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THE ANTI-MALARIAL ACTION OF CHANGSHAN (FEBRIFUGINE): A REVIEW

ANTHONY BlITLER AND JoHN MoFFETI

Abstract

The plant qinghao W;t; (Artemesia annua) has provided the world with a valuable anti-malarial drug (qinghaosu i!f~~). Another useful anti-malarial drug (febrifugine) of Chinese origin can be extracted from the shrub Dichroa febrifoga (changshan) but, unlike qinghaosu, its chemical structure is relatively simple and it could be easily synthesised in a pharmaceutical factory. However, the presence of two chiral centres in the molecule makes this unsuitable for pharmacological use as only one of the four isomers (the one found naturally) kills the malarial parasite, but all four isomers (as in the synthetic material) have serious adverse side effects. Encouraging African governments to consider growing Dichroa febrifoga as an alternative to the expensive and scarce qinghaosu should be considered.

The scourge of malaria has been with us since the dawn of civilisation and its effect today is probably greater than it has ever been. There are an estimated 300-500 million cases of malaria worldwide every year and, in Africa alone, one million children a year die of the condition. Until the seventeenth century there was no known drug for the treatment of the disease when Spanish Jesuit missionaries brought back from South America the bark of the cinchona tree. It was said by the local people to cure fevers and rapidly established itself in Europe as an effective treatment for malaria. In 1820 two French chemists, Pelletier and Caventou, extracted from the bark the active principle, that is, the substance in the bark that kills the malarial parasite. They named the active principle quinine and for many years the use of quinine kept malaria at bay and allowed Europeans to visit and, eventually, to colonise tropical parts of the world. However, supplies were limited and the deadly effect of malaria on the US forces fighting in the Pacific during World War Two led American scientists to develop an alternative, synthetic drug, chloroquine. Chloroquine and quinine are chemically related. For many years chloroquine was the drug of choice in the treatment of malaria


424 ANTHONY BUTLER AND JOHN MOFFETT

but, by the 1960s, it became increasingly clear that resistance was developing.

The search for new drugs, unrelated pharmacologically and chemically to chloroquine, led to the examination by Chinese scientists of numerous herbal remedies. Startling success has been achieved with a substance extracted from the Chinese plant qinghao ff ;I (sweet wormwood, Artemesia annua). Traditionally in China, qinghao has been used for the treatment of a number of disease conditions, of which intermittent fever (niie Ji ii~) is only one. In the 1970s the active principle in qinghao was extracted and identified by Chinese scientists as a polycyclic sesquiterpene with an endoperoxide bridge, a most unusual chemical structure for a natural product. It was named qinghaosu 'J!r;I~ or artemisinin. 1 It has proved very effective against the malarial parasite, particularly P. fakiparum, and is now the drug of choice for the treatment of malaria. Its discovery and development could radically change the situation in Africa but its very success has led to shortages and there is still interest in other traditional Chinese herbal remedies. One such herb is changshan ,m- LU (Di,chroa

.febrifoga). In contrast to qinghao, the only major use of changshan given in the traditional Chinese herbals (bencao *1\t) is as a treatment for intermittent fever. For example, in chapter 1 7 of his monumental Bencao gangmu *•* §, completed in 15 78, Li Shizhen *llif ft quotes a fifth-century source that gives this use alone, and an eleventh-century Song Dynasty commentator who notes that 'changshan is the most essential of plants for treating intermittent fever'. Processing the plant involved steeping in water and then reducing (often with wine), to make decoctions, pills and powders, sometimes combining it with other single drugs. Observing the serious side-effects, Li warns that changshan be used sparingly. He specifies combination and processing with other drugs as methods to alleviate the symptoms.

Modem research has shown that changshan is a cure for malaria, but, because of the serious nausea it causes, it has not been taken seriously by Western scientists. Lei and Bodecker have written an authoritative account of the development of changshan and the contrasting approaches to its promotion as a treatment for malaria in recent times. 2 They deal in detail with topics such as polypharmacy

1 Liu et al. 1979, pp. 129-43. 2 Lei and Bodeker 2004, pp. 61-81. See also Lei 1999, pp. 323-58. Here Lei


THE ANTI-MALARIAL ACTION OF CHANGSHAN 425

and the emetic effect. Although qinghaosu is still very successful, a new, second anti-malarial drug would be of enormous value should resistance to qinghaosu start to develop.

The active principle in changshan, responsible for its anti-malarial action, was isolated as long ago as 1946 and further work indicated that this 'principle' was one of a family of alkaloids (natural products containing nitrogen) produced by changshan.3 The principal antimalarial alkaloid was identified as a piperidine alkaloid containing a quinazoline structure and named febrifugine.4

~N~~)i U~) 8.m~ N HO

This is a relatively simple structure for a natural product and could be produced by a laboratory synthesis, rather than extracted from the plant. This might be seen as of enormous benefit as it is much easier to control the dose if the pure material is used, and it is also easier to produce large quantities. However, in spite of these advantages, there are structural features of this molecule that make a laboratory synthesis unlikely.

The carbon atom at positions 2' and 3' in the right hand piperidine ring are stereogenic centres. This means that the stereochemistry (the disposition of atoms in space about that carbon atom) can take either of two forms that bear the same relationship to each other as right and left-handed gloves. They are mirror images that, even after rotation, cannot be superimposed. This can be seen if we examine the piperidine ring of febrifugine and its mirror image. If the molecule on the right is rotated through 180° it is not possible to superimpose it upon the molecule on the left. This phenomenon

shows how at the time when investigation into changshan was in its early stages, western-style doctors in China guarded the boundary of their socio-technical network against Chinese drugs, creating a significant barrier of entry for anyone who wanted to assimilate Chinese drugs into this network.

3 Jang et al. 1946, p. 59. Jang et al. 1948, pp. 161-2. 4 Koepfli et al. 1950, pp. 3323-5.


426

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ANTHONY BUTLER AND JOHN MOFFETT

H

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mirror

H

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is known as chirality (from the Greek meaning 'handedness') and the two forms are described as isomers and, in this special case, as enantiomers. The two enantiomers are clearly the same compound but the atoms bonded to carbon atom 3' are disposed differently in space. One form is known as R and the other as S; there is an older convention that named them D and L but this nomenclature should no longer be used. It is quite acceptable to think of them as left and right-handed versions of the same molecule. The same phenomenon occurs with carbon atom 2' and that also may be either R or S. Thus, there are four isomers of februfugine: (2'R,3'R), (2'R,3'S), (2'S,3'R) and (2'S,3'S). The rest of the molecule is identical in all isomers. The significance of the isomeric forms of februfugine for medicine is that the plant produces only one of them and this is the only one that is effective against the malarial parasite. However, all four forms give rise to the same serious side effects, of which nausea is the most conspicuous.

In 1952 Baker et al. successfully completed a laboratory synthesis of f ebrifugine and, based on this work, a configuration of the atoms about carbon atoms 2' and 3' in the natural isomer was proposed.5

This designation was changed by Barringer et al. in the light of new evidence, 6 and corrected yet again in 1999 following a clever catalytic asymmetric synthesis (see later) by a group of Japanese workers. 7

The accepted designation is now (2'R,3'S). This account of the chirality of natural febrifugine may appear

rather arcane but it is of vital importance to its use in medicine. The amount of febrifugine in the leaves of D. febrifoga is low and

5 Baker et al. 1953, pp. 178-82. 6 Barringer et al. 1973, pp. 1937-40. 7 Kobayashi et al. 1999, pp. 6833-41.



extraction is difficult. Therefore it would be much more efficient to synthesise febrifugine in a pharmaceutical factory and use that product as the drug. However, older laboratory syntheses of febrifugine result in the production of all four isomers. It will be recalled that only one, (2'R,3'S)-febrifugine, is effective against the malarial parasite and so, if using the synthetic drug, four times the dose is required compared with natural febrifugine. But the adverse side effects are common to all isomers and so synthetic febrifugine is far less acceptable therapeutically than febrifugine extracted from a plant. The production of only one isomer by a plant may possibly be a reason why some herbal remedies have weaker side effects than synthetic drugs.

There has been considerable effort by medicinal chemists in recent years to devise laboratory syntheses that produce only one isomer of the drug. These are known as asymmetric syntheses. These synthetic procedures are rated so important that the 2001 Nobel Prize in chemistry was awarded to three workers in this area (William Knowles, Ryoji Noyori and Barry Sharpless). So far, what plants do effortlessly has proved difficult to achieve in a laboratory. However some success has been reported in asymmetric syntheses of (2'R,3'S)febrifugine. The asymmetric synthesis that fixed the stereochemistry around carbon atoms 2' and 3' employed a tin(Il)-catalysed asymmetric aldol condensation.8 The toxicity of tin compounds would render this process unacceptable for the manufacture of a therapeutic drug. Equally an asymmetric synthesis involving the use of samarium iodide would, on a commercial scale, be prohibitively expensive, particularly for a drug destined for developing countries.9

Other asymmetric syntheses have features that are unsuitable for scaling up from laboratory to manufacturing plant. 10 We conclude that, for the time being, any febrifugine used medically would be obtained from herbal sources.

Although Di,chroa febrifaga is the main source of· f ebrifugine it can also be obtained from a number of species of Hydrangea (including H. umbellate, H. stringosa and H. chinesis).'' None of these is mentioned

8 Kobayashi et al. 1999, pp. 2175-8. 9 Kotah et al. 2004, pp. 6221-3.

10 Huang et al. 2003, pp. 1663-7; Takeuchi et al. 2001, pp. 1213-8; Taniguchi and Ogasawara 2000, pp. 3193-5.

11 Khalil et al. 2003, pp. 15-20.



in early Chinese bencao and so their use is not part of traditional Chinese herbal medicine. However they are mentioned in modem herbals and so might be seen as within TCM. 12

In view of the success of qinghaosu derivatives for the treatment of malaria the use of f ebrifugine, particularly in view of its emetic nature, might be considered unlikely. However the emergence of tolerance to qinghaosu is an ever-present worry and another anti-malarial drug in the wings would be of enormous value in containing the disease. Also, modem drug treatment often involves the use of a cocktail of drugs; this is the case for both TB and AIDS. It may be that febrifugine will have a role as one component in a cocktail of drugs for the control of malaria, where the amount of febrifugine is sufficiently low to reduce the side effects to an acceptable level. The practice in traditional Chinese herbal medicine of using mixtures of herbs, as in a modem drug cocktail, may have a sound scientific basis. 13

It is interesting to compare the mode of action of qinghaosu with that of febrifugine. With the former, the endoperoxide bridge of the drug reacts with iron in blood cells with generation of a highly destructive carbon-centred radical. This then reacts with the DNA of Plasmodium, killing the parasite, 14 or it may inhibit a key enzyme in Plasmodium. 15 In contrast, febrifugine appears to stimulate the body's immune system. Of the array of substances produced by the immune system as a defence against pathogenic invaders, the one most in evidence during an attack of malaria is nitric oxide. 16 Febrifugine was found to stimulate NO production from peritoneal macrophages activated by lipopolysaccharide. 17 Also, mice infected with P. berghei and treated with febrifugine displayed enhanced levels of plasma nitrate, a marker for enhanced production of nitric oxide by the immune system. 18

What of the future of febrifugine as an anti-malarial agent? Its emetic action is probably a serious barrier to its use. However, there are several ways in which this might be overcome.

12 A distinction between traditional practices and TCM is made by Taylor 2004. 13 It has been reported that a mixture of febrifugine and chloroquine is more

effective than either alone in killing P/,asmodium berghei (not a species that causes malaria in humans) in mice. Ishih et al. 2003, pp. 1234-6.

14 Wu et al. 1996, pp. 2213-4. 15 Eckstein-Ludwig et al. 2003, pp. 957-61. 16 Rockett et al. 1991, p. 3280. 17 Murata et al. 1998, pp. 729-33. 18 Murata et al. 1999, pp. 1593-160 I.



It might be possible to modify febrifugine chemically to produce a version that has identical, or even enhanced, anti-malarial action but is no longer an emetic. Some steps in this direction have already been taken. The adduct of febrifugine with acetone shows potent activity against both P. berghei and P. fakiparum. 19 An extensive range of febrifugine derivatives were examined by Kikuchi et al., and many were found to be potent anti-malarial agents.20 However, the evaluation of the chemically modified versions of f ebrifugine would take many years and would be costly. A second approach is to ascertain what it is in the herb that reduces the emetic effect and mix febrifugine with these substances to make a drug. Again, because of regulatory procedures, this would be a long and costly matter.

In view of the malaria crisis in Africa, which needs immediate attention, it might be easier to encourage Africans to experiment with growing Di,chroafebri.faga and to use it as a herbal remedy. There is not going to be a laboratory synthesis of febrifugine and so to have it as an anti-malarial drug the herb will have to be grown. As the herb appears to provide valuable secondary substances that make febrifugine palatable, it seems sensible not to extract it but to use the herb intact. For many years this served the Chinese well as a cure for malaria; modern doctors might learn something from that.

Dichroa febrifuga is not native to Africa but grows widely throughout China, Cambodia, Northern India, Nepal and Sikkim. As a cultivated plant it is grown in North America where the blue flowers and berries look attractive in a shrubbery. The native plant is found in mixed forests on mountain slopes or in valleys between 200 and 2000m. It is subtropical and, therefore, West Africa would probably be unsuitable for cultivation but, as the plant is not too fussy about soil, other parts of Africa might be possible. Because of the widespread incidence of malaria in Africa the demand for qinghaosu is now so great that China has been able to turn the growth of Artemesia annua into a very profitable enterprise, but there is still a shortage. It clearly would have been beneficial for Africa if, ten years ago, the possibility of growing it there commercially had been fully investigated. If febrifugine were ever to become important as an anti-malarial drug, now is the time to consider growing Di,chroa febri.faga in Africa. There may be political difficulties, but the science is clear.

19 Takaya et al. 1999, pp. 3136-66. 20 Kikuchi et al. 2002, pp. 2563-70.



References

Baker, B.R., FJ. McEvoy, R.E. Schaub, J.P. Joseph and J.H. Williams 1953, 'An anti-malarial alkaloid from Hydrangea. XXI. Synthesis and structure of febrifugine and isofebrifugine', Journal of Organic Chemistry, 17: 178-182.

Barringer, D.F., G. Berkelhammer and R.S. Wayne 1973, 'The stereochemistry of febrifugine. II. Evidence for the trans configuration in the piperidine ring', Journal of Organic Chemistry, 38: 193 7-1940.

Eckstein-Ludwig, U., RJ. Webb, I. D.A. van Goethem, J.M. East, A.G. Lee, M. Kimura, P.M. O'Neill, P.G. Bray, S.A. Ward and S. Krishna 2003, 'Artemisinins target the SER CA of P/,asmodium fakiparum', Nature, 424: 95 7-961.

Huang, P.Q, B.G. Wei and Y.P. Ruan 2003, 'Asymmetric synthesis of anti-malarial alkaloids (+)-febrifugine and (+)-isofebrifugine', Synlett, 11: 1663-1667.

lshih, A., T. Suzuki, M. Watanabe, T. Miyase and M. Terada 2003, 'Combination effects of chloroquine with the februfugine and isofebrifugine mixture against a blood induced infection with chloroquine-resistant P/,asmodium berghei NK65 in ICR mice', Phytotherapy Research, 17: 1234-1236.

Jang, C.S., F.Y. Fu, C.Y. Wang, K.C. Huang, G. Lu and T.C. Chou 1946, 'Ch'ang shan, a Chinese anti-malarial herb', Science, 103: 59.

Jang, C.S., F.Y. Wu, K.C. Huang and C.Y. Wang 1948, 'Pharmacology of Ch'ang Shan (Dichroa febrifoga), a Chinese anti-malarial herb', Nature, 161: 161-162

Khalil, A.T., F.R. Chang, Y.H. Lee, C.Y. Chen, C.C. Liaw, P. Ramesh, S.S.F. Yuan and Y.C. Wu 2003, 'Chemical constituents of the Hydrangea chinensis', Archives of Pharmaceutical Research, 126: 15-20.

Kikuchi, H., H. Tasaka, S. Hirai, Y. Takaya, Y. lwabuchi, H. Ooi, S. Hatakeyama, H.-Y. Kim, Y. Wataya and Y. Oshima 2002, 'Potential anti-malarial febrifugine analogues against the Plasmodium malaria parasite', Journal of Medicinal Chemistry, 45: 2563-2570.

Kobayashi, S., M. Ueno, R. Suzuki, H. Ishitani, H.-Y. Kim and Y. Wataya 1999, 'Catalytic asymmetric synthesis of the anti-malarial alkaloids febrifugine and isofebrifugine and their biological activity', Journal of Organic Chemistry, 64: 6833-6841.

Kobayashi, S., M. Ueno, R. Suzuki and H. Ishitani 1999, 'Catalytic asymmetric synthesis of februfugine and isofebrifugine', Tetrahedron Letters, 40: 2175-2178.

Koepfli, J.B., J.A. Brockman and J. Moffatt 1950, 'The structure of febrifugine and isofebrifugine', Journal of the American Chemical Sociery, 72: 3323-3325.

Kotah, M., R. Matsune, H. Nagase and T. Honda 2004, 'Stereocontrolled synthesis of a potent anti-malarial ( + )-febrifugine', Tetrahedron Letters, 45: 6221-6223.

Lei, S.H. and G. Bodeker 2004, 'Changshan (Dichroa febri.faga)~Ancient febrifuge and modern anti-malarial: Lessons for research from a forgotten tale', Traditional Medical P/,ants and Ma/,aria, Boca Raton: CRC Press, 61-81.

Lei, Sean Hsiang-Lin 1999, 'From Changshan to a New Anti-Malarial Drug: ReNetworking Chinese Drugs and Excluding Chinese Doctors', Social Studies of Science, 29: 323-358.

Liu, M., M.-Y. Ni,J.-F. Fan, Y.-Y. Tu, Z.-H. Wu,J.-L. Wu and W.-S. Chou 1979, 'Structure and reaction of arteannuin', Acta Chimica Sinica, 37: 129--143.

Murata, K., F. Takano, S. Fushiya and Y. Oshima 1998, 'Enhancement of NO production in activated macrophages in vivo by an anti-malarial drug, Dichroa febrifuga', Journal of Natural Products, 61: 729--733.

Murata, K., F. Takano, S. Fushiya and Y. Oshima 1999, 'Potentiation by febrifugine of host defense in mice against P/,asmodium berghei NK65', Biochemical Pharmacowgy, 58: 1593-1601.

Rockett, K.A., M.M. Awburn, W.B. Cowden and I.A. Clark 1991, 'Killing of P/,asmodium Jakiparum in vitro by nitric oxide derivatives', lrifection and lmmuniry, 3280.

Takeuchi, Y., K. Azuma, K. Takakura, H. Abe, H.S. Kim, Y. Wataya and



T. Harayama 2001, 'Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction', Tetrahedron, 5 7: 1213-1218.

Takaya, Y., H. Tasaka, T. Chiba, K. Uwai, M. Tanitsu, H.S. Kim, Y. Wataya, M. Miura, M. Takeshita and Y. Oshima 1999, 'New type of febrifugine analogues, bearing a quinolizidine moiety, show potent anti-malarial activity against Plasmodium malaria parasite', Journal of Medicinal Chemistry, 42: 3136-3166.

Taniguchi, T. and K. Ogasawara 2000, 'A diastereocontrolled synthesis of (+)febrifugine: A potent anti-malarial piperidine alkaloid', Organic Letters, 2: 3193-3195.

Taylor, Kim 2004, Chinese Medicine in Ear!J Communist China, 1945-63, Abingdon: RoutledgeCurzon.

Wu, W.-M., Z.:J. Yao, Y.-L. Wu, K. Jiang, Y.-F. Wang, H.-B. Chen, F. Shan and Y. Li 1996, 'Ferrous ion induced cleavage of the peroxy bond in qinghaosu and its derivatives and the DNA damage associated with this process', Chemical Communications: 2213-2214.


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