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Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products pp 121–214Cite as

Artemisinin: An Endoperoxidic Antimalarial from Artemisia annua L.

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Abstract

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.

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References

  1. Klayman, D.L.: Qinghaosu (Artemisinin): An Antimalarial Drug from China. Science, 228, 1049 (1985).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. Xmen, L.: A New Drug for Malaria. China Reconstructs, 191, 48 (1979).

    Google Scholar 

  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. 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. Woerdenbag, HJ., C.B. Lugt, and N. Pras: Artemisia annuaL. : A Source of Novel Antimalarial Drugs. Pharm. Weekbl. [Sci.], 12, 169 (1990).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  11. Butler, A.R.: Artemisinin (Qinghaosu): A New Type of Antimalarial Drug. Chem. Soc. Rev., 21, 85 (1992).

    CAS  Google Scholar 

  12. Jung, M.: Current Developments in the Chemistry of Artemisinin and Related Compounds. Current Med. Chem., 1, 35 (1994).

    CAS  Google Scholar 

  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. Fernald, M.L.: Gray’s Manual of Botany. New York: American Book Company. 1950, p. 1522.

    Google Scholar 

  15. 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. 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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  19. Laughlin, J.C.: Agricultural Production of Artemisinin: A Review. Trans. Royal Soc. Trop. Med. and Hyg., 88, S. 21 (1994).

    CAS  Google Scholar 

  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. 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. Acton, N., D.L. Klayman, and I. Rollman: Reductive Electrochemical HPLC Assay for Artemisinin (Qinghaosu). Planta Medica, 445 (1985).

    Google Scholar 

  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. 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. 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. 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).

    CAS  Google Scholar 

  27. Singh, A., R.A. Vishwakarma, and A. Husain: Evaluation of Artemisia annuaStrains for Higher Artemisinin Production. Planta Medica, 475 (1988).

    Google Scholar 

  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. 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. Weathers, P.J., R.D. Cheetham, E. Follansbee, and K. Teoh: Artemisinin Production by Transformed Roots of Artemisia annua. Biotech. Lett., 16, 1281 (1994).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  34. Acton, N., and D.L. Klayman: Artemisitene, A New Sesquiterpene Lactone Peroxide from Artemisia annua. Planta Medica, 441 (1985).

    Google Scholar 

  35. 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. Wei, Z.X., J.U.P. Pan, and Y. Li: Artemisinin G: A Sesquiterpene from Artemisia annua. Planta Medica, 300 (1992).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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. Büchi, G., and H. Wüest: Ozonolysis of Vinylsilanes. J. Am. Chem. Soc, 99, 294 (1977).

    Google Scholar 

  40. Hmid, G., and W. Hofheinz: Total Synthesis of Qinhaosu. J. Am. Chem. Soc, 105, 624 (1983).

    Google Scholar 

  41. Xu, X.X., J. Zhu, D.Z. Huang, and W.S. Zhou: Total Synthesis of Arteannuin and Deoxyarteannuin. Tetrahedron, 42, 819 (1986).

    CAS  Google Scholar 

  42. Zhou, W.S.: Total Synthesis of Arteannuin (Quinghaosu) and Related Compounds. Pure Appl. Chem., 58, 817 (1986).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  44. Ravindranathan, T., M.A. Kumar, R.B. Menon, and S.V. Hiremath: Stereoselective Synthesis of Artemisinin. Tetrahedron Lett., 31, 755 (1990).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  47. Roth, R.J., and N. Acton: A Facile Semisynthesis of the Antimalarial Drug Qinghaosu. J. Chem. Ed., 68, 613 (1991).

    Google Scholar 

  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. 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. 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. Lansbury, P.T., and D.M. Nowak: An Efficient Partial Synthesis of (+)-Artemisinin and (+)Deoxoartemisin. Tetrahedron Lett., 1029 (1992).

    Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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)

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  59. Liang, X.T.: Circular Dichroism of the Peroxidic Linkage. Acta Chim. Sinica, 40, 288 (1982).

    Google Scholar 

  60. Ziffer, H.: Unpublished observation.

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  63. Schwartz, H., and H.M. Schiebel: Chemistry of the Peroxides (S. Patai, ed.), p. 105. New York: Wiley, 1983.

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  73. Zhu, H.S.: Titrimetric Analysis of Artemisinin in Artemisia annua. Yao Hsueh Tlung Pao, 15, 6 (1980); Chem. Abstr., 95, 86359v (1981).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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. 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. 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).

    CAS  Google Scholar 

  87. Avery, M.A., J.D. Bonk, and J. Bupp: Radiolabelled Antimalarials: Synthesis of 14C-Artemisinin. J. Labelled Compounds and Radiopharmaceuticals, 38, 263 (1996).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  90. Ding, S.F., and L.X. Li: Zhongyao Tongbao, 6, 25 (1981).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  93. Luo, X.D., H.J.C. Yeh, and A. Brossi: The Chemistry of Drugs. VI Thermal Decomposition of Qinghaosu. Heterocycles, 23, 881 (1985).

    CAS  Google Scholar 

  94. Lin, A.J., A.T. Theoharides, and D.L. Klayman: Thermal Decomposition Products of Dihydroartemisinin (Dihydroqinghaosu). Tetrahedron, 42, 2181 (1986).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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. Torok, D.S., and H. Ziffer: Synthesis and Reactions of 11-Azaartemisinin and its Derivatives. Tetrahedron Lett., 36, 829 (1995).

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  102. Imakura, Y, K. Hachiya, T. Ikemoto, and S. Yamashita: Acid Degradation Products of Qinhaosu and their structure-Activity Relationships. Heterocycles, 31, 1011 (1990).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  104. Acton, N., and R.J. Roth: Acid Decomposition of the Antimalarial Beta-Arteether. Heterocycles, 41, 95 (1995).

    CAS  Google Scholar 

  105. El-Feraly, F., S.A. Ayalp, and M.A. Al-Yahya: Conversion of Artemisinin to Artemisitene. J. Nat. Prod., 53, 66 (1990).

    CAS  Google Scholar 

  106. Pu, Y.M., and H. Ziffer: Diastereofacial Addition to a /β-Substituted Glycal, Anhydroartemisinin. Heterocycles, 39, 649 (1994).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  109. El-Feraly, F.S., A. Ayalp, and M.A. Al-Yahya: Decomposition of Dihydroartemisitene on Silica Gel. J. Nat. Prod., 53, 920 (1990).

    CAS  Google Scholar 

  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. 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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  120. Petrov, O., and I. Ognyanov: An Approach to the Synthesis of Novel 11-Hydro-xyartemisinin Derivatives. Collect. Czech. Chem. Commun., 56, 1037 (1991).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  122. Pu, Y.-M., B. Yagen, and H. Ziffer: Stereoselective Oxidations of a β-Methylglycal, Anhydrodihydroartemisinin. Tetrahedron Lett., 35, 2129 (1994).

    CAS  Google Scholar 

  123. China Cooperative Research Group: The Chemistry and Synthesis of Qinghaosu Derivatives. J. Traditional Chin. Med., 2, 9 (1982).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  126. Chinese Cooperative Research Group: Studies on the Toxicity of Qinghaosu and its Derivatives. J. Trad. Chin. Med., 2, 31 (1982).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  131. China Cooperative Research Group: J. Trad. Chinese Med., 2, 9 (1982).

    Google Scholar 

  132. Li, X.-Y., and H.-Z. Liang: Effects of Artemether on Red Blood Cell Immunity in Malaria. Acta Pharmacol. Sinica, 7, 471 (1986).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  135. Lin, A.J., D.L. Klayman, and W.K. Milhous: Novel Antimalarial Dihydroartemisinin Derivatives. USP 4, 791, 135.

    Google Scholar 

  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).

    CAS  Google Scholar 

  137. Lin, A.J., and R.E. Miller: Antimalarial Activity of New Dihydroartemisininin Derivatives. 6. α-Alkylbenzylic Ethers. J. Med. Chem., 38, 764 (1995).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  139. Bustos, D.A., M. Jung, H.N. Elsohly, and J.D. Mcchesney: Stereospeciflc Synthesis of (+)-Homodeoxoartemisinin. Heterocycles, 29, 2273 (1989).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  144. Pu, Y.M., and H. Ziffer: Synthesis and Antimalarial Activities of 12β=Allyl-deoxoartemisinin. J. Med. Chem., 38, 613 (1995).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. Avery, M.A., C. Jennings-White, and W.K.M. Chong: The Total Synthesis of (+)-Artemisinin and (+)-9-Desmethylartemisinin. Tetrahedron Lett., 28, 4629 (1987).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  149. Still, W.C.: A Simple Synthesis of Bicyclo[4.n.1]enones by Cyclodialkylation. Synthesis, 453 (1976).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  157. Ye, B., and Y.L. Wu: Syntheses of Carba-Analogues of Qinghaosu. Tetrahedron, 45, 7287 (1989).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  166. Lee, I.S., H.N. Elsohly, and CD. Hufford: Microbial Metabolism Studies of the Antimalarial Drug Arteether. Pharm. Res., 7, 199 (1990).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  170. 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. Hu, Y, H. Ziffer, G. Li, and HJ.C Yeh: Microbial Oxidation of the Antimalarial Drug Arteether. Bioorganic Chem., 20 148 (1992).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  173. Torok, D.S., and H. Ziffer: Synthesis and Antimalarial Activities of N-Substituted 11-Azaartemisinins. J. Med. Chem., 38, 5045 (1995).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  175. Zhao, Y: Studies on Systemic Pharmacological Effects of Artesunate. J. Trop. Med. Hyg., 88, 391 (1985).

    CAS  Google Scholar 

  176. Ames, B.N.: Methods for Detecting Carcinogens and Mutagens with the Salmonella/ Mammalian Microsome Mutagenicity Test. Mutat. Res., 31, 347 (1975).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  181. Nosten, F.: Artemisinin: Large Community Studies. Royal Society Tropical Medicine and Hygiene, 88, Supplement, 1, 45 (1994).

    Google Scholar 

  182. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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. Zhao, K., and Z. Song: Distribution and Excretion of Artesunate in Rats. Proc. CAMS and PUMC, 4, 186 (1989).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  191. Qinghaosu Antimalaria Coordinating Research Group: Antimalarial Studies on Qinghaosu. Chin. Med. J., 92, 811 (1979).

    Google Scholar 

  192. 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. 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. 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).

    CAS  Google Scholar 

  195. Arnold, K.: Qinghaosu, Mefloquine, and Pyrimethamine Sulfadoxide in falciparum Malaria. Lancet, 704 (1985).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  201. Zhang, F., D.K. Gosser Jr., and S.R. Meshnick: Hemin-Catalyzed Decomposition of Artemisinin (Qinghaosu). Biochem. Pharmacol., 43, 1805 (1992).

    CAS  Google Scholar 

  202. Yang, Y.-Z., W. Asawamahasakda, and S.R. Meshnick: Alkylation of Human Albumin by the Antimalarial Artemisinin. Biochem. Pharmacol., 46, 336 (1993).

    CAS  Google Scholar 

  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. 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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  210. Liang, X.T.: The Chemistry of Peroxidic Antimalarials. Adv. Chin. Med. Mater. Res. Int. Symp., 427 (1984).

    Google Scholar 

  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. Xu, X.-X., J. Zhu, D.-Z. Huang, and W.-S. Zhou: Total Synthesis of (+)-Yingzhaosu A. Tetrahedron Lett., 32, 5785 (1991).

    CAS  Google Scholar 

  213. Xu, X.-X., and X. Xie: Total Synthesis of Yingzhaosu B and its Three Diastereoi-somers. Chinese J. Chem., 12, 381 (1994).

    CAS  Google Scholar 

  214. Xu, X.-X., and H.-Q. Dong: Enantioselective Total Synthesis of All Four Stereoisomers of Yingzhaosu C. Tetrahedron Lett., 35, 9429 (1994).

    CAS  Google Scholar 

  215. Xu, X.-X., and Q.-S. Hu: Synthesis of the Diastereoisomeric Yingzhaosu D. Chinese J. Chem., 10, 285 (1992).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  217. Hashidoko, Y, S. Tahara, and S.J. Mizutani: Antimicrobial Sesquiterpene from Damaged Rosa rugosaLeaves. Phytochemistry, 28, 425 (1989).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  220. Vennerstrom J.L., and J.W. Eaton: Oxidants, Oxidant Drugs and Malaria. J. Med. Chem., 3, 1269 (1988).

    Google Scholar 

  221. Clark, I.A., W.B. Cowden, and G.A. Butcher: Lancet, 234, 1983.

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Chemical Physics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    H. Ziffer

  2. Laboratory of Biophysical Chemistry, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    R. J. Highet

  3. Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC, 20307, USA

    D. L. Klayman

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  1. H. Ziffer
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  3. D. L. Klayman
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Ziffer, H., Highet, R.J., Klayman, D.L. (1997). Artemisinin: An Endoperoxidic Antimalarial from Artemisia annua L.. In: Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products. Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products, vol 72. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6527-0_2

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