Trioxaquines: Hybrid molecules for the treatment of malaria

Drug News and Perspectives

Volumn 23, Issue 10, 2010, Pages 632-646

  Chauhan, Shikha S ^a   Sharma, Moni ^a   Chauhan, Prem M S ^a  

^a CENTRAL DRUG RESEARCH INSTITUTE   (India)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOQUINOLINE DERIVATIVE; ANTIMALARIAL AGENT; ARTEETHER; ARTEMETHER; ARTEMISININ; ARTEMISININ DERIVATIVE; ARTESUNATE; CHLOROQUINE; DU 1102; DU 1106; DU 1108; DU 1112; DU 1114; DU 1301; DU 1302; DU 1402; DU 2302; ENDOPEROXIDE; PA 1103; PA 1110; PA 1120; PA 1252; PA 1259; PA 1302; PRIMAQUINE; TRIOXAQUINE DERIVATIVE; UNCLASSIFIED DRUG; 4 AMINOQUINOLINE; 4-AMINOQUINOLINE; AMINOQUINOLINE DERIVATIVE;

ALKYLATION; ANTIMALARIAL ACTIVITY; COVALENT BOND; DRUG DESIGN; DRUG MECHANISM; DRUG SELECTIVITY; DRUG SYNTHESIS; ERYTHROCYTE; HYBRID; MALARIA; MULTIDRUG RESISTANCE; NONHUMAN; PARASITE TRANSMISSION; PLASMODIUM FALCIPARUM; PLASMODIUM YOELII; REVIEW; SCHISTOSOMA MANSONI; STRUCTURE ACTIVITY RELATION; SYMPTOM; ANIMAL; CHEMISTRY; DISEASE TRANSMISSION; DRUG RESISTANCE; HUMAN; PARASITOLOGY;

AMINOQUINOLINES; ANIMALS; ANTIMALARIALS; ARTEMISININS; DRUG DESIGN; DRUG RESISTANCE; ERYTHROCYTES; HUMANS; MALARIA;

EID: 79954426980     PISSN: 02140934     EISSN: None     Source Type: Journal    
DOI: 10.1358/dnp.2010.23.10.1468390     Document Type: Review

References (118)

1. Chauhan, P.M.S., Srivastava, S.K. Present trends and future strategy in chemotherapy of malaria. Curr Med Chem 2001, 8(13): 1535-42. (Pubitemid 33076801)
2. Kumar, A., Katiyar, S.B., Agarwal, A., Chauhan, P.M.S. Perspective in antimalarial chemotherapy. Curr Med Chem 2003, 10(13): 1137-50. (Pubitemid 36758227)
3. Kumar, A., Katiyar, S.B., Agarwal, A., Chauhan, P.M.S. Current trends in antimalarial chemotherapy. Drugs Fut 2003, 28(3): 243-55. (Pubitemid 36644201)
4. Snow, R.W., Guerra, C.A., Noor, A.M., Myint, H.Y., Hay, S.I. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 2005, 434(7030): 214-7. (Pubitemid 40388051)
5. Sachs, J., Malaney, P. The economic and social burden of malaria. Nature 2002, 415(6872): 680-5. (Pubitemid 34136401)
6. Turner, R.B., Woodward, R.B. The chemistry of the cinchona alkaloids. In: The Alkaloids. Vol. 3. R.H.F. Manske (Ed.). Academic Press: New York 1953,
7. Uskokovic, M.R., Grethe, G. The cinchona alkaloids. In: The Alkaloids. Vol. 14. R.H.F. Manske (Ed.). Academic Press: New York 1973, 181.
8. Grethe, G., Uskokovic, M.R. In: The Chemistry of Heterocyclic Compounds. Vol. 23. J.E. Sexton (Ed.). Wiley-Interscience: New York 1983, 279.
9. Ridley, R.G. Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 2002, 415(6872): 686-93. (Pubitemid 34136402)
10. Jeyadevan, J.P., Bray, P.G., Chadwick, J. et al. Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10beta-(2-hydroxyethyl) deoxoartemisinin. J Med Chem 2004, 47(5): 1290-8. (Pubitemid 38229131)
11. O'Neill, P.M., Searle, N.L., Kan, K.W. et al. Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether. J Med Chem 1999, 42(26): 5487-93. (Pubitemid 30036783)
12. Posner, G.H., Chang, W., Hess, L. et al. Malaria-infected mice are cured by oral administration of new artemisinin derivatives. J Med Chem 2008, 51(4): 1035-42. (Pubitemid 351304711)
13. Chadwick, J., Jones, M., Mercer, A.E., Stocks, P.A., Ward, S.A., Park, B.K., O'Neill, P.M. Design, synthesis and antimalarial/anticancer evaluation of spermidine linked artemisinin conjugates designed to exploit polyamine transporters in Plasmodium falciparum and HL-60 cancer cell lines. Bioorg Med Chem 2010, 18(7): 2586-97.
14. O'Neill, P.M., Posner, G.H. A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem 2004, 47(12): 2945-64. (Pubitemid 38702690)
15. Ittarat, W., Pickard, A.L., Rattanasinganchan, P. et al. Recrudescence in artesunate-treated patients with falciparum malaria is dependent on parasite burden not on parasite factors. Am J Trop Med Hyg 2003, 68(2): 147-52. (Pubitemid 38240537)
16. Olliaro, P. Drug resistance hampers our capacity to roll back malaria. Clin Infect Dis 2005, 41(Suppl. 4): S247-57.
17. Posner, G.H., Jeon, H.B., Ploypradith, P., Paik, I.H., Borstnik, K., Xie, S., Shapiro, T.A. Orally active, water-soluble antimalarial 3-aryltrioxanes: short synthesis and preclinical efficacy testing in rodents. J Med Chem 2002, 45(18): 3824-8. (Pubitemid 35024287)
18. O'Neill, P.M., Mukhtar, A., Ward, S.A., Bickley, J.F., Davies, J., Bachi, M.D., Stocks, P.A. Application of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore. Org Lett 2004, 6(18): 3035-8.
19. Singh, C., Kanchan, R., Sharma, U., Puri, S.K. New adamantane-based spiro 1,2,4-trioxanes orally effective against rodent and simian malaria. J Med Chem 2007, 50(3): 521-7.
20. Sabbani, S., Stocks, P.A., Ellis, G.L., Davies, J., Hedenstrom, E., Ward, S.A., O'Neill, P.M. Piperidine dispiro-1,2,4-trioxane analogues. Bioorg Med Chem Lett 2008, 18(21): 5804-8.
21. Griesbeck, A.G., Neudorfl, J., Horauf, A., Specht, S., Raabe, A. Antimalarial peroxide dyads from natural artemisinin and hydroxyalkylated 1,2,4-trioxanes. J Med Chem 2009, 52(10): 3420-3.
22. Singh, C., Verma, V.P., Naikade, N.K., Singh, A.S., Hassam, M., Puri, S.K. 6-(4′-Aryloxy-phenyl) vinyl-1,2,4-trioxanes: a new series of orally active peroxides effective against multidrug- resistant Plasmodiumyoelii in Swiss mice. Bioorg Med Chem Lett 2010, 20(15): 4459-63.
23. Robert, A., Dechy-Cabaret, O., Cazelles, J., Meunier, B. From mechanistic studies on artemisinin derivatives to new modular anti-malarial drugs. Acc Chem Res 2002, 35(3): 167-74.
24. Cosledan, F., Fraisse, L., Pellet, A. et al. Selection of a trioxaquine as an antimalarial drug candidate. Proc Natl Acad Sci U S A 2008, 105(45): 17579-84.
25. Ojima, I. Modern molecular approaches to drug design and discovery. Acc Chem Res 2008, 41(1): 2-3.
26. Burger, R.M. Cleavage of Nucleic Acids by Bleomycin. Chem Rev 1998, 98(3): 1153-70.
27. Sausville, E.A., Stein, R.W., Peisach, J., Horwitz, S.B. Properties and products of the degradation of DNA by bleomycin and iron(II). Biochemistry 1978, 17(14): 2746-54. (Pubitemid 8385273)
28. Zou, Y., Fahmi, N.E., Vialas, C., Miller, G.M., Hecht, S.M. Total synthesis of deamido bleomycin a(2), the major catabolite of the antitumor agent bleomycin. J Am Chem Soc 2002, 124(32): 9476-88.
29. Peters, W., Robinson, B.L. The chemotherapy of rodent malaria XXXV. Further studies on the retardation of drug resistance by the use of a triple combination of mefloquine, pyrimethamine and sulfadoxine in mice infected with P. berghei and 'P. berghei NS'. Ann Trop Med Parasitol 1984, 78(5): 459-66.
30. Grellepois, F., Grellier, P., Bonnet-Delpon, D., Begue, J.P. Design, synthesis and antimalarial activity of trifluoromethylartemisinin-mefloquine dual molecules. Chembiochem 2005, 6(4): 648-52. (Pubitemid 40873765)
31. Nosten, F., Brasseur, P. Combination therapy for malaria: the way forward? Drugs 2002, 62(9): 1315-29.
32. Dasgupta, T., Chitnumsub, P., Kamchonwongpaisan, S. et al. Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria. ACS Chem Biol 2009, 4(1): 29-40.
33. Willcox, M., Bodeker, G., Rosoanaivo, P. Traditional Medicinal Plants and Malaria. Vol. 4. CRC Press: Boca Raton 2004.
34. Gelb, M.H., Van Voorhis, W.C., Buckner, F.S. et al. Protein farnesyl and N-myristoyl transferases: piggy-back medicinal chemistry targets for the development of antitrypanosomatid and antimalarial therapeutics. Mol Biochem Parasitol 2003, 126(2): 155-63. (Pubitemid 36255614)
35. Martin, S.K., Oduola, A.M., Milhous, W.K. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 1987, 235(4791): 899-901. (Pubitemid 17019130)
36. Zhao, R., al-Said, N.H., Sternbach, D.L., Lown, J.W. Camptothecin and minor-groove binder hybrid molecules: synthesis, inhibition of topoisomerase I, and anticancer cytotoxicity in vitro. J Med Chem 1997, 40(2): 216-25.
37. Wang, J.J., Shen, Y.K., Hu, W.P., Hsieh, M.C., Lin, F.L., Hsu, M.K., Hsu, M.H. Design, synthesis, and biological evaluation of pyrrolo[2,1-c][1,4] benzodiazepine and indole conjugates as anticancer agents. J Med Chem 2006, 49(4): 1442-9.
38. Pizzirani, D., Roberti, M., Grimaudo, S., Di Cristina, A., Pipitone, R.M., Tolomeo, M., Recanatini, M. Identification of biphenyl-based hybrid molecules able to decrease the intracellular level of Bcl-2 protein in Bcl-2 overexpressing leukemia cells. J Med Chem 2009, 52(21): 6936-40.
39. Rizzo, S., Riviere, C., Piazzi, L. et al. Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, beta amyloid aggregation, and abeta neurotoxicity. J Med Chem 2008, 51(10): 2883-6. (Pubitemid 351706016)
40. Meunier, B. Hybrid molecules with a dual mode of action: dream or reality? Acc Chem Res 2008, 41(1): 69-77.
41. Muregi, F.W., Ishih, A. Next-generation antimalarial drugs: hybrid molecules as a new strategy in drug design. Drug Dev Res 2009, 71(1): 20-32.
42. Chen, C., Li, X., Neumann, C.S., Lo, M.M., Schreiber, S.L. Convergent diversity-oriented synthesis of small-molecule hybrids. Angew Chem Int Ed Engl 2005, 44(15): 2249-52. (Pubitemid 40560895)
43. Chyan, C.L., Huang, P.C., Lin, T.H., Huang, J.W., Lin, S.S., Huang, H.B., Chen, Y.C. Purification, crystallization and preliminary crystallographic studies of a calmodulin-OLFp hybrid molecule. Acta Crystallogr Sect F Struct Biol Cryst Commun 2005, 61(Pt 8): 785-7. (Pubitemid 44210805)
44. Singh, P., Paul, K., Holzer, W. Synthesis of pyrazole-based hybrid molecules: search for potent multidrug resistance modulators. Bioorg Med Chem 2006, 14(14): 5061-71. (Pubitemid 43767121)
45. Dechy-Cabaret, O., Benoit-Vical, F., Robert, A., Meunier, B. Preparation and antimalarial activities of "trioxaquines", new modular molecules with a trioxane skeleton linked to a 4-aminoquinoline. Chembiochem 2000, 1(4): 281-3.
46. Sharma, M., Chaturvedi, V., Manju, Y.K., Bhatnagar, S., Srivastava, K., Puri, S.K., Chauhan, P.M.S. Substituted quinolinyl chalcones and quinolinyl pyrimidines as a new class of anti-infective agents. Eur J Med Chem 2009, 44(5): 2081-91.
47. Sunduru, N., Sharma, M., Srivastava, K., Rajakumar, S., Puri, S.K., Saxena, J.K., Chauhan, P.M.S. Synthesis of oxalamide and triazine derivatives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial activity. Bioorg Med Chem 2009, 17(17): 6451-62.
48. Kumar, A., Srivastava, K., Raja Kumar, S., Puri, S.K., Chauhan, P.M.S. Synthesis and bioevaluation of hybrid 4-aminoquinoline triazines as a new class of antimalarial agents. Bioorg Med Chem Lett 2008, 18(24): 6530-3.
49. Morphy, R., Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem 2005, 48(21): 6523-43. (Pubitemid 41504710)
50. Fikkert, V., Van Maele, B., Vercammen, J. et al. Development of resistance against diketo derivatives of human immunodeficiency virus type 1 by progressive accumulation of integrase mutations. J Virol 2003, 77(21): 11459-70. (Pubitemid 37271644)
51. Kelly, J.X., Smilkstein, M.J., Brun, R. et al. Discovery of dual function acridones as a new antimalarial chemotype. Nature 2009, 459(7244): 270-3.
52. Dechy-Cabaret, O., Benoit-Vical, F., Loup, C. et al. Synthesis and antimalarial activity of trioxaquine derivatives. Chemistry 2004, 10(7): 1625-36.
53. Davioud-Charvet, E., Delarue, S., Biot, C. et al. A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline. J Med Chem 2001, 44(24): 4268-76. (Pubitemid 33095332)
54. Chiyanzu, I., Clarkson, C., Smith, P.J., Lehman, J., Gut, J., Rosenthal, P.J., Chibale, K. Design, synthesis and anti-plasmodial evaluation in vitro of new 4-aminoquinoline isatin derivatives. Bioorg Med Chem 2005, 13(9): 3249-61. (Pubitemid 40462126)
55. Burgess, S.J., Selzer, A., Kelly, J.X., Smilkstein, M.J., Riscoe, M.K., Peyton, D.H. A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum. J Med Chem 2006, 49(18): 5623-5. (Pubitemid 44373193)
56. Gupta, L., Srivastava, K., Singh, S., Puri, S.K., Chauhan, P.M.S. Synthesis of 2-[3-(7-chloroquinolin- 4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-beta-carbolines as a new class of antimalarial agents. Bioorg Med Chem Lett 2008, 18(11): 3306-9.
57. Bellot, F., Cosledan, F., Vendier, L., Brocard, J., Meunier, B., Robert, A. Trioxaferroquines as new hybrid antimalarial drugs. J Med Chem 2010, 53(10): 4103-9.
58. Opsenica, I., Opsenica, D., Lanteri, C.A., Anova, L., Milhous, W.K., Smith, K.S., Solaja, B.A. New chimeric antimalarials with 4-aminoquinoline moiety linked to a tetraoxane skeleton. J Med Chem 2008, 51(19): 6216-9.
59. Gemma, S., Campiani, G., Butini, S. et al. Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials. J Med Chem 2009, 52(2): 502-13.
60. Walsh, J.J., Coughlan, D., Heneghan, N., Gaynor, C., Bell, A. A novel artemisinin-quinine hybrid with potent antimalarial activity. Bioorg Med Chem Lett 2007, 17(13): 3599-602. (Pubitemid 46898817)
61. Araujo, N.C., Barton, V., Jones, M. et al. Semi-synthetic and synthetic 1,2,4-trioxaquines and 1,2,4-trioxolaquines: synthesis, preliminary SAR and comparison with acridine endoperoxide conjugates. Bioorg Med Chem Lett 2009, 19(7): 2038-43.
62. Capela, R., Oliveira, R., Goncalves, L.M. et al. Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition. Bioorg Med Chem Lett 2009, 19(12): 3229-32.
63. Schlitzer, M. Malaria chemotherapeutics part I: History of antimalarial drug development, currently used therapeutics, and drugs in clinical development. Chem Med Chem 2007, 2(7): 944-86.
64. Frosch, T., Schmitt, M., Bringmann, G., Kiefer, W., Popp, J. Structural analysis of the antimalaria active agent chloroquine under physiological conditions. J Phys Chem B 2007, 111(7): 1815-22. (Pubitemid 46384275)
65. Wellems, T.E. Plasmodium chloroquine resistance and the search for a replacement antimalarial drug. Science 2002, 298(5591): 124-6.
66. Ersmark, K., Samuelsson, B., Hallberg, A. Plasmepsins as potential targets for new antimalarial therapy. Med Res Rev 2006, 26(5): 626-66. (Pubitemid 44230415)
67. Omodeo-Sale, F., Cortelezzi, L., Basilico, N., Casagrande, M., Sparatore, A., Taramelli, D. Novel antimalarial aminoquinolines: heme binding and effects on normal or Plasmodium falciparum-parasitized human erythrocytes. Antimicrob Agents Chemother 2009, 53(10): 4339-44.
68. Bray, P.G., Martin, R.E., Tilley, L., Ward, S.A., Kirk, K., Fidock, D.A. Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. Mol Microbiol 2005, 56(2): 323-33. (Pubitemid 40516774)
69. Sanchez, C.P., McLean, J.E., Rohrbach, P., Fidock, D.A., Stein, W.D., Lanzer, M. Evidence for a pfcrt-associated chloroquine efflux system in the human malarial parasite Plasmodium falciparum. Biochemistry 2005, 44(29): 9862-70. (Pubitemid 41033452)
70. Sidhu, A.B., Verdier-Pinard, D., Fidock, D.A. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 2002, 298(5591): 210-3.
71. Meshnick, S.R., Taylor, T.E., Kamchonwongpaisan, S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 1996, 60(2): 301-15. (Pubitemid 26171692)
72. Cumming, J.N., Ploypradith, P., Posner, G.H. Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Adv Pharmacol 1997, 37: 253-97.
73. Hien, T.T., White, N.J. Qinghaosu. Lancet 1993, 341(8845): 603-8.
74. Molyneux, M.E., Taylor, T.E., Wirima, J.J., Borgstein, A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med 1989, 71(265): 441-59. (Pubitemid 19161768)
75. Balint, G.A. Artemisinin and its derivatives: an important new class of antimalarial agents. Pharmacol Ther 2001, 90(2-3): 261-5.
76. Klayman, D.L. Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985, 228(4703): 1049-55.
77. Meshnick, S.R., Thomas, A., Ranz, A., Xu, C.M., Pan, H.Z. Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action. Mol Biochem Parasitol 1991, 49(2): 181-9.
78. Posner, G.H., Wang, D., Cumming, J.N., Oh, C.H., French, A.N., Bodley, A.L., Shapiro, T.A. 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(13): 2273-5.
79. Posner, G.H., Oh, C.H., Wang, D., Gerena, L., Milhous, W.K., Meshnick, S.R., Asawamahasadka, W. 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(9): 1256-8.
80. Robert, A., Meunier, B. Characterization of the first covalent adduct between artemisinin and a heme model. J Am Chem Soc 1997, 119(25): 5968-9.
81. Robert, A., Cazelles, J., Meunier, B. Characterization of the alkylation product of heme by the antimalarial drug artemisinin. Angew Chem Int Ed Engl 2001, 40(10): 1954-7. (Pubitemid 32525107)
82. Laurent, S.A., Robert, A., Meunier, B. C10-modified artemisinin derivatives: efficient heme-alkylating agents. Angew Chem Int Ed Engl 2005, 44(14): 2060-3; author reply 4-5.
83. Cazelles, J., Robert, A., Meunier, B. Alkylating capacity and reaction products of antimalarial trioxanes after activation by a heme model. J Org Chem 2002, 67(3): 609-19. (Pubitemid 34135656)
84. O'Neill, P.M., Barton, V.E., Ward, S.A. The molecular mechanism of action of artemisinin - the debate continues. Molecules 2010, 15(3): 1705-21.
85. Barradell, L.B., Fitton, A. Artesunate. A review of its pharmacology and therapeutic efficacy in the treatment of malaria. Drugs 1995, 50(4): 714-41.
86. Awad, M.I., Alkadru, A.M., Behrens, R.H., Baraka, O.Z., Eltayeb, I.B. Descriptive study on the efficacy and safety of artesunate suppository in combination with other antimalarials in the treatment of severe malaria in Sudan. Am J Trop Med Hyg 2003, 68(2): 153-8. (Pubitemid 38240538)
87. Posner, G.H., Jeon, H.B., Parker, M.H., Krasavin, M., Paik, I.H., Shapiro, T.A. Antimalarial simplified 3-aryltrioxanes: synthesis and preclinical efficacy/toxicity testing in rodents. J Med Chem 2001, 44(19): 3054-8. (Pubitemid 32862335)
88. Robert, A., Meunier, B. Is alkylation the main mechanism of action of the antimalarial drug artemisinin? Chem Soc Rev 1998, 27(4): 273-9.
89. Dondorp, A.M., Newton, P.N., Mayxay, M. et al. Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Trop Med Int Health 2004, 9(12): 1241-6. (Pubitemid 40037159)
90. Mutabingwa, T.K. Artemisinin-based combination therapies (ACTs): best hope for malaria treatment but inaccessible to the needy! Acta Trop 2005, 95(3): 305-15.
91. Hastings, I.M., Watkins, W.M., White, N.J. The evolution of drug-resistant malaria: the role of drug elimination half-life. Philos Trans R Soc Lond B Biol Sci 2002, 357(1420): 505-19. (Pubitemid 34489862)
92. Francis, S.E., Sullivan, D.J., Jr., Goldberg, D.E. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu Rev Microbiol 1997, 51: 97-123. (Pubitemid 27433044)
93. Pandey, A.V., Tekwani, B.L., Singh, R.L., Chauhan, V.S. Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite. J Biol Chem 1999, 274(27): 19383-8.
94. Mungthin, M., Bray, P.G., Ridley, R.G., Ward, S.A. Central role of hemoglobin degradation in mechanisms of action of 4-aminoquinolines, quinoline methanols, and phenanthrene methanols. Antimicrob Agents Chemother 1998, 42(11): 2973-7. (Pubitemid 28501235)
95. Avery, M.A., Alvim-Gaston, M., Rodrigues, C.R., Barreiro, E.J., Cohen, F.E., Sabnis, Y.A., Woolfrey, J.R. Structure-activity relationships of the antimalarial agent artemisinin. 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies. J Med Chem 2002, 45(2): 292-303.
96. Cumming, J.N., Wang, D., Park, S.B., Shapiro, T.A., Posner, G.H. Design, synthesis, derivatization, and structure-activity relationships of simplified, tricyclic, 1,2,4-trioxane alcohol analogues of the antimalarial artemisinin. J Med Chem 1998, 41(6): 952-64.
97. Robert, A., Meunier, B. Alkylating properties of antimalarial artemisinin derivatives and synthetic trioxanes when activated by a reduced heme model. Chem Eur J 1998, 4(7): 1287-96.
98. Egan, T.J., Marques, H.M. The role of haem in the activity of chloroquine and related antimalarial drugs. Coord Chem Rev 1999, 192: 493-517.
99. Basco, L.K., Dechy-Cabaret, O., Ndounga, M., Meche, F.S., Robert, A., Meunier, B. In vitro activities of DU-1102, a new trioxaquine derivative, against Plasmodium falciparum isolates. Antimicrob Agents Chemother 2001, 45(6): 1886-8.
100. De, D., Krogstad, F.M., Cogswell, F.B., Krogstad, D.J. Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro. Am J Trop Med Hyg 1996, 55(6): 579-83.
101. Ridley, R.G., Hofheinz, W., Matile, H. et al. 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum. Antimicrob Agents Chemother 1996, 40(8): 1846-54.
102. Vennerstrom, J.L., Dong, Y., Andersen, S.L. et al. Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes. J Med Chem 2000, 43(14): 2753-8.
103. Wongsrichanalai, C., Wimonwattrawatee, T., Sookto, P., Laoboonchai, A., Heppner, D.G., Kyle, D.E., Wernsdorfer, W.H. In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand. Bull World Health Organ 1999, 77(5): 392-8.
104. Loup, C., Lelievre, J., Benoit-Vical, F., Meunier, B. Trioxaquines and hemeartemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. Antimicrob Agents Chemother 2007, 51(10): 3768-70.
105. Pukrittayakamee, S., Chotivanich, K., Chantra, A., Clemens, R., Looareesuwan, S., White, N.J. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother 2004, 48(4): 1329-34.
106. von Seidlein, L., Milligan, P., Pinder, M. et al. Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial. Lancet 2000, 355(9201): 352-7.
107. Singh, C. Preparation of beta-hydroxyhydroperoxides by photooxygenation of allylic alcohols and their elaboration into 1,2,4-trioxanes. Tetrahedron Lett 1990, 31(47): 6901-2.
108. Singh, C., Gupta, N., Puri, S.K. Photo-oxygenation of geraniol: synthesis of a novel series of hydroxy-functionalized anti-malarial 1,2,4-trioxanes. Bioorg Med Chem Lett 2002, 12(15): 1913-6.
109. Singh, C., Gupta, N., Puri, S.K. Geraniol-derived 1,2,4-trioxanes with potent in-vivo antimalarial activity. Bioorg Med Chem Lett 2003, 13(20): 3447-50.
110. Singh, C., Malik, H., Puri, S.K. Synthesis and antimalarial activity of a new series of trioxaquines. Bioorg Med Chem 2004, 12(5): 1177-82.
111. Laurent, S.A., Loup, C., Mourgues, S., Robert, A., Meunier, B. Heme alkylation by artesunic acid and trioxaquine DU1301, two antimalarial trioxanes. Chembiochem 2005, 6(4): 653-8.
112. Bousejra-El Garah, F., Claparols, C., Benoit-Vical, F., Meunier, B., Robert, A. The antimalarial trioxaquine DU1301 alkylates heme in malaria-infected mice. Antimicrob Agents Chemother 2008, 52(8): 2966-9.
113. Egan, T.J., Hunter, R., Kaschula, C.H., Marques, H.M., Misplon, A., Walden, J. Structure-function relationships in amino-quinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity. J Med Chem 2000, 43(2): 283-91.
114. Ncokazi, K.K., Egan, T.J. A colorimetric high-throughput beta-hematin inhibition screening assay for use in the search for antimalarial compounds. Anal Biochem 2005, 338(2): 306-19.
115. Haynes, R.K., Monti, D., Taramelli, D., Basilico, N., Parapini, S., Olliaro, P. Artemisinin antimalarials do not inhibit hemozoin formation. Antimicrob Agents Chemother 2003, 47(3): 1175.
116. Olliaro, P.L., Haynes, R.K., Meunier, B., Yuthavong, Y. Possible modes of action of the artemisinin-type compounds. Trends Parasitol 2001, 17(3): 122-6.
117. Boissier, J., Cosledan, F., Robert, A., Meunier, B. In vitro activities of trioxaquines against Schistosoma mansoni. Antimicrob Agents Chemother 2009, 53(11): 4903-6.
118. Oliveira, M.F., Kycia, S.W., Gomez, A. et al. Structural and morphological characterization of hemozoin produced by Schistosoma mansoni and Rhodnius prolixus. FEBS Lett 2005, 579(27): 6010-6.