University of Texas at Austin where he worked with Michael J.S. Dewar on the development and application of semiempirical molecular orbital calculations. He then returned to the UK and heterocyclic chemistry as an ICI Post-doctoral Fellow at the University of East Anglia in Norwich where he worked with Alan Katritzky. During the 1980s he worked as a chemist in the pharmaceutical industry and was appointed Head of Medicinal Chemistry at Rhone-Poulenc's Dagenham research centre in London in 1987. In 199€2 he was appointed Professor of Organic Chemistry at Keele University. His research interests at Keele are focused on heterocyclic chemistry and the chemistry of molecules containing three-centre, four-electron bonds, particularly hypervalent compounds of Te, I and Xe, 1,3-dipoles and heteroylides. This work is directed towards the discovery of new reactions and their application to biological problems. Recent studies have included an investigation of the mechanism of tyrosinase oxidation which led to new quinone and quinomethane chemistry and the use of xenon difluoride as a fluorinating agent via two quite different mechanisms.
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    Sunday, 22 July 2018

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