Artemisinin: An Endoperoxidic Antimalarial from Artemisia annua L.

  • H. Ziffer
  • R. J. Highet
  • D. L. Klayman
Part of the Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products book series (FORTCHEMIE (closed), volume 72)


For thousands of years, physicians in China have treated fever with a decoction of the plant qinghao (1). In 1972 Chinese chemists isolated the active febrifuge from this plant, determining its structure, 1, by single crystal x-ray crystallography (2, 3). The discovery was timely, for the world sorely needs a better treatment for malaria. More than 270 million people suffer from the disease, two to three million dying each year. The majority of the deaths are of children under 5 years of age, who are especially sensitive because of their lack of immunity to the disease.


Antimalarial Activity Total Synthesis Peroxide Group Rose Bengal Artemisinin Derivative 


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  1. 1.
    Klayman, D.L.: Qinghaosu (Artemisinin): An Antimalarial Drug from China. Science, 228, 1049 (1985).Google Scholar
  2. 2.
    Coordinating Group FOR Research ON THE Structure OF Qing Hau Sau: K’O Hsueh T’ung Pao, 22, 142 (1977); Chem. Abstr., 87, 98788g (1977).Google Scholar
  3. 3.
    Liu, J.-M., M.Y. Ni, J.-F. Fan, Y.-Y. Tu, Z.H. Wu, Y.-L Wu, and W.-S. Chou: Structure and Reactions of Arteannuin. Acta Chim. Sinica, 37, 129 (1979).Google Scholar
  4. 4.
    Luo, X.-D., and C.C. Shen: The Chemistry, Pharmacology, and Clinical Applications of Qinghaosu (Artemisinin) and its Derivatives. Med. Res. Rev., 7, 29 (1987).Google Scholar
  5. 5.
    Zhang, M., Y. Tu, M. Ni, Y. Zhong, L. Li, S. Cui, X. Wang, and Z. Ji: Studies on the Constituents of Artemisia annua. Planta Medica, 143 (1982).Google Scholar
  6. 6.
    Xmen, L.: A New Drug for Malaria. China Reconstructs, 191, 48 (1979).Google Scholar
  7. 7.
    Qinghaosu Antimalaria Coordinating Research Group: Crystal Structure and Absolute Configuration of Qinghaosu. Scientia Sinica, 23, 380 (1980); Chem. Abstr., 93, 71991e (1980).Google Scholar
  8. 8.
    Jeremic, D., A. Jokic, A. Behbud, and M. Stefanovic: A New Type of Sesquiterpene-Lactone Isolated from Artemisia annuaL. Ozonide of Dihydroarteannuin. 8th Internat. Symp. Chem. Nat. Prod., New Delhi, 2, 222, Abstr. C-57 (1972).Google Scholar
  9. 9.
    Woerdenbag, HJ., C.B. Lugt, and N. Pras: Artemisia annuaL. : A Source of Novel Antimalarial Drugs. Pharm. Weekbl. [Sci.], 12, 169 (1990).Google Scholar
  10. 10.
    Zaman, S.S., and R.P. Sharma: Some Aspects of the Chemistry and Biological Activity of Artemisinin and Related Antimalarials. Heterocycles, 32, 1593 (1991).Google Scholar
  11. 11.
    Butler, A.R.: Artemisinin (Qinghaosu): A New Type of Antimalarial Drug. Chem. Soc. Rev., 21, 85 (1992).Google Scholar
  12. 12.
    Jung, M.: Current Developments in the Chemistry of Artemisinin and Related Compounds. Current Med. Chem., 1, 35 (1994).Google Scholar
  13. 13.
    Meshnick, S.R., T.E. Taylor, and S. Kamchonwongpaisan: Artemisinin and the Antimalarial Endoperoxides: from Herbal Remedy to Targeted Chemotherapy. Microbiological Rev., 301 (1996).Google Scholar
  14. 14.
    Fernald, M.L.: Gray’s Manual of Botany. New York: American Book Company. 1950, p. 1522.Google Scholar
  15. 75.
    Chen, T.H., H. Lin, K.C. Kao, and C.K. Fan: Cultivation of Hwa Hwo Gao (Artemisia annua). Zhongcaoyao Tonyxien, 11, 227 (1980).Google Scholar
  16. 16.
    Shukla, A., A.H.A. Farooqi, Y.N. Shukla, and S. Sharma: Effect of Tricontanol and Chlormequat on Growth, Plant Hormones and Artemisinin Yield in A. annua. Plant Growth Regul., 11, 165 (1992); Chem. Abstr., 116, 250407j (1992).Google Scholar
  17. 17.
    Singh, A., V.K. Kaul, V.P. Maha, A. Sinyh, L.N. Misra, R.S. Thakur, and A. Husain: Introduction of Artemisia annuain India and Isolation of Artemisinin. A Promising Antimalarial Drug. Indian J. Pharm. Sci., 137 (1986).Google Scholar
  18. 18.
    Cubukcu, B., A.H. Mericli, N. Ozhatay, and B. Damadyan: Artemisinin from Turkish Artemisia annua. Acta Pharm. Turc, 31, 41 (1989); Chem. Abstr., 111, 12390a (1989).Google Scholar
  19. 19.
    Laughlin, J.C.: Agricultural Production of Artemisinin: A Review. Trans. Royal Soc. Trop. Med. and Hyg., 88, S. 21 (1994).Google Scholar
  20. 20.
    Chen, H.R., M. Chen, F. Zhong, and F. Chen: Some Factors Affecting the Content of Artemisinin. Chinese Medicinal Reports, 7, 393 (1986).Google Scholar
  21. 21.
    Chan, K.L., C.K.H. Teo, S. Jinadasa, and K.H. Yuen: Selection of High Artemisinin Yielding Artemisia annua. Lhonyyao Planta Medica, 285 (1995).Google Scholar
  22. 22.
    Acton, N., D.L. Klayman, and I. Rollman: Reductive Electrochemical HPLC Assay for Artemisinin (Qinghaosu). Planta Medica, 445 (1985).Google Scholar
  23. 23.
    Charles, DJ., J.E. Simon, K.V. Wood, and P. Heinstein: Mixtures of Antimalarial Agents and Artemisinin Derivatives for the Treatment of Malaria. Europ. Pat. Appl. EP290,959; Chem. Abstr., 111, 50417x (1989).Google Scholar
  24. 24.
    Liersch, R., H. Soicke, C. Stehr, and H.U. Tullner: Formation of Artemisinin in Artemisia annuaduring One Vegetation Period. Planta Medica, 387 (1986).Google Scholar
  25. 25.
    Ferreira, J.F.S., J.E. Simon, and J. Janick: Developmental Studies of Artemisia annua:Flowering and Artemisinin Production Under Greenhouse and Field Conditions. Planta Medica, 67 (1995).Google Scholar
  26. 26.
    Nair, M.S.R., N. Acton, D.L. Klayman, K. Kendrick, and D.V. Basile: Production of Artemisinin in Tissue Cultures of Artemisia annua. J. Nat. Prod., 49, 504 (1986).Google Scholar
  27. 27.
    Singh, A., R.A. Vishwakarma, and A. Husain: Evaluation of Artemisia annuaStrains for Higher Artemisinin Production. Planta Medica, 475 (1988).Google Scholar
  28. 28.
    Kudakasseril, G.J., L. Lam, and E.J. Staba: Effect of Sterol Inhibitors on the Incorporation of 14C-Isopentenyl Pyrophosphate into Artemisinin by a Cell-Free System from A. annuaTissue Cultures and Plants. Planta Medica, 280 (1987).Google Scholar
  29. 29.
    Fulzele, D.P., A.T. Sipahimalani, and M.R. Sipahimalani: Tissue Cultures of Artemisia annua:Organogenesis and Artemisinin Production. Phytotherapy Res., 5, 149 (1991).Google Scholar
  30. 30.
    Weathers, P.J., R.D. Cheetham, E. Follansbee, and K. Teoh: Artemisinin Production by Transformed Roots of Artemisia annua. Biotech. Lett., 16, 1281 (1994).Google Scholar
  31. 31.
    Klayman, D.L., A.J. Lin, N. Acton, J.P. Scovill, J.M. Hoch, W.K. Milhous, A.D. Theoharides, and A.S. Dobek: Isolation of Artemisinin (Qinghaosu) from Artemisia annuaGrowing in the United States. J. Nat. Prod., 47, 715 (1984).Google Scholar
  32. 32.
    Acton, N., D.L. Klayman, I.J. Rollman, and J.F. Novotny: Isolation of Artemisinin (Qinghaosu) and its Separation from Artemisitene Using the ITO Multilayer Coil Separator-Extractor; Isolation of Arteannuin B.J. Chromo., 355, 448 (1986).Google Scholar
  33. 33.
    Elsohly, H.N., E.M. Croom, F.S. Elferaly, and M.M. Elsherei: A Large Scale Extraction Technique of Artemisinin from Artemisia annua. J. Nat. Prod., 53, 1560 (1990).Google Scholar
  34. 34.
    Acton, N., and D.L. Klayman: Artemisitene, A New Sesquiterpene Lactone Peroxide from Artemisia annua. Planta Medica, 441 (1985).Google Scholar
  35. 55.
    Milhous, W.: Personal communication. IC50 = 5.56 ng/ml vs. D-6 and 7.57 ng/ml vs W-2. The IC50 value for artemisinin is 2.5 ng/ml for these strains of P. falciparum.Google Scholar
  36. 36.
    Wei, Z.X., J.U.P. Pan, and Y. Li: Artemisinin G: A Sesquiterpene from Artemisia annua. Planta Medica, 300 (1992).Google Scholar
  37. 37.
    Blasko, G., G.A. Cordell, and D.C. Lankin: Definitive 1H and 13 C-NMR Assignments of Artemisinin (Qinghaosu). J. Nat. Prod., 51, 1273 (1988).Google Scholar
  38. 38.
    Schulte, K.H., and G. Ohloff: Über eine außergewöhnliche Stereospezifität bei der Hydroborierung der diastereomeren (lR)-Isopulegole mit Diboran. Helv. Chim. Acta, 50, 153 (1967).Google Scholar
  39. 39.
    Büchi, G., and H. Wüest: Ozonolysis of Vinylsilanes. J. Am. Chem. Soc, 99, 294 (1977).Google Scholar
  40. 40.
    Hmid, G., and W. Hofheinz: Total Synthesis of Qinhaosu. J. Am. Chem. Soc, 105, 624 (1983).Google Scholar
  41. 41.
    Xu, X.X., J. Zhu, D.Z. Huang, and W.S. Zhou: Total Synthesis of Arteannuin and Deoxyarteannuin. Tetrahedron, 42, 819 (1986).Google Scholar
  42. 42.
    Zhou, W.S.: Total Synthesis of Arteannuin (Quinghaosu) and Related Compounds. Pure Appl. Chem., 58, 817 (1986).Google Scholar
  43. 43.
    Avery, M.A., W.K.M. Chong, and C. JENNINGS-White: Stereoselective Total Synthesis of (+)-Artemisinin, the Antimalarial Constituent of Artemisia annuaL. J. Am. Chem. Soc, 114, 974 (1992).Google Scholar
  44. 44.
    Ravindranathan, T., M.A. Kumar, R.B. Menon, and S.V. Hiremath: Stereoselective Synthesis of Artemisinin. Tetrahedron Lett., 31, 755 (1990).Google Scholar
  45. 45.
    Xu, X.X., J. Zhu, D.Z. Huang, and W.S. Zhou: The Stereocontrolled Syntheses of Arteannuin and Deoxyarteannuin from Arteannuic Acid. Acta Chim. Sinica, 41, 574. (1983).Google Scholar
  46. 46.
    Roth, R.J., and N. Acton: A Simple Conversion of Artemisinic Acid into Artemisinin. J. Nat. Prod., 52, 1183 (1989). USP 4,992,561 (Feb. 12, 1991).Google Scholar
  47. 47.
    Roth, R.J., and N. Acton: A Facile Semisynthesis of the Antimalarial Drug Qinghaosu. J. Chem. Ed., 68, 613 (1991).Google Scholar
  48. 48.
    Haynes, R.K., and S.C. Vonwiller: Iron (III)-Induced Cleavage of Cyclic Allylic Hydroperoxides to Dicarbonyl Compounds under Aprotic Conditions. J. C. S., Chem. Commun., 449 (1990).Google Scholar
  49. 49.
    Haynes, R.K., and S.C. Vonwiller: Catalyzed Oxygenation of Allylic Hydroperoxides Derived from Qinghaosu (Artemisinic) Acid. Conversion of Qinghao Acid into Dehydroqinghaosu (Artemisitene) and Qinghaosu (Artemisinin). J.C.S., Chem. Commun., 451 (1990).Google Scholar
  50. 50.
    Ye, B., and Y.L. Wu: An Efficient Synthesis of Qinghaosu and Deoxoqinghaosu from Arteannuic Acid. J. C. S., Chem. Commun., 726 (1990).Google Scholar
  51. 57.
    Lansbury, P.T., and D.M. Nowak: An Efficient Partial Synthesis of (+)-Artemisinin and (+)Deoxoartemisin. Tetrahedron Lett., 1029 (1992).Google Scholar
  52. 52.
    Zhongshan, W, T.T. Nakashima, K.R. Kopecky, and J. Molina: Qinghaosu: 1H and 13C Nuclear Magnetic Resonance Assignments and Luminescence. Can. J. Chem., 63, 3070 (1985).Google Scholar
  53. 53.
    El-Feraly, F.S., M.M. El-Sherei, C.D. Hufford, E.M. Croom, and TJ. Mahier: 13C NMR Assignments of Artemisinin, Desoxyartemisinin and Artemether. Spectr. Lett., 18, 843 (1985).Google Scholar
  54. 54.
    Huang, J.J., K.M. Nicholls, C.H. Cheng, and Y. Wang: Two-Dimensional NMR Studies of Arteanunin; Huaxue Xuebao, 45, 305 (1987); Chem. Abstr., 107, 176248d (1987).Google Scholar
  55. 55.
    Lou, X., H.J.C. Yeh, A. Brossi, J.L. Flippen-Anderson, and R. Gilardi: Configurations of Antimalarials Derived from Qinghaosu: Dihydroqinghaosu, Artemether, and Artesunic Acid. Helv. Chim. Acta, 67, 1515 (1984).Google Scholar
  56. 56.
    Baker, J.K., H.N. Elsohly, and CD. Hufford: Nuclear Overhauser Effect Spectroscopy (NOESY) and 3JHH Coupling Measurements in the Determination of the Conformation of the Sesquiterpene Antimalarial Arteether in Solution. Spectrosc. Lett., 23, 111 (1990).Google Scholar
  57. 57.
    Lee, I.S., H.A. Elsohly, E.M. Croom, and CD. Hufford: Microbial Metabolism Studies of the Antimalarial Sesquiterpene Artemisinin. J. Nat. Prod., 52, 337 (1989)Google Scholar
  58. 58.
    Liu, J.J., and G.L. Duan: An Ab Initio Study on the Correlation between the Absolute Configuration and the CD Spectra of Organic Peroxides. Chin. Chem. Lett., 2, 245 (1991).Google Scholar
  59. 59.
    Liang, X.T.: Circular Dichroism of the Peroxidic Linkage. Acta Chim. Sinica, 40, 288 (1982).Google Scholar
  60. 60.
    Ziffer, H.: Unpublished observation.Google Scholar
  61. 61.
    Fang, Y., Z. Shu, and D. He: Confirmation of the Vibrational Frequency of the Peroxide Group in Arteannuin and Related Compounds. Huaxue Xuebao, 42, 1312 (1984); Chem. Abstr., 102, 166962q (1985).Google Scholar
  62. 62.
    Mohnhaupt, M., H. Hagemann, J.P Perler, H. Bill, J. Boukouvalas, J.C. Rossier, and C.W. Jefford: A Vibrational Study of Some 1,2,4-Trioxanes. Helv. Chim. Acta. 71, 992 (1988).Google Scholar
  63. 63.
    Schwartz, H., and H.M. Schiebel: Chemistry of the Peroxides (S. Patai, ed.), p. 105. New York: Wiley, 1983.Google Scholar
  64. 64.
    Fales, H.M., E.A. Sokoloski, L.K. Pannel, P. QUAN-Long, D. Klayman, AJ. Lin, A. Brossi, and J.A. Kelley: Comparison of Mass Spectral Techniques Using Organic Peroxides Related to Artemisinin. An. Chem., 62, 2494 (1990).Google Scholar
  65. 65.
    Madhusudanan, K.P., R.A. Vishwakarma, S. Balachandran, and S.P. Popli: Mass Spectral Studies on Artemisinin, Dihydroartemisinin and Artether. Indian J. Chem., 28B, 751 (1989).Google Scholar
  66. 66.
    Baker, J.K., R.H. Yarber, CD. Hufford, I.S. Lee, H.N. Elsohly, and J.D. Mcchesney: Thermospray Mass Spectroscopy/High Performance Liquid Chromatographie Identification of the Metabolites Formed from Arteether Using a Rat Liver Microsome Preparation. Biomed. Environ. Mass Spectr., 18, 337 (1988).Google Scholar
  67. 67.
    Theoharides, A.D., M.H. Smyth, R.W. Ashmore, J.M. Halverson, Z.M. Zhou, W.E. Ridder, and AJ. Lin: Determination of Dihydroqinghaosu in Blood by Pyrolysis Gas Chromatography/Mass Spectrometer. An. Chem., 60, 115 (1988).Google Scholar
  68. 68.
    Brossi, A., B. Venugopalan, L.D. Gerpe, H.J.C. Yeh, J.L. FLIPPEN-Anderson, P. Buchs, X.D. Luo, W. Nilhous, and W. Peters: Arteether, a New Antimalarial Drug: Synthesis and Antimalarial Properties. J. Med. Chem., 31, 645 (1988).Google Scholar
  69. 69.
    Lin, A.J., D.L. Klayman, J.M. Hoch, J.V. Silverton, and CF. George: J. Org. Chem., 50,4504 (1985). The structure for “4” in this paper shows an erroneous methyl group at the acetal carbon.Google Scholar
  70. 70.
    Niu, X.Y., L.Y. Ho, Z.Y Ren, and Z.Y. Song: Metabolic Fate of Qinghaosu in Rats; a New TLC Densitometric Method for its Determination in Biological Matter. Eur. J. Drug Metab. Pharmacokin., 10, 55 (1985).Google Scholar
  71. 71.
    Wang, Y, and Y. Zhang: Rapid Thin-Layer Densitometric Determination of Artemisinin in Injections. Yaowu Fenxci Zazhi, 3, 353 (1983); Chem. Abstr., 100, 74036W (1984).Google Scholar
  72. 72.
    Shu, H., G. Xu, W. Li, and Y. Zeng: Colorimetric Determination of Methyldihydroartemisinin with Vanillin. Fenxi Huaxue, 10, 678 (1982); Chem. Abstr., 99, 43606p (1983).Google Scholar
  73. 73.
    Zhu, H.S.: Titrimetric Analysis of Artemisinin in Artemisia annua. Yao Hsueh Tlung Pao, 15, 6 (1980); Chem. Abstr., 95, 86359v (1981).Google Scholar
  74. 74.
    Melendez, V., J.O. Peggins, T.G. Brewer, and A.D. Theoharides: Determination of the Antimalarial Arteether and its Deethylated Metabolite Dihydroartemisinin in Plasma by High-Performance Liquid Chromatography with Reductive Electrochemical Detection. J. Pharm. Sci., 80, 132 (1991).Google Scholar
  75. 75.
    Zhou, Z.M., J.C. Anders, H. Chung, and A.D. Theoharides: Analysis of Artesunic Acid and Dihydroqinghaosu in Blood by High-Performance Liquid Chromatography with Reductive Electrochemical Detection. J. Chromat., 414, 77(1987).Google Scholar
  76. 76.
    Zhou, Z.M., Y.X. Huang, G.H. Xie, X.M. Sun, Y.L. Wang, L.C. Fu, H.X. Jian, X.B. Guo, and G.Q. Li: HPLC with Polarographic Detection of Artemisinin and its Derivatives and Application of the Method to the Pharmokinetic Study of Artemether. J. Liq. Chrom., 11, 1117 (1988).Google Scholar
  77. 77.
    Zhang, X.Q., and L.X. Xu: Determination of Qinhaosu (Arteannuin) in Artemisia annua L. by Pulse Polarography. Yaoxue Xuebao, 20,283 (1985); Chem. Abstr., 103, 120036h (1985).Google Scholar
  78. 78.
    Idowu, O.R., S.A. Ward, and G. Edwards: Determination of Artelinic Acid in Blood Plasma by HPLC. J. Chrom. Biomed. Applicat., 495, 167 (1989).Google Scholar
  79. 79.
    Edlund, P.O., DJ. Westerlund, B. Wu, and Y. Jin: Determination of Artesunate and Dihydroartemisinin in Plasma by Liquid Chromatography with Post-Column Derivatization and U.V. Detection. Acta Pharm. Suec, 21, 223 (1984).Google Scholar
  80. 80.
    Luo, X.-D., M. Xie, and A.-Q. Zou: Subnanogram Detection of Dihydroartemisinin after Chemical Derivatization with Diacetyldihydrofluorescein followed by HPLC and UV Absorption. Chromatographia, 23, 112 (1987).Google Scholar
  81. 81.
    Luo, X.-D., H.J.C. Yeh, and A. Brossi: Detection of Metabolites of Qinghaosu and its Epoxy Analog. The Chemistry of Drugs. V. Heterocycles, 22, 2559 (1984).Google Scholar
  82. 82.
    El-Domiaty, M.M., I.A. Al-Meshal, and F.S. El-Feraly: Reversed-Phase High-Performance Chromatographic Determination of Artemisitene in Artemisinin. J. Liq. Chromatog., 14, 2317 (1991).Google Scholar
  83. 83.
    Yeng, M.Y.: A Modified Iodometric Method in Determination of Organic Bridged Peroxides; Iodometric Determination of Qing Hao Su. Yaowu Fenxi Zazhi, 4, 329 (1984).Google Scholar
  84. 84.
    Zhou, Z.M., YX. Huang, G.H. Xie, X.M. Sun, Y.L. Wang, L.C. Fu, H.X. Jian, X.B. Guo, and G.Q. Li: Isolation and Identification of Biotransformation Metabolites of Qin Hau Su. I Isolation and Identification of Biotransformation Metabolites in Humans. Yao Hsueh Hsueh Pao, 15, 509 (1980); Chem. Abstr., 109, 47745f (1980).Google Scholar
  85. 85.
    Sipahimalani, A.T., D.P. Fulzele, and M.R. Heble: Rapid Method for the Detection and Determination of Artemisinin by Gas Chromatography. J. Chromatog., 538, 432 (1991).Google Scholar
  86. 86.
    Wu, Z., L. Dai and G. Guo: Quantitative Analysis of the Active Constituents of Zinjiang Qinghao (Artemisia annua)by Capillary-Column Gas Chromatography. Zhongcaoyao, 17, 341 (1986); Chem. Abstr. 105, 232507k (1986).Google Scholar
  87. 87.
    Avery, M.A., J.D. Bonk, and J. Bupp: Radiolabelled Antimalarials: Synthesis of 14C-Artemisinin. J. Labelled Compounds and Radiopharmaceuticals, 38, 263 (1996).Google Scholar
  88. 88.
    Gu, H.M., D.C. Warhurst, and W. Peters: Uptake of [3H]Dihydroartemsinin by Erythrocytes Infected with Plasmodium falciparum in vitro. Trans. Royal Soc. Tropical Medicine and Hygiene, 78, 265 (1984). A modified version of this preparation was employed by Meshnick, Ziffer, et al. (unpublished data).Google Scholar
  89. 89.
    Pu, Y.-M., and H. Ziffer: Synthesis of 11-[3H]-Arteether, An Experimental Anti-malarial Drug. J. Labelled Compounds and Radiopharmaceuticals, 33, 1013 (1993).Google Scholar
  90. 90.
    Ding, S.F., and L.X. Li: Zhongyao Tongbao, 6, 25 (1981).Google Scholar
  91. 91.
    Song, Q.L., X.Y. Lin, K.D. Zange, and H.Z. Zhany: Action of Sodium Artesunate on Tritiated Uridine Incorporation and Cell Membrane of Mouse Spleen Cells. Acta Pharm. Sinica, 8, 72 (1987).Google Scholar
  92. 92.
    Song, Z.Y, K.C. Zhao, X.T. Liang, C.X. Liu and M.G. Yi: Radioimmunoassay of Qinghaosu and Artesunate. Acta Pharm. Sinica, 20, 610 (1985).Google Scholar
  93. 93.
    Luo, X.D., H.J.C. Yeh, and A. Brossi: The Chemistry of Drugs. VI Thermal Decomposition of Qinghaosu. Heterocycles, 23, 881 (1985).Google Scholar
  94. 94.
    Lin, A.J., A.T. Theoharides, and D.L. Klayman: Thermal Decomposition Products of Dihydroartemisinin (Dihydroqinghaosu). Tetrahedron, 42, 2181 (1986).Google Scholar
  95. 95.
    Zeng, M.Y., L.N. Li, S.F. Chen, G.Y. Li, X.T. Liang, M. Chen, and J. Clardy: Chemical Transformations of Qinghaosu, a Peroxidic Antimalarial. Tetrahedron, 39, 2941 (1983).Google Scholar
  96. 96.
    Zhou, W.S., L. Zhang, Z.C. Fan, and X.X. Xu: Studies on Structure and Synthesis of Arteannuin and Related Compounds XX. The Structure of a New Peroxidic Arteannuin Degradation Product and the Lactone Configuration of a Related Compound. Tetrahedron, 42, 4437 (1986).Google Scholar
  97. 97.
    Shang, X., C.H. He, Q.T. Zheng, J.J. Yand, and X.T. Lian: Chemical Transformations of Qinghaosu, a Peroxidic Antimalarial, II. Heterocycles, 28, 421 (1989).Google Scholar
  98. 98.
    Hummelen, J.C., T.M. Luider, D. Oudman, J.N. Koek, and H.W. Wynberg: 1,2-Dioxetanes: Luminescent and Nonluminescent Decomposition, Chemistry and Potential Application. Pract. Spectrosc, 567 (1991).Google Scholar
  99. 99.
    Acton, N., and D.L. Klayman: Conversion of Artemisinin (Qinghaosu) to Iso-Artemisitene and to 9-Epi-Artemisinin. Planta Medica, 266 (1987).Google Scholar
  100. 100.
    Torok, D.S., and H. Ziffer: Synthesis and Reactions of 11-Azaartemisinin and its Derivatives. Tetrahedron Lett., 36, 829 (1995).Google Scholar
  101. 101.
    Li, Y, P. Yu, Y Chen, J. Zhang, and Y Wu: Studies on Analogs of Qinghasou. Some Acidic Degradations of Qinghasou. Kexue Tongbao, 31, 1038 (1986). The paucity of experimental detail in this paper leaves uncertain the identity of the products with those of the following paper.Google Scholar
  102. 102.
    Imakura, Y, K. Hachiya, T. Ikemoto, and S. Yamashita: Acid Degradation Products of Qinhaosu and their structure-Activity Relationships. Heterocycles, 31, 1011 (1990).Google Scholar
  103. 103.
    Baker, J.K., and H.T. Chi: Novel Rearrangements of the Trioxane Ring System of the Antimalarial Arteether Upon Treatment with Acid in an Aqueous Methanol Solvent System. Heterocycles, 38, 1497 (1994).Google Scholar
  104. 104.
    Acton, N., and R.J. Roth: Acid Decomposition of the Antimalarial Beta-Arteether. Heterocycles, 41, 95 (1995).Google Scholar
  105. 105.
    El-Feraly, F., S.A. Ayalp, and M.A. Al-Yahya: Conversion of Artemisinin to Artemisitene. J. Nat. Prod., 53, 66 (1990).Google Scholar
  106. 106.
    Pu, Y.M., and H. Ziffer: Diastereofacial Addition to a /β-Substituted Glycal, Anhydroartemisinin. Heterocycles, 39, 649 (1994).Google Scholar
  107. 107.
    El-Feraly, F., M.A. Al-Yahya, K.Y Orabi, D.R. Mcphail, and A.T. Mcphail: A New Method for the Preparation of Arteether and its C-9 Epimer. J. Nat. Prod., 55, 878 (1992).Google Scholar
  108. 108.
    Pu, Y.M., H.J.C. Yeh, and H. Ziffer: An Unusual Acid-Catalyzed Rearrangement of 1,2,4-Trioxanes. Heterocycles, 36, 2099 (1993).Google Scholar
  109. 109.
    El-Feraly, F.S., A. Ayalp, and M.A. Al-Yahya: Decomposition of Dihydroartemisitene on Silica Gel. J. Nat. Prod., 53, 920 (1990).Google Scholar
  110. 110.
    Yagen, B., Y.-M. Pu, H.J.C. Yeh, and H. Ziffer, Tandem Silica Gel-Catalysed Rearrangements and Subsequent Baeyer-Villiger Reactions of Artemisinin Derivatives. J.C.S. Perkin Trans. I, 843 (1994).Google Scholar
  111. 111.
    Wu, Y.L., and J.L. Zhang: Reduction of Qinghasou (Artemisinin) with Lithium Aluminium Hydride. Youji Huaxue, 153 (1986); Chem. Abstr., 105, 191426n (1986).Google Scholar
  112. 112.
    Liu, J.M., M.Y Ni, J.F. Fan, Y.Y. Tu, Z.H. Wu, YL. Wu, and W.S. Chou: Structure and Reactions of Arteannuin. Acta Chim. Sinica, 37, 129 (1979); Chem. Abstr., 92, 94594 (1979).Google Scholar
  113. 113.
    Pettit, G.R., and D.M. Piatak,: Steroids and Redated Natural Products. XL Reduction of Esters to Ethers. J. Org. Chem., 27, 2127 (1962).Google Scholar
  114. 114.
    Jung, M., X. Li, D.A. Bustos, H.N. Elsohly, and J.D. Mcchesney: A Short and Stereospecific Synthesis of (+)-Deoxoartemisinin and (−)-Deoxodesoxyartemisin. Tetrahedron Lett., 30, 5973 (1989).Google Scholar
  115. 115.
    Venugopalan, B., S.L. Shinde, and P.J. Karnik: Role of Radical Initiated Cyclisation Reactions in the Synthesis of Artemisinin Based Novel Ring Skeletons. Tetrahedron Lett., 34, 6305 (1993).Google Scholar
  116. 116.
    Lin, A.J., L.-Q. Li, D.L. Klayman, C.F. George, and J.L. Flippen-Anderson: Antimalarial Activity of New Water-Soluble Dihydroartemisinin Derivatives. 3. Aromatic Amine Analogues. J. Med. Chem., 33, 2610 (1990).Google Scholar
  117. 117.
    Posner, G.H., D.J. Mcgarvey, C.H. Oh, S.R. Meshnick, and W. Asawamahasadka: Structure-activity Relationships of Lactone Ring-Opened Analogs of the Antimalarial 1,2,4-trioxane Artemisinin. J. Med. Chem., 38, 607 (1995).Google Scholar
  118. 118.
    Pu, Y.-M., D.S. Torok, and H. Ziffer, X.-Q. Pan, and S.R. Meshnick: Synthesis and Antimalarial Activities of Several Fluorinated Artemisinin Derivatives. J. Med.Chem., 38, 4120 (1995).Google Scholar
  119. 119.
    Lin, A.J., L.Q. Li, W.K. Milhous, and D.L. Klayman: Antimalarial Activity of Dihydroartemisinin Derivatives. 4. Stereoselectivity of 9-Hydroxy Series. Med. Chem. Res., 1, 20 (1991).Google Scholar
  120. 120.
    Petrov, O., and I. Ognyanov: An Approach to the Synthesis of Novel 11-Hydro-xyartemisinin Derivatives. Collect. Czech. Chem. Commun., 56, 1037 (1991).Google Scholar
  121. 121.
    Hufford, C.D., S.I. Khalifa, A.T. Mcphail, F.S. El-Feraly, and M.S. Ahmad: Preparation and Characterization of New C-11 Oxygenated Artemisinin Derivatives. J. Nat. Prod., 56, 62 (1993).Google Scholar
  122. 122.
    Pu, Y.-M., B. Yagen, and H. Ziffer: Stereoselective Oxidations of a β-Methylglycal, Anhydrodihydroartemisinin. Tetrahedron Lett., 35, 2129 (1994).Google Scholar
  123. 123.
    China Cooperative Research Group: The Chemistry and Synthesis of Qinghaosu Derivatives. J. Traditional Chin. Med., 2, 9 (1982).Google Scholar
  124. 124.
    Li, Y., L. Yu, Y.X. Chen, L.Q. Li, Y.Z. Gai, D.S. Wang, and Y.P. Zheng: Studies on Analogs of Artemisinine I. Synthesis of Ethers, Carboxylate Esters, and Carbonates of Dihydroartemisinin. Yaoxue Xuebao, 16, 429 (1981); Chem. Abstr., 97, 92245n (1982).Google Scholar
  125. 125.
    Li, Y, P. Yu, Y Chen, L. Li, YG. Al, D. Wang, and Y. Zheng: Synthesis of Some Artemisinine Derivatives. K’o Hsueh T’ung Pao, 24, 667 (1979); Chem. Abstr., 91, 211376u(1979).Google Scholar
  126. 126.
    Chinese Cooperative Research Group: Studies on the Toxicity of Qinghaosu and its Derivatives. J. Trad. Chin. Med., 2, 31 (1982).Google Scholar
  127. 127.
    Gu, Y.-X., Y-F. Cui, B.-A. Wu, X.-C. Shi, and X. Teng: Effects of Artemether on Peripheral T, B, T-mu, and T-gama Lymphocytes in Beagle Dog. J. Trad. Chin. Med., 9, 215 (1989).Google Scholar
  128. 128.
    Naing, U.T., U.H. Win, D.Y.Y Nwe, U.P.T. Myint, and U.T. Shwe: The Combined Use of Artemether, Sulfadoxine, and Pyrimethamine in the Treatment of Uncomplicated falciparum Malaria. Trans. Roy. Soc. Trop. Med. Hyg., 82, 530 (1988).Google Scholar
  129. 129.
    Chen, Y.-X., P.-L. Yu, Y Li, and R.-Y Ji: Studies on Anlogs of Qinghaosu. VII. The Synthesis of Ethers of Bis(dihydroqinghaosu) and Bis(dihydrodeoxyqinghaosu). Acta Pharm. Sinica, 20, 470 (1985).Google Scholar
  130. 130.
    Li, Y, P.-L. Yu, Y.-X. Chen, and R.-Y Ji: Studies on Analogs of Arteannuin. II Synthesis of Some Carboxylic Esters and Carbonates of Dihydroarteannuin by using 4-(N,N-dimethylamino)pyridine as an Active Acylation Catalyst. Huaxue Xuebao, 40, 557 (1982); Chem. Abstr., 98, 4420h (1983).Google Scholar
  131. 131.
    China Cooperative Research Group: J. Trad. Chinese Med., 2, 9 (1982).Google Scholar
  132. 132.
    Li, X.-Y., and H.-Z. Liang: Effects of Artemether on Red Blood Cell Immunity in Malaria. Acta Pharmacol. Sinica, 7, 471 (1986).Google Scholar
  133. 133.
    Yang, Q., W. Whi, R. Li, and J. Gan: The Antimalarial and Toxic Effects of Artesunate on Animal Models. J. Trad. Chinese Med., 2, 99 (1982).Google Scholar
  134. 134.
    Lin, A.J., D.L. Klayman, and W.K. Milhous: Antimalarial Activity of New Water-Soluble Dihydroartemisinin Derivatives. J. Med. Chem., 30, 2147 (1987).Google Scholar
  135. 135.
    Lin, A.J., D.L. Klayman, and W.K. Milhous: Novel Antimalarial Dihydroartemisinin Derivatives. USP 4, 791, 135.Google Scholar
  136. 136.
    Lin, A.J., M. Lee, and D.L. Klayman: Antimalarial Activity of New Water-Soluble Dihydroartemisinin Derivatives. 2. Stereospecificity of the Ether Side Chain. J. Med. Chem., 32, 1249 (1989).Google Scholar
  137. 137.
    Lin, A.J., and R.E. Miller: Antimalarial Activity of New Dihydroartemisininin Derivatives. 6. α-Alkylbenzylic Ethers. J. Med. Chem., 38, 764 (1995).Google Scholar
  138. 138.
    Lin, A.J., L.-Q. Li, S.L. Andersen, and D.L. Klayman: Antimalarial Activity of New Dihydroartemisninn Derivatives. 5. Sugar Analogs. J. Med. Chem., 35, 1639 (1992).Google Scholar
  139. 139.
    Bustos, D.A., M. Jung, H.N. Elsohly, and J.D. Mcchesney: Stereospeciflc Synthesis of (+)-Homodeoxoartemisinin. Heterocycles, 29, 2273 (1989).Google Scholar
  140. 140.
    Jung, M., D.A. Bustos, H.N. Elsohly, and J.D. Mcchesney: A Concise and Stereo-selective Synthesis of (+)-12-n-Butyldeoxoartemisinin. Syn. Lett., 743 (1990).Google Scholar
  141. 141.
    Jung, M., D. Yu, D.A. Bustos, H.N. Elsohly, and J.D. Mcchesney: A Concise Synthesis of 12-(3′-Hydroxy-n-propyl)-deoxoartemisinin. Bioorgan. Med. Chem. Lett., 1, 741 (1991).Google Scholar
  142. 142.
    Haynes, R.K., and S.C. Vonwiller: Efficient Preparation of Novel Qinghaosu (Artemisinin) Derivatives: Conversion of Qinghao Acid (Artemisinic) into Deo xoqinghaosu Derivatives and 5-Carboxy-4-deoxoartesunic Acid. Syn. Lett., 481 (1992).Google Scholar
  143. 143.
    Lewis, M.D., J.K. Cha, and Y. Kishi: Highly Stereoselective Approaches to α-and β-C-Glycopyranosides. J. Am. Chem. Soc, 104, 4976 (1982).Google Scholar
  144. 144.
    Pu, Y.M., and H. Ziffer: Synthesis and Antimalarial Activities of 12β=Allyl-deoxoartemisinin. J. Med. Chem., 38, 613 (1995).Google Scholar
  145. 145.
    Avery, M.A., S. Mehrotra, T.L. Johnson, J.D. Bonk, J.A. Vroman, and R. Miller: Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 5. Analogs of 10-Deoxoartemisinin Substituted at C-3 and C-9. J. Med. Chem., 39, 4149 (1996).Google Scholar
  146. 146.
    Jung, M., H.N. Elsohly, and J.D. Mcchesney: A Concise Synthesis of Novel C-13 Functionalized Deoxoartemisinins. Syn. Lett., 43 (1993).Google Scholar
  147. 147.
    Avery, M.A., C. Jennings-White, and W.K.M. Chong: The Total Synthesis of (+)-Artemisinin and (+)-9-Desmethylartemisinin. Tetrahedron Lett., 28, 4629 (1987).Google Scholar
  148. 148.
    Avery, M.A., C. Jennings-White, and W.K.M. Chong: Simplified Analogues of the Antimalarial Artemisinin: Synthesis of 6,9-Desmethylartemsinin. J. Org. Chem., 54, 1792 (1989).Google Scholar
  149. 149.
    Still, W.C.: A Simple Synthesis of Bicyclo[4.n.1]enones by Cyclodialkylation. Synthesis, 453 (1976).Google Scholar
  150. 150.
    Haynes, R.K., G.R. King, and S.C. Vonwiller: Preparation of a Bicyclic Analogue of Qinghao (Artemisinic) Acid Via a Lewis Acid Catalyzed Ionic Diels-Alder Reaction Involving a Hydroxy Diene and Cyclic Enone and Facile Conversion into 6,9-Desmethylqinghaosu. J. Org. Chem., 59, 4743 (1994).Google Scholar
  151. 151.
    Avery, M.A., W.K.M. Chong, and G. Detre: Synthesis of (+)-8a,9-Seco-artemisinin and Related Analogs. Tetrahedron Lett., 31, 1799 (1990).Google Scholar
  152. 152.
    Avery, M.A., W.K.M. Chong, and J.E. Bupp: Tricyclic Analogues of Artemisinin: Synthesis and Antimalarial Activity of (+)-4,5-Secoartemisinin and (−)-5-Nor-4,5-secoartemisinin. J. C. S., Chem. Commun., 1487 (1990).Google Scholar
  153. 153.
    Avery, M.A., C. Jennings-White, and W.K.M. Chong: Synthesis of a C,D-Ring Fragment of Artemisinin. J. Org. Chem., 54, 1789 (1989).Google Scholar
  154. 154.
    IMAKURA, Y, T. Yokoi, T. Yamagish, J. Koyama, H. Hu, D.R. Mcphail, A.T. Mcphail, and K.H. Lee: Synthesis of Desethanoqinghaosu, a Novel Analogue of the Anti-malarial Qinghaosu. J. C. S. Chem. Commun., 372 (1988).Google Scholar
  155. 155.
    Avery, M.A., F. Gao, W.K.M. Chong, S. Mehrotra, and W.K. Milhous: Structure-Activity Relationships of the Antimalaria Agent Artemisinin. 1. Synthesis and Comparative Molecular Field Analysis of C-9 Analogs of Artemisinin and 10-Deoxoartemisinin. J. Med. Chem., 36, 4264 (1993).Google Scholar
  156. 156.
    Avery, M.A., S. Mehrotra, J.D. Bonk, J.A. Vroman, D.K. Goins, and R. Miller: Structure-Activity relationships of the Antimalarial Agent Artemisinin. 4. Effect of Substitution at C-3. J. Med. Chem., 39, 2900 (1996).Google Scholar
  157. 157.
    Ye, B., and Y.L. Wu: Syntheses of Carba-Analogues of Qinghaosu. Tetrahedron, 45, 7287 (1989).Google Scholar
  158. 158.
    Avery, M.A., P. Fan, J.M. Karle, R. Miller, and D.K. Goins: Replacement of the Nonperoxidic trioxane Oxygen Atom of Artemisinin by Carbon: Total Synthesis of (+)-13-Carbaartemisinin and Related Structures. Tetrahedron Lett., 36, 3965 (1995).Google Scholar
  159. 159.
    Avery, M.A., P. Fan, J.M. Karle, J.D. Bonk, R. Miller, and D.K. Goins: Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 3. Total Synthesis of (+)-13-Carbaartemisinin and Related Tetra-and Tricyclic Structures. J. Med. Chem., 39, 1885 (1996).Google Scholar
  160. 160.
    Wu, J., R.-Y Ji, and Z. Y Kyi: A Quantitative Structure-Activity Study on Artemi-sinine Analogs. Acta Pharm. Sinica, 3, 55 (1982).Google Scholar
  161. 161.
    Avery, M.A., J.D. Bonk, W.K.M. Chong, S. Mehrotra, R. Miller, W.K. Milhous, D.K. Goins, S. Venkatesan, C. Wyandt, I. Khan, and B.A. Avery: Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 2. Effect of Heteroatom Substitution at O-11: Synthesis and Bioassay of N-Alkyl-11-aza-9-desmethylarte-misinins. J. Med. Chem., 38, 5038 (1995).Google Scholar
  162. 162.
    Avery, M.A., F. Gao, S. Mehrotra, W.K.M. Chong, and C. Jennings-White: The Organic and Medicinal Chemistry of Artemisinin and Analogs. Trends in Organic Chemistry; Trivandrum. India, 4, 413 (1993).Google Scholar
  163. 163.
    Posner, G.H., C.H. Oh, and W.K. Milhous: Olefin Oxidative Cleavage and Dioxetane Formation Using Triethylsilyl Hydrotrioxide: Application to Preparation of Potent Antimalarial 1,2,4-Trioxanes. Tetrahedron Lett., 32, 4235 (1991).Google Scholar
  164. 164.
    Posner, G.H., C.H. Oh, and W.K. Milhous: Extraordinarily Potent Antimalarial Compounds: New Structurally Simple, Easily Synthesized, Tricyclic 1,2,4-trioxanes. J. Med. Chem., 35, 2459 (1992).Google Scholar
  165. 165.
    Clark, A.M., and C.D. Hufford: Use of Microorganisms for the Study of Drug Metabolism: An Update. Med. Res. Rev., 11, 473 (1991).Google Scholar
  166. 166.
    Lee, I.S., H.N. Elsohly, and CD. Hufford: Microbial Metabolism Studies of the Antimalarial Drug Arteether. Pharm. Res., 7, 199 (1990).Google Scholar
  167. 167.
    Hufford, CD., I.-S. Lee, H.N. Elsohly, H.T. Chi, and J.K. Baker: Structure Elucidation and Thermospray High-Performance Liquid Chromatography/Mass Spectroscopy (HPLC/MS) of the Microbial and Mammalian Metabolites of the Antimalarial Arteether. Pharm. Res., 7, 923 (1990).Google Scholar
  168. 168.
    Khalifa, S.I., J.K. Baker, R.D. Rogers, F.S. El-Feraly, and C.D. Hufford: Microbial and Mammalian Metabolism Studies of the Semisynthetic Antimalarial, Anhydro-dihydroartemisinin. Pharm. Res., 11, 990 (1994).Google Scholar
  169. 169.
    Elmarakby, S.A., F.S. El-Feraly, H.N. Elsohly, E.M. Croom, and C.D. Hufford: Microbiological Transformations of Artemisinic Acid. Phytochem., 27, 3089 (1988).Google Scholar
  170. 770.
    Hu, Y., R.J. Highet, D. Marion, and H. Ziffer: Microbial Hydroxylation of a Dihydroartemisinin Derivative. J. C S. Chem. Commun., 1176 (1991).Google Scholar
  171. 171.
    Hu, Y, H. Ziffer, G. Li, and HJ.C Yeh: Microbial Oxidation of the Antimalarial Drug Arteether. Bioorganic Chem., 20 148 (1992).Google Scholar
  172. 172.
    Desjardins, R.E., C.J. Canfield, D.E. Haynes, and J.D. Chulay: Quantitative Assessment of Antimalarial Activity in vitroby a Semi-automated Microdilution Technique. Antimicrob. Agent Chemother., 16, 710 (1979).Google Scholar
  173. 173.
    Torok, D.S., and H. Ziffer: Synthesis and Antimalarial Activities of N-Substituted 11-Azaartemisinins. J. Med. Chem., 38, 5045 (1995).Google Scholar
  174. 174.
    Acton, N., J.M. Karle, and R.E. Miller: Synthesis and Antimalarial Activity of Some 9-Substituted Artemsinin Derivatives. J. Med. Chem., 36, 2552 (1993).Google Scholar
  175. 175.
    Zhao, Y: Studies on Systemic Pharmacological Effects of Artesunate. J. Trop. Med. Hyg., 88, 391 (1985).Google Scholar
  176. 176.
    Ames, B.N.: Methods for Detecting Carcinogens and Mutagens with the Salmonella/ Mammalian Microsome Mutagenicity Test. Mutat. Res., 31, 347 (1975).Google Scholar
  177. 177.
    Brewer, T.G., J.O. Peggins, S.J. Grate, J.M. Petras, B.S. Levine, P.J. Weina, J. Swearengen, M.H. Heiffer, and B.G. Schuster: Neurotoxicity in Animals due to Arteether and Artemether. Trans. Royal Soc. Trop. Med., 88, S1 33 (1994).Google Scholar
  178. 178.
    Brewer, T.G., SJ. Grate, J.O. Peggins, PJ. Weina, J.M. Petras, B.S. Levine, M.H. Heiffer, and B.G. Schuster: Fatal Neurotoxicity of Arteether and Artemether. Am. J. Trop. Med. Hyg., 51, 251 (1994).Google Scholar
  179. 179.
    Wesche, D.L., M.A. Decoster, F.C. Tortella, and T.G. Brewer: Neurotoxicity of Artemisinin Analogs in vitro. Antimicrobial Agents and Chemotherapy, 38, 1813 (1994).Google Scholar
  180. 180.
    Kamchonwongpaisan, S., P. Mckeever, P. Hossler, H. Ziffer, and S.R. Meshnick: Artemisinin Neurotoxicity: Neuropathology in Rats and Mechanistic Studies in vitro. Amer. J. Trop. Med. Hyg., 56, 7 (1997).Google Scholar
  181. 157.
    Nosten, F.: Artemisinin: Large Community Studies. Royal Society Tropical Medicine and Hygiene, 88, Supplement, 1, 45 (1994).Google Scholar
  182. 152.
    Walker, O., L.A. Salako, S.I. Omokhodion, and A. Sowumi: An Open Randomized Comparative Study of Intramuscular Artemether and Intravenous Quinine in Cerebral Malaria in Children. Royal Soc. Trop. Med. Hyg., 87, 564 (1993).Google Scholar
  183. 183.
    Zhao, K.-C., Q.-M. Chen, and Z.-Y Song: Studies of the Pharmacokinetics of Qinghaosu and Two of its Active Derivatives in Dogs. Acta Pharm. Sinica, 21, 736 (1986).Google Scholar
  184. 184.
    Zhao, K.C., and Z.Y Song: The Pharmacokinetics of Dihydroqinghaosu Given Orally to Rabbits and Dogs. Acta Pharm. Sinica, 25, 161 (1990).Google Scholar
  185. 185.
    Zhao, K., and Z. Song: Distribution and Excretion of Artesunate in Rats. Proc. CAMS and PUMC, 4, 186 (1989).Google Scholar
  186. 186.
    Benakis, A., C. Schopfer, M. Paris, CH. T. Plessas, P.E. Karayannakos, I. Dondas, D. Kotsarelis, S.T. Plessas, and G. Skalkeas: Pharmacokinetics of arteether in dog. European J. Drug Metabolism and Pharmacokinetics, 16, 325 (1991).Google Scholar
  187. 187.
    Titulaer, H.A.C., J. Suidema, P.A. Kager, J.C.F.M. Wetsteyn, Ch. B. Lugt, and F.W.H.M. Merkus: The Pharmacokinetics of Artemisinin After Oral, Intramuscular and Rectal Administration to Volunteers. J. Pharm. Pharmacol., 42, 810 (1990).Google Scholar
  188. 188.
    Klayman, D.L., A.L. Ager jr., L. Fleckenstein, and AJ. Lin: Transdermal Artelinic Acid: An Effective Treatment for P. berghei-lnfccted Mice. Am. J. Trop. Med., 45, 602 (1991).Google Scholar
  189. 189.
    Lin, A.J., A.L. Ager Jr., and D.L. Klayman: Antimalarial Activity of Dihydroarte-misinin Derivatives by Transdermal Application. Am. J. Trop. Med. Hyg., 50, 777 (1994).Google Scholar
  190. 190.
    Duc, D.D., P.J. Devries, N.X. Khanh, L.N. Binh, P.A. Kager, and C.J. Van Boxtel: The Pharmacokinetics of a Single Dose of Artemisinin in Healthy Vietnamese Subjects. Am. J. Med. Hyg., 51, 785 (1994).Google Scholar
  191. 191.
    Qinghaosu Antimalaria Coordinating Research Group: Antimalarial Studies on Qinghaosu. Chin. Med. J., 92, 811 (1979).Google Scholar
  192. 192.(a)
    Looareesuwan, S.: Overview of Clinical Studies on Artemisinin Derivatives in Thailand. Trans. Royal Soc. Trop. Med. Hyg., 88, Supplement 1, 9 (1994); (b) Bunnag, D., C. Viravan, S. Looareesuwan, J. Karbwang, and T. Harinasuta: Clinical Trial of Artesunate and Artemether on Multidrug Resistant P. falciparumMalaria in Thailand: A Preliminary Report. Southeast Asian Journal of Tropical Medicine and Public Health, 22, 380 (1991); (c) Bunnag, D., C. Viravan, S. Looareesuwan, J. Karbwang, and T. Harinasuta: Double Blind Randomized Clinical Trial of Two Different Regimens of Oral Artesunate in P. falciparumMalaria. Southeast Asian Tropical Medicine and Public Health, 22, 534 (1991); (d) Bunnag, D., C. Viravan, S. Looareesuwan, J. Karbwang, and T. Harinasuta: Double Blind Randomized Clinical Trial of Oral Artesunate at Once or Twice Daily Dose in P. falciparumMalaria. Southeast Asian Tropical Medicine and Public Health, 22, 762 (1991).Google Scholar
  193. 193.
    Karbwang, J., K. Sukontason, W. Rimchala, W. Namsiripongpun, T. Tin, P. Auprayoon, S. Tumsupapone, D. Bunnag. , and T. Harinasuta: Preliminary Report: A Comparative Clinical Trial of Artemether and Quinine in Severe Falciparum Malaria. Southeast Asian Tropical Medicine and Public Health, 23, 768 (1992); (b) Karbwang, J., K. Na Bangchang, A. Thanavibul, D. Bunnag, T. Chongsuphajai-Siddhi, and T. Harinasuta: Comparison of Artemether and Mefloquine in Acute Uncomplicated Falciparum Malaria. Lancet, 1245 (1992)Google Scholar
  194. 194.
    Luxemburger, C., F. Terkuile, F. Nosten, G. Dolan, J.H. Bradol, L. Phaipun, T. Chongsuphajaisiddhi, and N.J. White: Single Day Mefloquine-Artesunate Combination in the Treatment of Multi-Drug Resistant Falciparum Malaria. Trans. Royal Soc. Trop. Med. Hyg., 88, 213 (1994).Google Scholar
  195. 195.
    Arnold, K.: Qinghaosu, Mefloquine, and Pyrimethamine Sulfadoxide in falciparum Malaria. Lancet, 704 (1985).Google Scholar
  196. 196.
    Slater, A.F.G., A. Cerami: Inhibition by Chloroquine of a Novel Haem Polymerase Enzyme Activity in Malaria Trophozoites. Nature (London), 355, 167 (1992).Google Scholar
  197. 197.
    Zhao, Y., W.K. Hanton, and K.-H. Lee: Antimalarial agents, 2. Artesunate, an Inhibitor of Cytochrome Oxidase Activity in P. berghei. J. Nat. Prod., 49,139 (1986).Google Scholar
  198. 198.
    Ellis, D.S., Z.L. Li, H.M. Gu, W. Peters, B.L. Robinson, G. Tovey, and D.C. Warhurst: Ultrastructural Changes Following Treatment with Artemisinin of P. bergheiinfection in Mice, with Observations of the Localization of [3H]-Dihydroartemisinin in P. falciparum in vitro. Annals of Tropical Med. and Parasitology, 79, 367 (1985).Google Scholar
  199. 199.
    Kawai, S., S. Kano, and M. Suzuki: Morphologic effects of Artemether on P. falciparum in Aotus trivirgatus. Am. J. Trop. Med. Hyg., 49, 812 (1993).Google Scholar
  200. 200.
    Meshnick, S.R., A. Thomas, A. Ranz, C.-M. Xu, and H.-Z. Pan: Artemisinin (Qinghaosu): The Role of Intracellular Hemin and its Mechanism of Antimalarial Action. Mol. and Biochem. Parasitology, 49, 181 (1991).Google Scholar
  201. 201.
    Zhang, F., D.K. Gosser Jr., and S.R. Meshnick: Hemin-Catalyzed Decomposition of Artemisinin (Qinghaosu). Biochem. Pharmacol., 43, 1805 (1992).Google Scholar
  202. 202.
    Yang, Y.-Z., W. Asawamahasakda, and S.R. Meshnick: Alkylation of Human Albumin by the Antimalarial Artemisinin. Biochem. Pharmacol., 46, 336 (1993).Google Scholar
  203. 203.
    Asawamahasakda, W., I. Ittarat, Y.-M. Pu, H. Ziffer, and S.R. Meshnick: Reaction of Antimalarial Endoperoxides with Specific Parasite Proteins. Antimicrobial Agents Chemotherapy, 1854 (1994).Google Scholar
  204. 204.
    Clark, A., N.H. Hunt, W.B. Cowden, and L.E. Maxwell: Radical-Mediated Damage to Parasites and Erythrocytes in P. vinckeiInfected Mice after Injection of t-Butyl Hydroperoxide. Clin. Exp. Immunol., 56, 524 (1984).Google Scholar
  205. 205.
    Meshnick, S.R., Y.-Z. Yang, V. Lima, F. Kuypers, S. Kamchonwongpaisan, and Y. Yuthavong: Iron-Dependent Free Radical Generation from the Antimalarial Agent Artemisinin (Qinghaosu). Antimicrobial Agents and Chemotherapy, 37,1108 (1993).Google Scholar
  206. 206.
    Posner, G.H., C.H. Oh, D. Wang, L. Gerena, W.K. Milhous, S.R. Meshnick, and W. Asawamahasadka: Mechanism-Based Design, Synthesis, and in vitroAntimalarial Testing of New 4-Methylated Trioxanes Structurally Related to Artemisinin: The Importance of a Carbon-Centered Radical for Antimalarial Activity. J. Med. Chem., 37, 1256 (1994).Google Scholar
  207. 207.
    Posner, G.H., J.N. Cumming, P. Ploypradith, and C.H. Oh: Evidence for Fe(IV)=O in the Molecular Mechanism of Action of the Trioxane Antimalarial Artemisinin. J. Am Chem. Soc, 117, 5885 (1995).Google Scholar
  208. 208.
    Posner, G.H., D. Wang, J.N. Cumming, C.H. Oh, A.N. French, A.L. Bodley, and T.A. Shapiro: Further Evidence Supporting the Importance of and the Restrictions on a Carbon-Centered Radical for High Antimalarial Activity of 1,2,4-Trioxanes Like Artemisinin. J. Med. Chem., 38, 2273 (1995).Google Scholar
  209. 209.
    Posner, G.H., S.B. Park, L. Gonzalez, D. Wang, J.N. Cumming, D. Klinedinst, T.A. Shapiro, and M.D. Bachi: Evidence for the Importance of High-Valent Fe=O and of a Diketone in the Molecular Mechanism of Action of Antimalarial Trioxane Analogs of Artemisinin. J. Am. Chem. Soc, 118, 3537 (1996).Google Scholar
  210. 210.
    Liang, X.T.: The Chemistry of Peroxidic Antimalarials. Adv. Chin. Med. Mater. Res. Int. Symp., 427 (1984).Google Scholar
  211. 211.
    Zhang, L., W.S. Zhou, and X.X. Xu: A New Sesquiterpene Peroxide (Yingzhaosu C) and Sesquiterpenol (Yingzhaosu D) from Artabotrys uniciatus(L.) Meer. J. C. S. Chem. Commun., 523 (1988).Google Scholar
  212. 212.
    Xu, X.-X., J. Zhu, D.-Z. Huang, and W.-S. Zhou: Total Synthesis of (+)-Yingzhaosu A. Tetrahedron Lett., 32, 5785 (1991).Google Scholar
  213. 213.
    Xu, X.-X., and X. Xie: Total Synthesis of Yingzhaosu B and its Three Diastereoi-somers. Chinese J. Chem., 12, 381 (1994).Google Scholar
  214. 214.
    Xu, X.-X., and H.-Q. Dong: Enantioselective Total Synthesis of All Four Stereoisomers of Yingzhaosu C. Tetrahedron Lett., 35, 9429 (1994).Google Scholar
  215. 215.
    Xu, X.-X., and Q.-S. Hu: Synthesis of the Diastereoisomeric Yingzhaosu D. Chinese J. Chem., 10, 285 (1992).Google Scholar
  216. 216.
    Kamchonwongpaisan, S., C. Nilanonta, B. Tamchompoo, C. Thebtaranonth, Y Thebtaranonth, Y. Yuthavong, P. Kongsaeree, and J. Clardy: An Antimalarial Peroxide from Amomum krervanh Pierre. Tetrahedron Lett., 36, 1821 (1995).Google Scholar
  217. 217.
    Hashidoko, Y, S. Tahara, and S.J. Mizutani: Antimicrobial Sesquiterpene from Damaged Rosa rugosaLeaves. Phytochemistry, 28, 425 (1989).Google Scholar
  218. 218.
    Hofheinz, W., H. Burgin, E. Glocke, C. Jaquet, R. Masciadri, G. Schmid, H. Stohler, and H. Urwyler: Ro 42-1611 (Arteflene), A New Effective Antimalarial: Chemical Structure and Biological Activity. Trop. Med. Parasitai., 45, 261 (1994).Google Scholar
  219. 219.
    Posner, G.H., D. Wang, L. Gonzalez, S. Tao, J.N. Cumming, D. Klinedinst, and T.A. Shapiro: Mechanism-Based Design of Simple, Symmetrical, Easily Prepared, Potent Antimalarial Endoperoxides. Tetrahedron Lett., 37, 815 (1996).Google Scholar
  220. 220.
    Vennerstrom J.L., and J.W. Eaton: Oxidants, Oxidant Drugs and Malaria. J. Med. Chem., 3, 1269 (1988).Google Scholar
  221. 221.
    Clark, I.A., W.B. Cowden, and G.A. Butcher: Lancet, 234, 1983.Google Scholar
  222. 222.
    Vennerstrom, J.L., H.-N. Fu, W.Y. Ellis, A.L. Acer, Jr., J.K. Wood, S.L. Andersen, L. Gerena, and W.K. Milhous: J. Med. Chem., 35, 3023 (1992).Google Scholar
  223. 223.
    Kepler, J.A., A. Philip, Y.W. Lee, H.A. Musallam, and F.I. Carroll: Endoperoxides as Potential Antimalarial Agents. J. Med. Chem., 30, 1505 (1987).Google Scholar
  224. 224.
    Bunnelle, W.H., T.A. Isbell, C.L. Barnes, and S. Qualls: Cationic Ring Expansion of an Ozonide to a 1,2,4-Trioxane. J. Am. Chem. Soc, 113, 8168 (1991).Google Scholar

Copyright information

© Springer-Verlag Wien 1997

Authors and Affiliations

  • H. Ziffer
    • 1
  • R. J. Highet
    • 2
  • D. L. Klayman
    • 3
  1. 1.Laboratory of Chemical Physics, National Institute of Diabetes, Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Laboratory of Biophysical Chemistry, National Heart, Lung and Blood InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Division of Experimental TherapeuticsWalter Reed Army Institute of ResearchUSA

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