Current progress in the chemistry, medicinal chemistry and drug design of artemisinin based antimalarials

Current Pharmaceutical Design

Volumn 5, Issue 2, 1999, Pages 101-138

  Vroman, Jeffrey A ^a   Alvim Gaston, Maria ^a   Avery, Mitchell A ^b  

^a Environmental Toxicology Research Program   (United States)

^b UNIVERSITY OF MISSISSIPPI   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIMALARIAL AGENT; ARTEMISININ DERIVATIVE;

CHEMISTRY; DRUG DESIGN; DRUG MECHANISM; DRUG METABOLISM; DRUG SYNTHESIS; HUMAN; MALARIA; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ANIMALS; ANTIMALARIALS; ARTEMISININS; BIOTRANSFORMATION; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HUMANS; MALARIA; PLASMODIUM; RATS; SESQUITERPENES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032969901     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (133)

1. Smith, D. F. a. P., M. Molecular Biology of Parasitic Protozoa, (New York, Oxford University Press), 1996.
2. Klayman, D. L. Qinghaosu (Artemisinin): an Antimalarial Drug from China, Science, 228, pp. 1049-55, 1985.
3. () Drug Facts and Comparisons (St. Louis, MO, Facts and Comparisons Inc.) 1996.
4. Baird, J. K. B., H.; Subianto, B.; Fryauff, D. J.; McElroy, P. D.; Leksana, B.; Richie, T. L.; Masbar, S.; Wignall, F. S. and Hoffman, S. L. Treatment of Chloroquine-resistant Plasmodium vivax with Chloroquine and Primaquine or Halofantrine., J. Infect. Dis., 1995, 171, pp. 1678-1682.
5. Edwards, G. W., P. A. and Ward, S. A. Clinical Pharmacokinetics in the Treatment of Tropical Diseases. Some Applications and Limitations., Clin. Pharmacokinet., 1994, 27, pp. 150-165.
6. Nosten, F. L., C.; ter-Kuile, F. O.; Woodrow, C.; Eh, J. P.; Chongsuphajaisiddhi, T. and White, N. J Treatment of Multidrug-resistant Plasmodium falciparum Malaria with 3-day Artesunate-Mefloquine Combination., J. Infect. Dis., 1994, 170, pp. 971-977.
7. Coosemans, M. H. B., M.; Onori, E.; Otoul, C.; Gryseels, B. and Wery, M. Double-blind Study to Assess the Efficacy of Chlorproguanil Given Alone or in Combination with Chloroquine for Malaria Chemoprophylaxis in an Area with Plasmodium falciparum Resistance to Chloroquine, Trans. R. Soc. Trop. Med. Hyg, 1987, 81, pp. 151-156.
8. Phillips, R. E. L., S.; Karbwang, J., Warrell, D. A.; White, N. J.; Kasemsarn, P. and Warhurst, D. C. Failure of Chloroquine-Erythromycin and Chloroquine-Tetracycline Combinations in Treatment of Chloroquine-Resistant falciparum Malaria in Eastern Thailand., Lancet, 1984, 1, pp. 300-302.
9. Chongsuphajaisiddhi, T. S., A. and Attanath, P. Treatment of Quinine Resistant falciparum Malaria in Thai Children., Southeast Asian J. Trop. Med. Public Health., 1983, 14, pp. 357-362.
10. Tropical Diseases-Part 1 Are We Any Closer to Cures for These Ancient Scourges?, Washington Insight, 1994, pp. 7-8.
11. Krogstad, D. J. G., I. Y.; Kyle, D. E.; Oduola, A. M.; Martin, S. K.; Milhous, W. K. and Schlesinger, P. A. Efflux of Chloroquine from Plasmodium falciparum: Mechanism of Chloroquine Resistance, Science, 1987, 238, pp. 1283-1285.
12. Luo, X.-D. & Shen, C.-C. The chemistry, pharmacology, and clinical applications of qinghaosu (artemisinin) and its derivatives, Medical Research Reviews, 1987, 7, pp. 29-52.
13. Haynes, R. K. & Vonwiller, S. C. From Qinghao, Marvelous Herb of Antiquity, to the Antimalarial Trioxane Qinghaosu. Some Remarkable New Chemistry, Acc. Chem. Res., 1997, 30, pp. 73-79.
14. Zhou, W.-S. & Xu, X.-X. Total Synthesis of the Antimalarial Sesquiterpene Peroxide Qinghaosu and Yingzhaosu A, Acc. Chem. Res., 1994, 27, pp. 211-216.
15. Avery, M. A., Chong, W. K. M. & Jennings-White, C. Stereoselective Total Synthesis of (+)-Artemisinin, the Antimalarial Constituent of Artemisia annua L., J. Amer. Chem. Soc., 1992, 114, pp. 974-979.
16. Meshnick, S. R. Is hemozoin a target for antimalarial drugs?, Ann. Trop. Med. Parasitol., 1996, 90, pp. 367-372.
17. Jung, M. Current Developments in the Chemistry of Artemisinin and Related Compounds, Curr. Med. Chem., 1994, 1, pp. 35-49.
18. Avery, M. A., Gao, F., Mehrotra, S., Chong, W. K. & Jennings-White, C. The Organic and Medicinal Chemistry of Artemisinin and Analogs (Trivandrum, India, Research Trends), 1993.
19. Butler, A. R. & Wu, Y. L. Artemisinin (Qinghaosu): A New Type of Antimalarial Drug, Chem. Soc. Reviews, 1992, 21, pp. 85-90.
20. Hien, T. T. & White, N. J. Qinghaosu, Lancet, 1993, 341, pp. 603-608.
21. Paitayatat, S., Tarnchompoo, B., Thebtaranonth, Y. & Yuthavong, Y. Correlation of Antimalarial Activity of Artemisinin Derivatives with Binding Affinity with Ferroprotoporphyrin IX, J. Med. Chem., 1997, 40, pp. 633-638.
22. Jung, M., ElSohly, H. N., Croom, E. M., McPhail, A. T. & McPhail, D. R. Practical conversion of artemisinic acid into desoxyartemisinin, J. Org. Chem., 1986, 51, pp. 5417-5419.
23. Jung, M., Li, X., Bustos, D., ElSohly, H. N. & McChesney, J. D. A short and stereospecific synthesis of (+)-deoxoartemisinin and (-)-deoxodesoxyartemisinin, Tetrahedron Lett., 1989, 30, pp. 5973-6.
24. Jung, M., Li, X., Bustos, D. Elsohly, H. N., McChesney, J. D. & Milhous, W. K. Synthesis and Activity of (+)-10-Deoxoartemisinin, J. Med. Chem., 1990, 33, pp. 1516-1518.
25. Jung, M., Bustos, D. A., ElSohly, H. N. & McChesney, J. D. A Concise and Stereoselective Synthesis of (+)-12-butyldeoxoartemisinin., Synlett, 1990, pp. 743-4.
26. Jung, M., ElSohly, H. N. & McChesney, J. D. A concise synthesis of novel C-13 functionalized deoxoartemisinins, Synlett, 1993, pp. 43-4.
27. Jung, M. & Lee, S. A concise synthesis of novel aromatic analogs of artemisinin, Heterocycles, 1997, 45, pp. 1055-1058.
28. Haynes, R. K., Vonwiller, S. C. & Wang, H. J. The Preparation of D-ring-contracted Analogs of Qinghaosu (Artemisinin) from Qinghao (Artemisinic Acid) Acid and their In Vitro Activity against Plasmodium falciparum, Tetrahedron Lett., 1997, 38, pp. 2587.
29. Kim, S. U., Choi, J. H. & Kim, S. S. Preparation of a cyclopropane-containing analog of artemisinin, J. Nat. Prod., 1993, 56, pp. 857-63.
30. Roth, R. & Acton, N. A simple conversion of artemisinic acid into artemisinin, J. Nat. Prod., 1989, 52, pp. 1183-1185.
31. Roth, R. J. & Acton, N. A Facile Semisynthesis of the Antimalarial Drug Qinghaosu, J. Chem. Ed., 1991, 68, pp. 612.
32. Vroman, J. A., Khan, I. A. & Avery, M. A. Copper(I) catalyzed conjugate addition of Grignard reagents to acrylic acids: homologation of artemisinic acid and subsequent conversation to 9-substituted artemisinin analogs, Tetrahedron Lett., 1997, 38, pp. 6173-6176.
33. Zaman, S. S. & Sharma, R. P. Some Aspects of the Chemistry and Biological Activity of Artemisinin and Related Antimalarials, Heterocycles, 1991, 32, pp. 1593-1638.
34. Akhila, A. Thakur, R. S., & Popli, S. P. Biosynthesis of Artemisinin in Artemisia annua., Phytochemistry., 1987, 26, pp. 1927.
35. Akhila, A. Rani, K. & Thakur, R. S. Biosynthesis of Artemisinic Acid In Artemisia annua., Phytochemistry, 1990, 29, pp. 2129-2132.
36. Sangwan, R. S. Agarwal, K.; Luthra, R.; Thakur, R. S., & Singh-Sangwan, N. Biotransformation of Arteannuic Acid into Arteannuin-B and Artemisinin in Artemisia annua., Phytochemistry., 1993, 49, pp. 181-190.
37. Nair, M. S. R., & Basile, D. V. Bioconversion of Arteannuin B to Artemisinin., J. Nat. Prod., 1993, 34, pp. 1301-1302.
38. Meshnick, S. R., Thomas, A., Ranz, A., Xu, C. M. & Pan, H. Artemisinin (Qinghaosu), the Role of Intracellular Hemin in its Mechanism of Antimalarial Action, Molec. Biochem. Parasitol., 1991, 49, pp. 181-190.
39. Posner, G. & Oh, C. A Regiospecifically Oxygen-18 Labeled 1,2,4-Trioxane: A Simple Chemical Model System to Probe the Mechanism(s) for the Antimalarial Activity of Artemisinin (Qinghaosu), J. Amer. Chem. Soc., 1992, 114, pp. 8328.
40. Posner, G. H., Oh, C. H., Wang, D., Gerena, L., Milhous, W. K., Meshnick, S. R. & Asawamahasadka, W. A. Mechanism-Based Design, Synthesis, and In Vitro Antimalarial Testing of New 4-Methylated Trioxanes Structurally Related to Artemisinin: The Importance of a Carbon-centered Radical for Antimalarial Activity, J. Med. Chem., 1994, 37, pp. 1256-1258.
41. Posner, G. H., Wang, D., Cumming, J. N., Oh, C. H., French, A. N., Bodley, A. L. & Shapiro, T., 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., 1995, 38, pp. 2273-2275.
42. Posner, G. H., Cummings, J. N., Polypradith, P. & Oh, C. O. Evidence for Fe(IV)=O in the Molecular Mechanism of Action of the Trioxane Antimalarial Artemisinin, J. Amer. Chem. Soc., 1995, 117, pp. 5885-5886.
43. Jefford, C. W., Vicente, M. G. H., Jacquier, Y., Favarger, P., Mareda, J., MillassonSchmidt, P., Brunner, G., & Burger, U. The Deoxygenation and Isomerization of Artemisinin and Artemether and Their Relevance to Antimalarial Action, Helv. Chim. Acta, 1996, 79, pp. 1475-1487.
44. Haynes, R. K. & Vonwiller, S. C. The Behavior of Qinghaosu (Artemisinin) in the Presence of Heme Iron(II) and (III), Tetrahedron Lett., 1996, 37, pp. 253-256.
45. Haynes, R. K. & Vonwiller, S. C. The Behavior of Qinghaosu (Artemisinin) in the Presence of Non-heme Iron(II) and (III), Tetrahedron Lett., 1996, 37, pp. 257-260.
46. Kamchonwongpaisan, S. & Meshnick, S. R. The Mode of Action of the Antimalarial Artemisinin and its Derivatives, Gen. Pharmac., 1996, 27, pp. 587-592.
47. Meshnick, S. R., Yang, Y., Lima, V., Kuypers, F., Kamchonwongpaisan, S., Yuthavong, Y. Iron-dependent Free Radical Generation and the Antimalarial Artemisinin (Qinghaosu), Antimicrob. Agents Chemother., 1993, 37, pp. 1108-1114.
48. Asawamahasakda, W., Ittarat, I., Pu, Y.-M. Ziffer, H. & Meshnick, S. R. Alkylation of Parasite-specific Proteins by Endoperoxide Antimalarials, Antimicrob. Agents and Chemother., 1994, 38, pp. 1854-1858.
49. Asawamahasakda, W., Ittarat, I., Pu, Y., Ziffer, H. & Meshnick, S. R. Reaction of Antimalarial Endoperoxides with Specific Parasite Proteins, Antimicrob. Agents and Chemother., 1994, 38, pp. 1854-1858.
50. Lee, I. S. & Hufford, C. D. Metabolism of Antimalarial Sesquiterpene Lactones, Pharmac. Ther., 1990, 48, pp. 345-355.
51. Chi, H. T., Ramu, K., Baker, J. K., Hufford, C. D., Lee, I.S., Zeng, Y. L. & McChesney, J.D. Identification of the in vivo Metabolites of the Antimalarial Arteether by Thermospray High-Performance Liquid Chromatography/Mass Spectrometry, Biol. Mass Spectrom., 1991, 20, pp. 609-628.
52. Khalifa, S. I., Baker, J. K., Jung, M., McChesney, J. D. & Hufford, C. D. Microbial and Mammalian Metabolism Studies on the Semisynthetic Antimalarial, Deoxoartemisinin, Pharm. Res., 1995, 12, pp. 1493-1498.
53. Leskovac, V., Theoharides, A. D. & Peggins, J. Hepatic Metabolism of Artemisinin Drugs-II. Metabolism of Arteether in Rat Liver Cytosol, Comp. Biochem. Physiol., C: Comp. Pharmacol. Toxicol., 1991, 99C, pp. 391-6.
54. Leskovac, V., Theoharides, A. D. & Peggins, J. Hepatic Metabolism of Artemisinin Drugs-I. Drug Metabolism in Rat Liver Microsomes, Comp. Biochem. Physiol., C: Comp. Pharmacol. Toxicol., 1991, 99C, pp. 383-390.
55. Lee, I. S., ElSohly, H. N., Croom, E. M. & Hufford, C. D. Microbial Metabolism Studies of the Antimalarial Sesquiterpene Artemisinin, J. Nat. Prod., 1989, 52, pp. 337-341.
56. Lee, I. S., ElSohly, H. N. & Hufford, C. D. Microbial Metabolism Studies of the Antimalarial Drug Arteether, Pharm. Res., 1990, 7, pp. 199-203.
57. Hufford, C. D., Lee, I.-S., ElSohly, H. N., Chi, H. T. & Baker, J. K. Structure Elucidation and Thermospray High-Performance Liquid Chromatography/Mass Spectroscopy (HPLC/MS) of the Microbial and Mammalian Metabolites of the Antimalarial Arteether, Pharm. Res., 1990, 7, pp. 923-927.
58. Hu, Y., Ziffer, H., Li, G. & Yeh, H. Microbial Oxidation of the Antimalarial Drug Arteether, Bioorganic Chemistry, 1992, 20, pp. 148.
59. Hufford, C. D., Khalifa, S. I., Orabi, K. Y., Wiggers, F. T., Kumar, R., Rogers, R.D. & Campana, C. F. 1α-Hydroxyarteether, A New Microbial Transformation Product, J. Nat. Prod., 1995, 58, pp. 751-755.
60. Titulaer, H. A. C., Zuidema, J., Kager, P. A., Wetsteyn, J. C. F. M., Lugt, C. B. & Merkus, F. W. H. M. The Pharmacokinetics of Artemisinin After Oral, Intramuscular and Rectal Administration to Volunteers, J. Pharm. Pharmacol., 1990, 42, pp. 810-813.
61. Titulaer, H. A. C., Eling, W. M. C. a. & Zuidema, J. Pharmacokinetic and Pharmacodynamic Aspects of Artelinic in Rodents, J. Pharm. Pharmacol., 1993, 45, pp. 830-835.
62. Duc, D. D., De Vries, P. J., Khanh, N. X., Binh, L. N., Kager, P. A. & Van Boxtel, C. J. The Pharmacokinetics of a Single Dose of Artemisinin in Healthy Vietnamese Subjects, Am. J. Trop. Med. Hyg., 1994, 51, pp. 785-790.
63. Maeno, Y., Toyoshima, T., Fujiola, H., Ho, Y., Meshnick, S. R., Benakis, A., Milhhous, W. K. & Ailawa, M. Morphologic Effects of Artemisinin in Plasmodium falciparum, Am. J. Trop. Med. Hyg., 1993, 49, pp. 485-491.
64. Group, Q. A. C. R. Antimalarial Studies on Qinghaosu, Chinese Medical Journal, 1979, 92, pp. 811-816.
65. Brewer, T. G., Peggins, J. O. Grate, S. J., Petras, J. M., Levine, B. S., Weina, P. J., Swearengen, J., Heiffer, M. H. & Schuster, B. G. Neurotoxicity in Animals Due to Arteether and Artemether Trans. Royal Soc. Trop. Med. and Hygiene, 1994, pp. 33-36.
66. Brewer, T. G., Grate, S. J., Peggins, J. O., Weina, P. J., Petras, J. M., Levine, B. S., Heiffer, M. H. & Schuster, B. G. Fatal Neurotoxicity of Arteether and Artemether, Am. J. Trop. Med. Hyg., 1994, 51, pp. 251-259.
67. Wesche, D. L., DeCoster, M. A., Tortella, F. C. & Brewer, T. G. Neurotoxicity of Artemisinin Analogs In Vitro, Antimicrob. Agents and Chemother., 1994, 38, pp. 1813-1819.
68. Fishwick, J. & Edwards, G. The Toxicity of Artemisinin and Related Compounds on Neuronal and Glial Cells in Culture, Chemico-Biological Interact., 1995, 96, pp. 263-271.
69. Smith, S. L., Fishwick, J., McLean, W. G., Edwards, G. & Ward, S. A. Enhanced in vitro neurotoxicity of artemisinin derivatives in the presence of hemin, Biochem. Pharmacol., 1997, 53, pp. 5-10.
70. Schmid, G. & Hofheinz, W. Total Synthesis of Qinghaosu, J. Amer. Chem. Soc., 1983, 105, pp. 624-625.
71. Xu, X. X., Zhu, J., Huang, D. Z. & Zhou, W. S. Total Synthesis of Arteannuin and Deoxyarteannuin, Tetrahedron, 1986, 42, pp. 819-828.
72. Liu, H. J., Yeh, W. L. & Chew, S. Y. A Total Synthesis of the Antimalarial Natural Product (+)-Qinghaosu, Tetrahedron Lett., 1993, 34, pp. 4435-4438.
73. Ravindranathan, T., Kumar, M. A., Menon, R. B. & Hiremath, S. V. Stereoselective synthesis of artemisinin, Tetrahedron Lett., 1990, 31, pp. 755-758.
74. Xu, X.-X., Zhu, J., Huang, D.-A. & Zhou, W.-S. The Stereocontrolled Synthesis of Arteannuin and Deoxyarteannuin from Arteannuic Acid, Acta Chem. Sinica, 1983, 41, pp. 574.
75. Ye, B. & Wu, Y. L. An Efficient Synthesis of Qinghaosu and Deoxoqinghaosu from Arteannuic Acid, J. Chem. Soc. Chem. Comm., 1990, pp. 726.
76. Lansbury, P. T. & Novak, D. M. An efficient partial synthesis of (+)-artemisinin and (+)-deoxoartemisinin. Tetrahedron Lett., 1992, 33, pp. 1029-32.
77. Avery, M. A., Chong, W. K. M. & Jennings-White, C. The Total Synthesis of (+)-Artemisinin and (+)-9-Desmethylartemisinin, Tetrahedron Lett., 1987, 28, pp. 4629-12.
78. Acton, N., Karle, J. M. & Miller, R. E. Synthesis and Antimalarial Activity of some 9-Substituted Artemisinin Derivatives, J. Med. Chem., 1993, 36, pp. 2552-7.
79. Avery, M. A., Mehrotra, S., Johnson, T., Bonk J. D., Vroman, J. A. & Miller, R. Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 5. Analogs of 10-Deoxoartemisinin Substituted at C-3 and C-9, J. Med. Chem., 1996, 39, pp. 4149-4155.
80. Hill, R. K. , in: Morrison, J. D. (Ed.) Stereodifferentiating addition reactions. Part B, 1984, pp. 521-526 (San Diego, Academic Press).
81. Avery, M. A., Bonk, J. D., Chong, W. K. M., Mehrotra, S., Miller, R., Milhous, W., Goins, D. K, Venkatesan, S., Wyandt, C., Khan, I. & Avery, B. A. 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-desmethylartemisinins., J. Med. Chem., 1995, 38, pp. 5038-5044.
82. Torok, D. S. & Ziffer, H. Synthesis and Reactions of 11-Azaartemisinin and Derivatives, Tetrahedron Lett., 1995, 36, pp. 829-832.
83. Mekonnen, B. & Ziffer, H. A new route to N-substituted 11-azaartemisinins, Tetrahedron Lett., 1997, 38, pp. 731-734.
84. Brossi, A., Venugopalan, B., Gerpe, L. D. et al. Arteether, a New Antimalarial Drug: Synthesis and Antimalarial Properties, J. Med. Chem., 1988, 31, pp. 645-650.
85. Lin, A. J., Lee, M. & Klayman, D. L. Antimalarial Activity of New Water Soluble Dihydroartemisinin Derivatives. 2. Stereospecificity of the Ether Side Chain, J. Med. Chem., 1989, 32, pp. 1249-1252.
86. Lin, A. J., Li, L., Klayman, D. L., George, G. F. & Flippen-Anderson, J. L. Antimalarial Activity of New Water-Soluble Dihydroartemisinin Derivatives. 3. Aromatic Amine Analogues, J. Med. Chem., 1990, 33, pp. 2610-4.
87. Lin, A., Li, L., Andersen, S. L. & Klayman, D. L. Antimalarial activity of new dihydroartemisinin derivatives. 5. Sugar analogues, J. Med. Chem., 1992, 35, pp. 1639-42.
88. Lin, A. J. & Miller, R. Antimalarial Activity of New Dihydroartemisinin Derivatives. 6. alpha-Alkylbenzylic Ethers., J. Med. Chem., 1995, 38, pp. 764-770.
89. Lin, A. J., Klayman, D. L. & Milhous, W. K. Antimalarial Activity of New Water-soluble Dihydroartemisinin Derivatives, J. Med. Chem., 1987, 30, pp. 2147-2150.
90. Yu, P.-L., Chen, I.-H., Lee, Y. & Chi, J.-Y. Synthesis of artemisinin analogs containing halogen, nitrogen or sulfur atoms, Yao Hsueh T'ung Pao, 1980, 15, pp. 44.
91. Pu, Y. M., Torok, D. S., Ziffer, H., Pan, X.-Q. & Meshnick, S. R. Synthesis and Antimalarial Activity of Several Fluorinated Artemisinin Derivatives., J. Med. Chem., 1995, 38, pp. 4120-4124.
92. Jung, M., Freitas, A. C. C., McChesney, J. D. & ElSohly, H. N. A practical and general synthesis of (+)-carboxyalkyldeoxoartemisinins, Heterocycles, 1994, 39, pp. 23-9.
93. Woo, S. H., Parker, M. H., Ploypradith, P., Northrop, J. & Posner, G. H. Direct conversion of pyranose anomeric OH in the artemisinin family of antimalarial trioxanes, Tetrahedron Lett., 1998, 39, pp. 1533-1536.
94. Ramu, K. & Baker, J. K. Synthesis, Characterization, and Antimalarial Activity of the Glucuronides of the Hydroxylated Metabolites of Arteether, J. Med. Chem., 1995, 38, pp. 1911-21.
95. Avery, M. A., Gao, F., Chong, W. K., Mehrotra, S. & Milhous, W. K. Structure-Activity Relationships of the Antimalarial Agent Artemisinin. I. Synthesis and Comparative Molecular Field Analysis of C-9 Analogs of Artemisinin and 10-Deoxoartemisinin, J. Med. Chem., 1993, 36, pp. 4264-4275.
96. Avery, M. A., Gao, F., Chong, W. K. M., Hendrickson, T. F., Inman, W. D. & Crews, P. Synthesis, Conformational Analysis, and Antimalarial Activity of Tricyclic Analogs of Artemisinin, Tetrahedron, 1994, 50, pp. 957-972.
97. Avery, M. A., Chong, W. K. M. & Bupp, J. E. Tricyclic Analogs of Artemisinin: Synthesis and Antimalarial Activity of (+)-4.5-Secoartemisinin and (-)-5-nor-4,5-Secoartemisinin, J. Chem. Soc., Chem. Comm., 1990, 21, pp. 1487-1489.
98. Avery, M. A., Chong, W. K. M. & Detre, G. Synthesis of (+)-8a,9-Secoartemisinin and Related Analogs, Tetrahedron Lett., 1990, 31, pp. 1799-1802.
99. Posner, G. H., Oh, C. H., Gerena, L. & Milhous, W. K. Extraordinarily Potent Antimalarial Compounds: New, Structurally Simple, Easily Synthesized, Tricyclic 1,2,4-Trioxanes, J. Med. Chem., 1992, 35, pp. 2459-2467.
100. Posner, G. H., McGarvey, D. J., Oh, C. H., Kumar, N., Meshnick, S. R. & Asawamahasadka, W. Structure-Activity Relationships of Lactone Ring-Opened Analogs of the Antimalarial 1,2,4-Trioxane Artemisinin., J. Med. Chem., 1995, 38, pp. 607-12.
101. Posner, G. H., Wang, D., Gonzalez, L., Tao, X., Cumming, J. N., Klinedinst, D. & Shapiro, T. A. Mechanism-based Design of Simple, Symmetrical, Easily Prepared, Potent Antimalarial Endoperoxides, Tetrahedron Lett., 1996, 37, pp. 815-818.
102. Posner, G. H., Oh, C. H. & Milhous, W. K. Olefin Oxidative Cleavage and Dioxetane Formation Using Triethylsilyl Hydrotrioxide: Applications to Preparation of Potent Antimalarial 1,2,4-Trioxanes, Tetrahedron Lett., 1991, 32, pp. 4235-8.
103. Jefford, C. W., Velarde, J. A., Bernardinelli, G., Bray, D. H., Warhurst, D. C. & Milhous, W. K. Synthesis, Structure, and Antimalarial Activity of Tricyclic 1,2,4-Trioxanes Related to Artemisinin., Helv. Chim. Acta., 1993, 76, pp. 2775-88.
104. Jefford, C. W., McGoran, E., Boukouvalas, J., Richardson, G., Robinson, B. L. & Peters, W. Synthesis of new 1,2,4-trioxanes and their antimalarial activity, Helv. Chim. Acta., 1988, 71, pp. 1805-1812.
105. Jefford, C. W., Bernardinelli, G. & McGoran, E. C. The Reaction of 4-Hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dieneone with Acetaldehyde. Formation of the Bis(peroxyacetal)., Helv. Chim. Acta, 1984, 67, pp. 1952-56.
106. Pu, Y. M., Yeh, H. & Ziffer, H. An unusual acid-catalyzed rearrangement of 1,2,4-trioxanes, Heterocycles, 1993, 36, pp. 2099-107.
107. Vennerstrom, J. L., Fu, H.-N. Ellis, W. Y., Ager, A. L., Jr., Wood, J. K., Anderson, S. L., Gerena, L. & Milhous, W. K. Dispiro-1,2,4,5-Tetraoxanes: A New Class of Antimalarial Peroxides, J. Med. Chem., 1992, 35, pp. 3023-3027.
108. Casteel, D. A., Eun, J. K., Gerena, L. & Milhous, W. Synthesis and antimalarial evaluation of 2,3,5-trioxabicyclo[2.2.2]octanes, models for the putative pharmacophore of qinghaosu (artemisinin), Bioorg. Med. Chem. Lett., 1992, 2, pp. 623-6.
109. Casteel, D. A., Peri, S. P. & Gerena, L. Synthesis and antimalarial evaluation of 2,3,5-trioxabicyclo[2.2.3]nonane, a model for the putative pharmacophore of artemisinin, Bioorg. Med. Chem. Lett., 1993, 3, pp. 1707-10.
110. Provot, O., Hamzaoui, M., Huy, D. N., Mayrargue, J. & Moskowitz, H. Diastereoselective synthesis of a simplified analog of, Heterocycl. Commun., 1996, 2, pp. 267-271.
111. Hamzaoui, M., Provot, O., Gregoire, F., Riche, C., Chiaroni, A., Gay, F., Moskowitz, H. & Mayargue, J. Enantioselective synthesis of functionalized 2-oxocyclohexane carbonitrites. Access to a trioxane analog of artemisinin, Tetrahedron: Asymmetry, 1997, 8, pp. 2085-2088.
112. Avery, M. A., Fan, P.-C., Karle, J. M., Bonk, J. D., Miller, R. & Goins, D. K. Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 3. Replacement of the Nonperoxidic Trioxane Oxygen Atom of Artemisinin by Carbon: Total Synthesis of (+)-Carbaartemisinin and Related Structures, J. Med. Chem., 1996, 39, pp. 1885-1897.
113. Avery, M. A., Fan, P.-C., Karle, J., Miller, B. & Goins, K. Replacement of the Nonperoxidic Trioxane Oxygen Atom of Artemisinin by Carbon: Total Synthesis of (+)-Carbaartemisinin and Related Structures, Tetrahedron Lett., 1995, 36, pp. 3965-3968.
114. Vroman, J. A., Mehrotra, S., Avery, M. A. & Miller, R. (195) Three Synthetic Routes to 9-Butyl Artemisinin, Paper presented at the 22nd Anual MALTO Medicinal Chemistry-Pharmacognosy Meeting, Xavier University, New Orleans, LA, May 21-23, 1995.
115. Vroman, J. A., Avery, M. A., Mehrotra, S., Bonk, J. D., Srivastava, R., Srivastava, A., Ager, A. L. Jr. & Miller, R. Continuing Studies on the Synthesis and Activity of Some 9-Substituted-10-Deoxo-Artemisinin Analogs., Paper presented at the 23rd Annual MALTO Medicinal Chemistry-Pharmacognosy Meeting., 1996, University of Mississippi, University, MS 38677.
116. Bustos, D. A., Jung, M., ElSohly, H. N. & McChesney, J. D. Stereospecific Synthesis of (+)-Homodecxoartemisinin., Heterocycles, 1989, 29, pp. 2273-7.
117. Haynes, R. K., Vonwiller, S. C. & Wang, H.-J. The preparation of D-ring-contracted analogs of qinghaosu (Artemisinin) from qinghao (artemisinic) acid and their in vitro activity against Plasmodium falciparum, Tetrahedron Lett., 1995, 36, pp. 4641-2.
118. Posner, G. H., Tao, X. & Cumming, J. N. Antimalarially Potent, Easily Prepared, Fluorinated Endoperoxides, Tetrahedron Lett., 1996, 37, pp. 7225-7228.
119. Haraldson, C. A., Karle, J. M., Freeman, S. G., Duvadie, R. K. & Avery, M. A. The synthesis of 8,8-disubstituted tricyclic analogs of artemisinin, Bioorg. Med. Chem. Lett., 1997, 7, pp. 2357-2362.
120. Huber, S. N. & Mischne, M. P. A simple and efficient approach to the synthesis of a 1,2,4-trioxane related to Artemisinin, Nat. Prod. Lett., 1995, 7, pp. 43-46.
121. Kepler, J. A., Philip, A., Lee., Y. W., Morey, M. C. & Carroll, F. I. 1,2,4-Trioxanes as potential antimalarial agents, J. Med. Chem., 1988, 31, pp. 713-6.
122. Posner, G. H., Gonzalez, L., Cumming, J. N., Klinedinst, D. & Shapiro, T. A. Synthesis and Antimalarial Activity of Heteroatom-containing Bicyclic Endoperoxides, Tetrahedron, 1997, 53, pp. 37-50.
123. de Almeida Barbosa, L.-C., Cutler, D., Mann, J., Crabbe, M. J., Kirby, G. C. & Warhurst, D. C. The design, synthesis and biological evaluation of stable ozonides with antimalarial activity, J Chem. Soc., Perkin Trans. 1, 1996, pp. 1101-1105.
124. Ye, B. & Wu, Y.-L. Syntheses of carba-analogues of qinghaosu, Tetrahedron, 1989, 45, pp. 7287-7290.
125. Ye, B., Wu, Y. L., Li, G. F. & Jiao, X. Q. Antimalarial Activity of Deoxoqinghaosu, Yaoxue Xuebao, 1991, 26, pp. 228-230.
126. Wu, J. & Ji, R. A Quantitative Hansch Structure-Activity Study on Artemisinin Derivatives, Acta Pharmacologica Sinica, 1982, 3, pp. 55-60.
127. Tang, Y., Jiang, H. L., Chen, K. X. & Ji, R. Y. QSAR study of artemisinin (Qinghaosu) derivatives using neural network method. Indian Journal of Chemistry, 1996, 35B, pp. 325-332.
128. Woolfrey, J. R., Avery, M. A. & Doweyko, A. M. Comparison of 3D Quantitative Structure-Activity Relationship Methods: Analysis of the in vitro Antimalarial Activity of 154 Artemisinin Analogues by Hypothethical Active-site Lattice and Comparative Molecular Field Analysis. Journal of Computer-Aided Molecular Design, 1998, 12, pp. 165-181.
129. Acton, N. & Klayman, D. L. Conversion of Artemisinin to Isoartemisitene and to 9-epi-artemisinin, Planta Med., 1987, pp. 266-268.
130. Gu, H. M., Lu, B. F. & Qu, Z.X. Activities of 25 Derivatives of Artemisinin against Chloroquine-resistant Plasmodium berghei, Acta pharmacol. Sinica, 1980, 1, 48-50.
131. Avery, M. A.; Alvim-Gaston, M.; Woolfrey, J. R. Synthesis and Structure-Activity Relationships of Peroxidic Antimalarials Based on Artemisinin, Advances in Medicinal Chemistry, JAI Press Inc., 1999, Vol. 4, pp. 125-217, In Press.
132. Avery, M. A.; McLean, G.; Edwards, G.; Ager, A. Structure-Activity Relationships of Peroxide-Based Artemisinin Antimalarials, American Chemical Society Symposium on Biologically Active Natural Products: Potential in Agriculture, CRC Press, 1999, In Press.
133. Gund, T. M., Shukla, K. L., Meshnick, S. R Molecular Modeling Studies of the Artemisinin-Hemin Interaction: Docking between the Antimalarial Agent and its Putative Receptor, J. Mol. Graphics, 1995, 13, pp. 215-222.