Antimalarial drugs and their useful therapeutic lives: Rational drug design lessons from pleiotropic action of quinolines and artemisinins

Current Drug Discovery Technologies

Volumn 7, Issue 4, 2010, Pages 280-316

  Mureg, Francis W ^a,b  

^a HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^b KENYA MEDICAL RESEARCH INSTITUTE   (Kenya)

Author keywords

Antimalarial resistance; Antimalarial targets; Antimalarials design; Malaria chemotherapy; Plasmodium falciparum; Useful therapeutic life

Indexed keywords

ALBITIAZOLIUM BROMIDE; AMODIAQUINE; ANTIMALARIAL AGENT; AQ 31; ARTEMETHER PLUS BENFLUMETOL; ARTEMISININ; ARTEMISONE; ARTEROLANE; ARTESUNATE; ARTESUNATE PLUS CHLORPROGUANIL PLUS DAPSONE; ARTESUNATE PLUS PYRONARIDINE; ATOVAQUONE; BISQUINOLINE DERIVATIVE; CHLORPROGUANIL PLUS DAPSONE; COARSUCAM; CYCLOGUANIL; DACART; DAPSONE; DIHYDROARTEMISININ PLUS PIPERAQUINE; DUOCOTEXCIN; EURARTESIM; FERROQUINE; FOLIC ACID ANTAGONIST; HYDROXYNAPHTHOQUINONE DERIVATIVE; MEFLOQUINE; NAPHTHOQUINONE; PROGUANIL; PYRAMAX; PYRIMETHAMINE; PYRIMETHAMINE PLUS SULFADOXINE; QUININE; QUINOLINE DERIVED ANTIINFECTIVE AGENT; RBX 1160; SULFADOXINE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTIMALARIAL ACTIVITY; ANTIMALARIAL DRUG RESISTANCE; ARTEMISIA ANNUA; ARTICLE; BIOINFORMATICS; COST EFFECTIVENESS ANALYSIS; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG EFFICACY; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENTIATION; DRUG SAFETY; DRUG SYNTHESIS; DRUG TARGETING; GENE MUTATION; GENE OVEREXPRESSION; HOST PARASITE INTERACTION; HUMAN; LEUKOCYTE; LIVER TOXICITY; MALARIA; MALARIA FALCIPARUM; MEMBRANE PERMEABILITY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PLEIOTROPY; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTIMALARIALS; ARTEMISININS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; DRUG RESISTANCE; HUMANS; MALARIA; PLASMODIUM FALCIPARUM; QUINOLONES; TIME FACTORS;

EID: 78650736083     PISSN: 15701638     EISSN: None     Source Type: Journal    
DOI: 10.2174/157016310793360693     Document Type: Article

References (451)

1. Weisman JL, Liou AP, Shelat AA, Cohen FE, Guy RK, DeRisi JL. Searching for new antimalarial therapeutics amongst known drugs. Chem Biol Drug Des 2006; 67: 409-16.
2. World Health Organization, 2010. Fact Sheet No. 94 on Malaria. http://www.who.int/mediacentre/factsheets/fs094/en/ (accessed June, 2010).
3. Schlitzer M. Malaria chemotherapeutics part I: History of antimalarial drug development, currently used therapeutics, and drugs in clinical development. ChemMedChem 2007; 2: 944-86.
4. White NJ. Plasmodium knowlesi: the fifth human malaria parasite. Clin Infect Dis 2008; 46: 172-3.
5. Van den Eede P, Van HN, Van Overmeir C, et al. Human Plasmo-dium knowlesi infections in young children in central Vietnam. Malar J 2009; 8: 249.
6. World Health Organization, 2009. World Malaria Report 2009. http://www.who.int/malaria/publications/atoz/9789241563901/en/i ndex.html (accessed June, 2010).
7. Sponer U, Prajakwong S, Wiedermann G, Kollaritsch H, Werns-dorfer G, Wernsdorfer WH. Pharmacodynamic interaction of doxy-cycline and artemisinin in Plasmodium falciparum. Antimicrob Agents Chemother 2002; 46: 262-4.
8. World Health Organization, 2006. WHO briefing on malaria treatment guidelines and artemisinin monotherapies. http://www.who.-int/malaria/ publications/atoz/meeting-briefing19april/en/index.htm l (accessed July, 2010).
9. Fidock DA. Drug discovery: Priming the antimalarial pipeline. Nature 2010; 465: 297-8.
10. Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009; 361: 455-67.
11. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 359: 2619-20.
12. Noedl H, Socheat D, Satimai W. Artemisinin-resistant malaria in Asia. N Engl J Med 2009; 361: 540-1.
13. Lim P, Alker AP, Khim N, et al. Pfmdrl copy number and artemi-nisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malar J 2009; 8: 11.
14. [14a] Medicines for Malaria Venture. Tackling resistance. http://www.mmv.org/research-development/tackling-resistance (accessed in July, 2010).
15. [14b] Medicines for malaria Venture. http://www.mmv.org/research- development/r-d-process (accesed July, 2010).
16. Ekland EH, Fidock DA. In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes. Int J Parasitol 2008; 38: 743-7.
17. Kaitin KI. Deconstructing the drug development process: the new face of innovation. Clin Pharmacol Ther 2010; 87: 356-61.
18. Gardner MJ, Tettelin H, Carucci DJ, et al. Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum. Science 1998; 282: 1126-32.
19. Guiguemde WA, Shelat AA, Bouck D, et al. Chemical genetics of Plasmodium falciparum. Nature; 465: 311-5.
20. Gamo FJ, Sanz LM, Vidal J, et al. Thousands of chemical starting points for antimalarial lead identification. Nature; 465: 305-10.
21. Fidock DA, Rosenthal PJ, Croft SL, Brun R, Nwaka S. Antimalar-ial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov 2004; 3: 509-20.
22. Talisuna AO, Bloland P, D'Alessandro U. History, dynamics, and public health importance of malaria parasite resistance. Clin Mi-crobiol Rev 2004; 17: 235-54.
23. Wellems TE, Plowe CV. Chloroquine-resistant malaria. J Infect Dis 2001; 184: 770-6.
24. Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol Ther 1998; 79: 55-87.
25. Meshnick SR, Dobson MJ. In: Antimalarial chemotherapy: Mechanisms of action, resistance and new directions in drug discovery; Rosenthal PJ, Ed. Human Press Inc.: New Jersey 2001; Vol. 2; pp. 15-24.
26. Cui L, Su XZ. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther 2009; 7: 999-1013.
27. Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 2002; 32: 1655-60.
28. Sanchez CP, Lanzer M. Changing ideas on chloroquine in Plasmo-dium falciparum. Curr Opin Infect Dis 2000; 13: 653-658.
29. Gregson A, Plowe CV. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 2005; 57: 117-45.
30. Olliaro P. Mode of action and mechanisms of resistance for antima-larial drugs. Pharmacol Ther 2001; 89: 207-19.
31. Famin O, Krugliak M, Ginsburg H. Kinetics of inhibition of glu-tathione-mediated degradation of ferriprotoporphyrin IX by antima-larial drugs. Biochem Pharmacol 1999; 58: 59-68.
32. Zhang J, Krugliak M, Ginsburg H. The fate of ferriprotorphyrin IX in malaria infected erythrocytes in conjunction with the mode of action of antimalarial drugs. Mol Biochem Parasitol 1999; 99: 12941.
33. Famin O, Ginsburg H. Differential effects of 4-aminoquinoline-containing antimalarial drugs on hemoglobin digestion in Plasmo-dium falciparum-infected erythrocytes. Biochem Pharmacol 2002; 63: 393-8.
34. Peel SA, Merritt SC, Handy J, Baric RS. Derivation of highly me-floquine-resistant lines from Plasmodium falciparum in vitro. Am J Trop Med Hyg 1993; 48: 385-97.
35. Coatney GR. Pitfalls in a discovery: the chronicle of chloroquine. Am J Trop Med Hyg 1963; 12: 121-8.
36. Vangapandu S, Sachdeva S, Jain M, et al. 8-quinolinamines and their pro prodrug conjugates as potent blood-schizontocidal antima-larial agents. Bioorg Med Chem 2003; 11: 4557-68.
37. Kouznetsov VV, Gomez-Barrio A. Recent developments in the design and synthesis of hybrid molecules based on aminoquinoline ring and their antiplasmodial evaluation. Eur J Med Chem 2009; 44: 3091-113.
38. Ruscoe JE, Tingle MD, O'Neill PM, Ward SA, Park BK. Effect of disposition of mannich antimalarial agents on their pharmacology and toxicology. Antimicrob Agents Chemother 1998; 42: 2410-6.
39. Olliaro P, Wells TN. The global portfolio of new antimalarial medicines under development. Clin Pharmacol Ther 2009; 85: 584-95.
40. O'Neill PM, Mukhtar A, Stocks PA, et al. Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials. J Med Chem 2003; 46: 4933-45.
41. GlaxoSmithKline, 2009. Our Responsibility: Corporate Responsibility Report 2008. http://www.gsk.com/ (accessed July, 2010).
42. Ramharter M, Kurth F, Schreier AC, et al. Fixed-dose pyro-naridine- artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. J Infect Dis 2008; 198: 911-9.
43. Tshefu AK, Gaye O, Kayentao K, et al. Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether- lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet 2010; 375: 1457-67.
44. Medicines for Malaria Venture. http://www.mmv.org/search/apach-esolr- search/pyramax (accessed in July, 2010).
45. Vennerstrom JL, Ellis WY, Ager AL, Jr, Andersen SL, Gerena L, Milhous WK. Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria. J Med Chem 1992; 35: 2129-34.
46. Bassat Q, Mulenga M, Tinto H, et al. Dihydroartemisinin-piperaquine and artemether-lumefantrine for treating uncomplicated malaria in African children: a randomised, non-inferiority trial. PLoS One 2009; 4: e7871.
47. Uhlemann AC, Wittlin S, Matile H, Bustamante LY, Krishna S. Mechanism of antimalarial action of the synthetic trioxolane RBX11160 (OZ277). Antimicrob Agents Chemother 2007; 51: 667-72.
48. Ranbaxy: Research and development. http://www.ranbaxy.com/re- searchndevelopment/overview.aspx (acessed in July, 2010).
49. Dong Y, Wittlin S, Sriraghavan K, et al. The structure-activity relationship of the antimalarial ozonide arterolane (OZ277). J Med Chem 2010; 53: 481-91.
50. Wang JY, Cao WC, Shan CQ, et al. Naphthoquine phosphate and its combination with artemisinine. Acta Trop 2004; 89: 375-81.
51. Schmidt LH, Crosby R, Rasco J, Vaughan D. Antimalarial activities of various 4-quinolonemethanols with special attention to WR-142,490 (mefloquine). Antimicrob Agents Chemother 1978; 13: 1011-30.
52. Gupta S, Thapar MM, Wernsdorfer WH, Bjorkman A. In vitro interactions of artemisinin with atovaquone, quinine, and meflo-quine against Plasmodium falciparum. Antimicrob Agents Che-mother 2002; 46: 1510-5.
53. Hutagalung R, Paiphun L, Ashley EA, et al. A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the [143] Berman PA, Adams PA. Artemisinin enhances heme-catalysed oxidation of lipid membranes. Free Radic Biol Med 1997; 22: 1283-8.
54. Yeung S, Van Damme W, Socheat D, White NJ, Mills A. Access to artemisinin combination therapy for malaria in remote areas of Cambodia. Malar J 2008; 7: 96.
55. Duffy PE, Sibley CH. Are we losing artemisinin combination therapy already? Lancet 2005; 366: 1908-9.
56. Peel SA, Bright P, Yount B, Handy J, Baric RS. A strong association between mefloquine and halofantrine resistance and amplification, overexpression, and mutation in the P-glycoprotein gene ho-molog (pfmdr) of Plasmodium falciparum in vitro. Am J Trop Med Hyg 1994; 51: 648-58.
57. Cowman AF, Galatis D, Thompson JK. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc Natl Acad Sci USA 1994; 91: 1143-7.
58. Coker SJ, Batey AJ, Lightbown ID, Diaz ME, Eisner DA. Effects of mefloquine on cardiac contractility and electrical activity in vivo, in isolated cardiac preparations, and in single ventricular myocytes. Br J Pharmacol 2000; 129: 323-30.
59. Basco LK, Bickii J, Ringwald P. In vitro activity of lumefantrine (benflumetol) against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon. Antimicrob Agents Chemother 1998; 42: 2347-51.
60. Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ. Phar-macokinetics and pharmacodynamics of lumefantrine (benflume-tol) in acute falciparum malaria. Antimicrob Agents Chemother 2000; 44: 697-704.
61. Abdulla S, Sagara I, Borrmann S, et al. Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. Lancet 2008; 372: 1819-27.
62. Goldberg DE, Slater AF, Cerami A, Henderson GB. Hemoglobin degradation in the malaria parasite Plasmodium falciparum: an ordered process in a unique organelle. Proc Natl Acad Sci USA 1990; 87: 2931-5.
63. Goldberg DE, Slater AF, Beavis R, Chait B, Cerami A, Henderson GB. Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease. J Exp Med 1991; 173: 961-9.
64. Francis SE, Sullivan DJ, Jr., Goldberg DE. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu Rev Mi-crobiol 1997; 51: 97-123.
65. Ginsburg H, Famin O, Zhang J, Krugliak M. Inhibition of glu-tathione-dependent degradation of heme by chloroquine and amo-diaquine as a possible basis for their antimalarial mode of action. Biochem Pharmacol 1998; 56: 1305-13.
66. Loria P, Miller S, Foley M, Tilley L. Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials. Biochem J 1999; 339 (Pt 2): 363-70.
67. Atamna H, Ginsburg H. Heme degradation in the presence of glu-tathione. A proposed mechanism to account for the high levels of non-heme iron found in the membranes of hemoglobinopathic red blood cells. J Biol Chem 1995; 270: 24876-83.
68. Hawley SR, Bray PG, Mungthin M, Atkinson JD, O'Neill PM, Ward SA. Relationship between antimalarial drug activity, accumulation, and inhibition of heme polymerization in Plasmodium falciparum in vitro. Antimicrob Agents Chemother 1998; 42: 682-6.
69. Solar I, Muller-Eberhard U, Shaklai N. Serum proteins as mediators of hemin efflux from red cell membranes: specificity of he-mopexin. FEBS Lett 1989; 256: 225-9.
70. van Schalkwyk DA, Egan TJ. Quinoline-resistance reversing agents for the malaria parasite Plasmodium falciparum. Drug Resist Updat 2006; 9: 211-26.
71. Sullivan DJ, Jr., Gluzman IY, Russell DG, Goldberg DE. On the molecular mechanism of chloroquine's antimalarial action. Proc Natl Acad Sci USA 1996; 93: 11865-70.
72. Slater AF. Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Pharmacol Ther 1993; 57: 203-35.
73. Ginsburg H, Stein WD. Kinetic modelling of chloroquine uptake by malaria-infected erythrocytes. Assessment of the factors that may determine drug resistance. Biochem Pharmacol 1991; 41: 1463-70.
74. Krogstad DJ, Schlesinger PH, Gluzman IY. Antimalarials increase vesicle pH in Plasmodium falciparum. J Cell Biol 1985; 101: 2302-9.
75. Yayon A, Cabantchik ZI, Ginsburg H. Susceptibility of human malaria parasites to chloroquine is pH dependent. Proc Natl Acad Sci USA 1985; 82: 2784-8.
76. Malhotra K, Salmon D, Le Bras J, Vilde JL. Potentiation of chloro-quine activity against Plasmodium falciparum by the peroxidase-hydrogen peroxide system. Antimicrob Agents Chemother 1990; 34: 1981-5.
77. Dubois VL, Platel DF, Pauly G, Tribouley-Duret J. Plasmodium berghei: implication of intracellular glutathione and its related enzyme in chloroquine resistance in vivo. Exp Parasitol 1995; 81: 117-24.
78. Egan TJ, Ross DC, Adams PA. Quinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). FEBS Lett 1994; 352: 54-7.
79. Cowman AF, Karcz S, Galatis D, Culvenor JG. A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. J Cell Biol 1991; 113: 1033-42.
80. Riffkin CD, Chung R, Wall DM, et al. Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug meflo-quine. Biochem Pharmacol 1996; 52: 1545-52.
81. Bray PG, Martin RE, Tilley L, Ward SA, Kirk K, Fidock DA. Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. Mol Microbiol 2005; 56: 323-33.
82. Foote SJ, Thompson JK, Cowman AF, Kemp DJ. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 1989; 57: 921-30.
83. Foote SJ, Kyle DE, Martin RK, et al. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 1990; 345: 255-8.
84. Wellems TE, Panton LJ, Gluzman IY, et al. Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 1990; 345: 253-5.
85. Ginsburg H, Krugliak M. Quinoline-containing antimalarials--mode of action, drug resistance and its reversal. An update with unresolved puzzles. Biochem Pharmacol 1992; 43: 63-70.
86. Bray PG, Howells RE, Ritchie GY, Ward SA. Rapid chloroquine efflux phenotype in both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. A correlation of chloroquine sensitivity with energy-dependent drug accumulation. Biochem Pharmacol 1992; 44: 1317-24.
87. Geary TG, Divo AD, Jensen JB, Zangwill M, Ginsburg H. Kinetic modelling of the response of Plasmodium falciparum to chloro-quine and its experimental testing in vitro. Implications for mechanism of action of and resistance to the drug. Biochem Pharmacol 1990; 40: 685-91.
88. Volkman SK, Cowman AF, Wirth DF. Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of Plasmodium falciparum. Proc Natl Acad Sci USA 1995; 92: 8921-5.
89. Davioud-Charvet E, Delarue S, Biot C, et al. A prodrug form of a Plasmodium falciparum GR inhibitor conjugated with a 4-anilinoquinoline. J Med Chem 2001; 44: 4268-76.
90. Wellems TE, Walker-Jonah A, Panton LJ. Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc Natl Acad Sci USA 1991; 88: 3382-6.
91. White NJ. Drug resistance in malaria. Br Med Bull 1998; 54: 703-15.
92. Price RN, Nosten F, Luxemburger C, et al. Artesunate versus arte-mether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria. Trans R Soc Trop Med Hyg 1995; 89: 523-7.
93. Barnes DA, Foote SJ, Galatis D, Kemp DJ, Cowman AF. Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plas-modium falciparum. EMBO J 1992; 11: 3067-75.
94. Wilson CM, Volkman SK, Thaithong S, et al. Amplification of pfmdr 1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand. Mol Biochem Parasitol 1993; 57: 151-60.
95. Basco LK, Le Bras J, Rhoades Z, Wilson CM. Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subsaharan Africa. Mol Biochem Parasitol 1995; 74: 157-66.
96. Chaiyaroj SC, Buranakiti A, Angkasekwinai P, Looressuwan S, Cowman AF. Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug-resistant Plasmodium falciparum isolates from Thailand. Am J Trop Med Hyg 1999; 61: 780-3.
97. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2002; 2: 209-18.
98. Kelly JX, Smilkstein MJ, Brun R, et al. Discovery of dual function acridones as a new antimalarial chemotype. Nature 2009; 459: 270-3.
99. Oduola AM, Omitowoju GO, Gerena L, et al. Reversal of meflo-quine resistance with penfluridol in isolates of Plasmodium falcipa-rum from South-west Nigeria. Trans R Soc Trop Med Hyg 1993; 87: 81-3.
100. Peters W, Robinson BL. The chemotherapy of rodent malaria. XLVI. Reversal of mefloquine resistance in rodent Plasmodium. Ann Trop Med Parasitol 1991; 85: 5-10.
101. Borstnik K, Paik IH, Shapiro TA, Posner GH. Antimalarial che-motherapeutic peroxides: artemisinin, yingzhaosu A and related compounds. Int J Parasitol 2002; 32: 1661-7.
102. Ploypradith P. Development of artemisinin and its structurally simplified trioxane derivatives as antimalarial drugs. Acta Trop 2004; 89: 329-42.
103. Krishna S, Uhlemann AC, Haynes RK. Artemisinins: mechanisms of action and potential for resistance. Drug Resist Updat 2004; 7: 233-44.
104. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J 2005; 81: 71-8.
105. Haynes RK. Artemisinin and derivatives: the future for malaria treatment? Curr Opin Infect Dis 2001; 14: 719-26.
106. Nacher M, Silachamroon U, Singhasivanon P, et al. Comparison of artesunate and chloroquine activities against Plasmodium vivax gametocytes. Antimicrob Agents Chemother 2004; 48: 2751-2.
107. Li Q, Xie LH, Si Y, et al. Toxicokinetics and hydrolysis of arteli-nate and artesunate in malaria-infected rats. Int J Toxicol 2005; 24: 241-50.
108. O'Neill PM. The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents. Expert Opin Inves-tig Drugs 2005; 14: 1117-28.
109. Vennerstrom JL, Arbe-Barnes S, Brun R, et al. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 2004; 430: 900-4.
110. Ellis GL, Amewu R, Hall C, Rimmer K, Ward SA, O'Neill PM. An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity. Bioorg Med Chem Lett 2008; 18: 1720-4.
111. Perry CS, Charman SA, Prankerd RJ, et al. Chemical kinetics and aqueous degradation pathways of a new class of synthetic ozonide antimalarials. J Pharm Sci 2006; 95: 737-47.
112. Vivas L, Rattray L, Stewart LB, et al. Antimalarial efficacy and drug interactions of the novel semi-synthetic endoperoxide artemi-sone in vitro and in vivo. J Antimicrob Chemother 2007; 59: 65865.
113. Obaldia N, 3rd, Kotecka BM, Edstein MD, et al. Evaluation of artemisone combinations in Aotus monkeys infected with Plasmo-dium falciparum. Antimicrob Agents Chemother 2009; 53: 3592-4.
114. Medicines for malaria Venture. http://www.mmv.org/research- development/project-portfolio/phase-iia (accesed July, 2010).
115. ClinicalTrials.gov. Artemisone for the treatment of uncomplicated falciparum malaria in Western Cambodia (AMOS). http://clinicaltrials.gov/ct2/ show/NCT00936767/ (accessed July, 2010).
116. Gautam A, Ahmed T, Batra V, Paliwal J. Pharmacokinetics and pharmacodynamics of endoperoxide antimalarials. Curr Drug Me-tab 2009; 10: 289-306.
117. Sabbani S, Stocks PA, Ellis GL, et al. Piperidine dispiro-1,2,4-trioxane analogues. Bioorg Med Chem Lett 2008; 18: 5804-8.
118. Jefford CW. New developments in synthetic peroxidic drugs as artemisinin mimics. Drug Discov Today 2007; 12: 487-95.
119. Muraleedharan KM, Avery MA. Progress in the development of peroxide-based anti-parasitic agents. Drug Discov Today 2009; 14: 793-803.
120. Araujo NC, 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: 2038-43.
121. Swiss Tropical and Public Health (Swiss TPH). http://www.swis- stph.ch/ (accessed July, 2010).
122. ClinicalTrials.gov. RBx11160 Phase II Dose Ranging Study RBx/MMV05-06. http://clinicaltrials.gov/ct2/show/study/NCT-00362050? term=RBx11160&rank=1 (accessed July, 2010).
123. Medicines for Malaria Venture. http://www.mmv.org/research- development/project-portfolio/oz-439 (accessed July, 2010).
124. Tang Y, Dong Y, Wittlin S, et al. Weak base dispiro-1,2,4-trioxolanes: potent antimalarial ozonides. Bioorg Med Chem Lett 2007; 17: 1260-5.
125. Dong Y, Tang Y, Chollet J, et al. Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes. Bioorg Med Chem 2006; 14: 6368-82.
126. Dong Y, Chollet J, Matile H, et al. Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes. J Med Chem 2005; 48: 4953-61.
127. Tang Y, Dong Y, Vennerstrom JL. Synthetic peroxides as antima-larials. Med Res Rev 2004; 24: 425-48.
128. Tang Y, Dong Y, Wittlin S, et al. Weak base dispiro-1,2,4-trioxolanes: potent antimalarial ozonides. Bioorg Med Chem Lett 2007; 17: 1260-5.
129. Crespo MD, Avery TD, Hanssen E, et al. Artemisinin and a series of novel endoperoxide Antimalarials exert early effects on digestive vacuole morphology. Antimicrob Agents Chemother 2008; 52: 98-109.
130. Meshnick SR, Yang YZ, Lima V, Kuypers F, Kamchonwongpaisan S, Yuthavong Y. Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu). Antimicrob Agents Chemother 1993; 37: 1108-14.
131. Meshnick SR, Thomas A, Ranz A, Xu CM, Pan HZ. Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of an-timalarial action. Mol Biochem Parasitol 1991; 49: 181-9.
132. Robert A, Benoit-Vical F, Claparols C, Meunier B. The antimalar-ial drug artemisinin alkylates heme in infected mice. Proc Natl Acad Sci USA 2005; 102: 13676-80.
133. 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: 2966-9.
134. Wei N, Sadrzadeh SM. Enhancement of hemin-induced membrane damage by artemisinin. Biochem Pharmacol 1994; 48: 737-41.
135. Robert A, Meunier B. Is alkylation the main mechanism of action of the antimalarial drug artemisinin? Chem Soc Rev 1998; 27: 273279.
136. Robert A, Cazelles J, Meunier B. Characterization of the Alkyla-tion Product of Heme by the Antimalarial Drug Artemisinin. Angew Chem Int Ed Engl 2001; 40: 1954-1957.
137. Pandey AV, Tekwani BL, Singh RL, Chauhan VS. Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite. J Biol Chem 1999; 274: 19383-8.
138. Meshnick SR, Tsang TW, Lin FB, et al. Activated oxygen mediates the antimalarial activity of qinghaosu. Prog Clin Biol Res 1989; 313: 95-104.
139. Hartwig CL, Rosenthal AS, D'Angelo J, Griffin CE, Posner GH, Cooper RA. Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent. Biochem Pharmacol 2009; 77: 322-36.
140. Zhou HJ, Wang Z, Li A. Dihydroartemisinin induces apoptosis in human leukemia cells HL60 via downregulation of transferrin receptor expression. Anticancer Drugs 2008; 19: 247-55.
141. Eckstein-Ludwig U, Webb RJ, Van Goethem ID, et al. Artemis-inins target the SERCA of Plasmodium falciparum. Nature 2003; 424: 957-61.
142. Scott MD, Meshnick SR, Williams RA, et al. Qinghaosu-mediated oxidation in normal and abnormal erythrocytes. J Lab Clin Med 1989; 114: 401-6.
143. Asawamahasakda W, Ittarat I, Pu YM, Ziffer H, Meshnick SR. Reaction of antimalarial endoperoxides with specific parasite proteins. Antimicrob Agents Chemother 1994; 38: 1854-8.
144. Bhisutthibhan J, Meshnick SR. Immunoprecipitation of [(3)H] dihydroartemisinin translationally controlled tumor protein (TCTP) adducts from Plasmodium falciparum-infected erythro-cytes by using anti-TCTP antibodies. Antimicrob Agents Che-mother 2001; 45: 2397-9.
145. Walker DJ, Pitsch JL, Peng MM, et al. Mechanisms of artemisinin resistance in the rodent malaria pathogen Plasmodium yoelii. An-timicrob Agents Chemother 2000; 44: 344-7.
146. Bhisutthibhan J, Pan XQ, Hossler PA, et al. The Plasmodium falci-parum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J Biol Chem 1998; 273: 16192-8.
147. Bhisutthibhan J, Philbert MA, Fujioka H, Aikawa M, Meshnick SR. The Plasmodium falciparum translationally controlled tumor protein: subcellular localization and calcium binding. Eur J Cell Biol 1999; 78: 665-70.
148. Jambou R, Legrand E, Niang M, et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 2005; 366: 1960-3.
149. Uhlemann AC, Cameron A, Eckstein-Ludwig U, et al. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat Struct Mol Biol 2005; 12: 628-9.
150. Creek DJ, Charman WN, Chiu FC, et al. Relationship between antimalarial activity and heme alkylation for spiro-and dispiro-1,2,4-trioxolane antimalarials. Antimicrob Agents Chemother 2008; 52: 1291-6.
151. Maerki S, Brun R, Charman SA, Dorn A, Matile H, Wittlin S. In vitro assessment of the pharmacodynamic properties and the partitioning of OZ277/RBx-11160 in cultures of Plasmodium falcipa-rum. J Antimicrob Chemother 2006; 58: 52-8.
152. Maeno Y, Toyoshima T, Fujioka H, et al. Morphologic effects of artemisinin in Plasmodium falciparum. Am J Trop Med Hyg 1993; 49: 485-91.
153. Wang J, Huang L, Li J, et al. Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS One 2010; 5: e9582.
154. Jiang JB, Jacobs G, Liang DS, Aikawa M. Qinghaosu-induced changes in the morphology of Plasmodium inui. Am J Trop Med Hyg 1985; 34: 424-8.
155. Kawai S, Kano S, Suzuki M. Morphologic effects of artemether on Plasmodium falciparum in Aotus trivirgatus. Am J Trop Med Hyg 1993; 49: 812-8.
156. Ellis DS, Li ZL, Gu HM, et al. The chemotherapy of rodent malaria, XXXIX. Ultrastructural changes following treatment with artemisinine of Plasmodium berghei infection in mice, with observations of the localization of [3H]-dihydroartemisinine in P. falci-parum in vitro. Ann Trop Med Parasitol 1985; 79: 367-74.
157. O'Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin--the debate continues. Molecules 2010; 15: 1705-21.
158. Rathod PK, McErlean T, Lee PC. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 1997; 94: 9389-93.
159. Miller JH. Spontaneous mutators in bacteria: insights into pathways of mutagenesis and repair. Annu Rev Microbiol 1996; 50: 625-43.
160. Hyde JE. Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs. Microbes Infect 2002; 4: 165-74.
161. Sisowath C, Stromberg J, Martensson A, et al. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis 2005; 191: 1014-7.
162. Afonso A, Hunt P, Cheesman S, et al. Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic re-ticulum Ca2+ ATPase), tctp, mdr1, and cg10. Antimicrob Agents Chemother 2006; 50: 480-9.
163. Imwong M, Dondorp AM, Nosten F, et al. Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum. Antimicrob Agents Chemother; 54: 2886-92.
164. Sirawaraporn W. Dihydrofolate reductase and antifolate resistance in malaria. Drug Resist Updat 1998; 1: 397-406.
165. Nosten F, White NJ. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg 2007; 77: 181-92.
166. Nzila A, Ward SA, Marsh K, Sims PF, Hyde JE. Comparative folate metabolism in humans and malaria parasites (part I): pointers for malaria treatment from cancer chemotherapy. Trends Parasitol 2005; 21: 292-8.
167. Nzila A. The past, present and future of antifolates in the treatment of Plasmodium falciparum infection. J Antimicrob Chemother 2006; 57: 1043-54.
168. Brooks DR, Wang P, Read M, Watkins WM, Sims PF, Hyde JE. Sequence variation of the hydroxymethyldihydropterin pyrophos-phokinase: dihydropteroate synthase gene in lines of the human malaria parasite, Plasmodium falciparum, with differing resistance to sulfadoxine. Eur J Biochem 1994; 224: 397-405.
169. Triglia T, Cowman AF. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 1994; 91: 7149-53.
170. Yuthavong Y. Basis for antifolate action and resistance in malaria. Microbes Infect 2002; 4: 175-82.
171. Bzik DJ, Li WB, Horii T, Inselburg J. Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate re-ductase-thymidylate synthase gene. Proc Natl Acad Sci USA 1987; 84: 8360-4.
172. Hyde JE, Sims PF. Sulfa-drug resistance in Plasmodium falcipa-rum. Trends Parasitol 2001; 17: 265-6.
173. Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, et al. Insights into antifolate resistance from malarial DHFR-TS structures. Nat Struct Biol 2003; 10: 357-65.
174. Olliaro PL, Yuthavong Y. An overview of chemotherapeutic targets for antimalarial drug discovery. Pharmacol Ther 1999; 81: 91-110.
175. Cowman AF, Morry MJ, Biggs BA, Cross GA, Foote SJ. Amino acid changes linked to pyrimethamine resistance in the dihydrofo-late reductase-thymidylate synthase gene of Plasmodium falcipa-rum. Proc Natl Acad Sci USA 1988; 85: 9109-13.
176. Peterson DS, Walliker D, Wellems TE. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci USA 1988; 85: 9114-8.
177. Peterson DS, Milhous WK, Wellems TE. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci USA 1990; 87: 3018-22.
178. Foote SJ, Galatis D, Cowman AF. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc Natl Acad Sci USA 1990; 87: 3014-7.
179. Thaithong S, Ranford-Cartwright LC, Siripoon N, et al. Plasmo-dium falciparum: gene mutations and amplification of dihydrofo-late reductase genes in parasites grown in vitro in presence of pyrimethamine. Exp Parasitol 2001; 98: 59-70.
180. Kan SC, Siddiqui WA. Comparative studies on dihydrofolate re-ductases from Plasmodium falciparum and Aotus trivirgatus. J Pro-tozool 1979; 26: 660-4.
181. Inselburg J, Bzik DJ, Horii T. Pyrimethamine resistant Plasmodium falciparum: overproduction of dihydrofolate reductase by a gene duplication. Mol Biochem Parasitol 1987; 26: 121-34.
182. Kundig C, Leblanc E, Papadopoulou B, Ouellette M. Role of the locus and of the resistance gene on gene amplification frequency in methotrexate resistant Leishmania tarentolae. Nucleic Acids Res 1999; 27: 3653-9.
183. Papadopoulou B, Roy G, Ouellette M. A novel antifolate resistance gene on the amplified H circle of Leishmania. EMBO J 1992; 11: 3601-8.
184. Thaithong S, Chan SW, Songsomboon S, et al. Pyrimethamine resistant mutations in Plasmodium falciparum. Mol Biochem Para-sitol 1992; 52: 149-57.
185. Liu J, Schmitz JC, Lin X, et al. Thymidylate synthase as a transla-tional regulator of cellular gene expression. Biochim Biophys Acta 2002; 1587: 174-82.
186. Zhang K, Rathod PK. Divergent regulation of dihydrofolate reduc-tase between malaria parasite and human host. Science 2002; 296: 545-7.
187. Plowe CV, Cortese JF, Djimde A, et al. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J Infect Dis 1997; 176: 1590-6.
188. GlaxoSmithkline. Update on GSK's malaria treatments: Dacart and Lapdap. http://www.gsk.com/media/pressreleases/2008/2008-pres- srelease-0014.htm (accessed July, 2010).
189. Ferlan JT, Mookherjee S, Okezie IN, Fulgence L, Sibley CH. Mutagenesis of dihydrofolate reductase from Plasmodium falciparum: analysis in Saccharomyces cerevisiae of triple mutant alleles resistant to pyrimethamine or WR99210. Mol Biochem Parasitol 2001; 113: 139-50.
190. Hunt SY, Detering C, Varani G, et al. Identification of the optimal third generation antifolate against P. falciparum and P. vivax. Mol Biochem Parasitol 2005; 144: 198-205.
191. Shearer TW, Kozar MP, O'Neil MT, et al. In vitro metabolism of phenoxypropoxybiguanide analogues in human liver microsomes to potent antimalarial dihydrotriazines. J Med Chem 2005; 48: 2805-13.
192. McKie JH, Douglas KT, Chan C, et al. Rational drug design approach for overcoming drug resistance: application to pyrimeth-amine resistance in malaria. J Med Chem 1998; 41: 1367-70.
193. Sardarian A, Douglas KT, Read M, et al. Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites. Org Biomol Chem 2003; 1: 960-4.
194. Xie LH, Li Q, Lin AJ, Smith K, Zhang J, Skillman DS. New potential antimalarial agents: therapeutic-index evaluation of pyrrolo-quinazolinediamine and its prodrugs in a rat model of severe malaria. Antimicrob Agents Chemother 2006; 50: 1649-55.
195. Biagini GA, Viriyavejakul P, O'Neill P M, Bray PG, Ward SA. Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria. Antimicrob Agents Chemother 2006; 50: 1841-51.
196. Melo AM, Bandeiras TM, Teixeira M. New insights into type II NAD(P)H:quinone oxidoreductases. Microbiol Mol Biol Rev 2004; 68: 603-16.
197. Phillips MA, Rathod PK. Plasmodium dihydroorotate dehydro-genase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets 2010; 10: 226-39.
198. Vaidya AB. Mitochondrial and plastid functions as antimalarial drug targets. Curr Drug Targets Infect Disord 2004; 4: 11-23.
199. Vaidya AB, Mather MW. A post-genomic view of the mitochondrion in malaria parasites. Curr Top Microbiol Immunol 2005; 295: 233-50.
200. Kessl JJ, Lange BB, Merbitz-Zahradnik T, et al. Molecular basis for atovaquone binding to the cytochrome bc1 complex. J Biol Chem 2003; 278: 31312-8.
201. Schlitzer M. Antimalarial drugs-what is in use and what is in the pipeline. Arch Pharm (Weinheim) 2008; 341: 149-63.
202. Patel V, Booker M, Kramer M, et al. Identification and characterization of small molecule inhibitors of Plasmodium falciparum di-hydroorotate dehydrogenase. J Biol Chem 2008; 283: 35078-85.
203. Schwarz E, Neupert W. Mitochondrial protein import: mechanisms, components and energetics. Biochim Biophys Acta 1994; 1187: 270-4.
204. Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J Biol Chem 1997; 272: 3961-6.
205. Nyakeriga AM, Perlmann H, Hagstedt M, et al. Drug-induced death of the asexual blood stages of Plasmodium falciparum occurs without typical signs of apoptosis. Microbes Infect 2006; 8: 1560-8.
206. Leblanc C, Boyen C, Richard O, Bonnard G, Grienenberger JM, Kloareg B. Complete sequence of the mitochondrial DNA of the rhodophyte Chondrus crispus (Gigartinales). Gene content and genome organization. J Mol Biol 1995; 250: 484-95.
207. Srivastava IK, Morrisey JM, Darrouzet E, Daldal F, Vaidya AB. Resistance mutations reveal the atovaquone-binding domain of cy-tochrome b in malaria parasites. Mol Microbiol 1999; 33: 704-11.
208. Korsinczky M, Chen N, Kotecka B, Saul A, Rieckmann K, Cheng Q. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother 2000; 44: 2100-8.
209. Looareesuwan S, Wilairatana P, Chalermarut K, Rattanapong Y, Canfield CJ, Hutchinson DB. Efficacy and safety of atova-quone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999; 60: 526-32.
210. Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg 1996; 54: 62-6.
211. Radloff PD, Philipps J, Nkeyi M, Hutchinson D, Kremsner PG. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet 1996; 347: 1511-4.
212. White NJ, Olliaro PL. Strategies for the prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria. Parasitol Today 1996; 12: 399-401.
213. Hong YL, Yang YZ, Meshnick SR. The interaction of artemisinin with malarial hemozoin. Mol Biochem Parasitol 1994; 63: 121-8.
214. Eastman RT, Fidock DA. Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol 2009; 7: 864-74.
215. Mendis K, Rietveld A, Warsame M, Bosman A, Greenwood B, Wernsdorfer WH. From malaria control to eradication: The WHO perspective. Trop Med Int Health 2009; 14: 802-9.
216. Lines J, Schapira A, Smith T. Tackling malaria today. BMJ 2008; 337: a869.
217. Payne D. Spread of chloroquine resistance in Plasmodium falcipa-rum. Parasitol Today 1987; 3: 241-6.
218. Robert A, Benoit-Vical F, Dechy-Cabaret O, Meunier B. From classical antimalarial drugs to new compounds based on the mechanism of action of artemisinin. Pure Appl Chem 2001; 73: 1173-1188.
219. Ridley RG. Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 2002; 415: 686-93.
220. D'Alessandro U, Buttiens H. History and importance of antimalar-ial drug resistance. Trop Med Int Health 2001; 6: 845-8.
221. Payne D. Did medicated salt hasten the spread of chloroquine resistance in Plasmodium falciparum? Parasitol Today 1988; 4: 112-5.
222. Eyles DE, Hoo CC, Warren M, Sandosham AA. Plasmodium falci-parum Resistant to Chloroquine in Cambodia. Am J Trop Med Hyg 1963; 12: 840-3.
223. Giglioli G, Rutten FJ, Ramjattan S. Interruption of malaria transmission by chloroquinized salt in Guyana, with observations on a chloroquine-resistant strain of Plasmodium falciparum. Bull World Health Organ 1967; 36: 283-301.
224. Stepniewska K, White NJ. Pharmacokinetic determinants of the window of selection for antimalarial drug resistance. Antimicrob Agents Chemother 2008; 52: 1589-96.
225. White NJ, Pongtavornpinyo W. The de novo selection of drug-resistant malaria parasites. Proc Biol Sci 2003; 270: 545-54.
226. White NJ. Antimalarial drug resistance. J Clin Invest 2004; 113: 1084-92.
227. Ginsburg H. Should chloroquine be laid to rest? Acta Trop 2005; 96: 16-23.
228. Goodman C, Kachur SP, Abdulla S, et al. Retail supply of malaria-related drugs in rural Tanzania: risks and opportunities. Trop Med Int Health 2004; 9: 655-63.
229. Foster S. Economic prospects for a new antimalarial drug. Trans R Soc Trop Med Hyg 1994; 88 Suppl 1: S55-6. (Pubitemid 24206491)
230. Lim P, Wongsrichanalai C, Chim P, et al. Decreased in vitro susceptibility of Plasmodium falciparum isolates to artesunate, meflo-quine, chloroquine, and quinine in Cambodia from 2001 to 2007. Antimicrob Agents Chemother 2010; 54: 2135-42.
231. Sanchez CP, Wunsch S, Lanzer M. Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype. J Biol Chem 1997; 272: 2652-8.
232. Kamya MR, Bakyaita NN, Talisuna AO, Were WM, Staedke SG. Increasing antimalarial drug resistance in Uganda and revision of the national drug policy. Trop Med Int Health 2002; 7: 1031-41.
233. Bakyaita N, Dorsey G, Yeka A, et al. Sulfadoxine-pyrimethamine plus chloroquine or amodiaquine for uncomplicated falciparum malaria: a randomized, multisite trial to guide national policy in Uganda. Am J Trop Med Hyg 2005; 72: 573-80.
234. Heikkila T, Thirumalairajan S, Davies M, et al. The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate de-hydrogenase. Bioorg Med Chem Lett 2006; 16: 88-92.
235. Hekmat-Nejad M, Rathod PK. Kinetics of Plasmodium falciparum thymidylate synthase: interactions with high-affinity metabolites of 5-fluoroorotate and D1694. Antimicrob Agents Chemother 1996; 40: 1628-32.
236. Jiang L, Lee PC, White J, Rathod PK. Potent and selective activity of a combination of thymidine and 1843U89, a folate-based thymidylate synthase inhibitor, against Plasmodium falciparum. Antimicrob Agents Chemother 2000; 44: 1047-50.
237. Rathod PK, Reshmi S. Susceptibility of Plasmodium falciparum to a combination of thymidine and ICI D1694, a quinazoline antifo-late directed at thymidylate synthase. Antimicrob Agents Che-mother 1994; 38: 476-80
238. Rathod PK, Leffers NP, Young RD. Molecular targets of 5-fluoroorotate in the human malaria parasite, Plasmodium falcipa-rum. Antimicrob Agents Chemother 1992; 36: 704-11.
239. Muregi FW, Kano S, Kino H, Ishih A. Plasmodium berghei: efficacy of 5-fluoroorotate in combination with commonly used anti-malarial drugs in a mouse model. Exp Parasitol 2009; 121: 376-80.
240. Baldwin J, Farajallah AM, Malmquist NA, Rathod PK, Phillips MA. Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. J Biol Chem 2002; 277: 41827-34.
241. Rathod PK, Khosla M, Gassis S, Young RD, Lutz C. Selection and characterization of 5-fluoroorotate-resistant Plasmodium falcipa-rum. Antimicrob Agents Chemother 1994; 38: 2871-6.
242. Baldwin J, Michnoff CH, Malmquist NA, et al. High-throughput screening for potent and selective inhibitors of Plasmodium falci-parum dihydroorotate dehydrogenase. J Biol Chem 2005; 280: 21847-53.
243. Biagini GA, Fisher N, Berry N, et al. Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex. Mol Pharmacol 2008; 73: 1347-55.
244. Ellis JE. Coenzyme Q homologs in parasitic protozoa as targets for chemotherapeutic attack. Parasitol Today 1994; 10: 296-301.
245. Mogi T, Matsushita K, Murase Y, et al. Identification of new inhibitors for alternative NADH dehydrogenase (NDH-II). FEMS Microbiol Lett 2009; 291: 157-61.
246. Fisher N, Bray PG, Ward SA, Biagini GA. The malaria parasite type II NADH:quinone oxidoreductase: an alternative enzyme for an alternative lifestyle. Trends Parasitol 2007; 23: 305-10.
247. Uyemura SA, Luo S, Moreno SN, Docampo R. Oxidative phosphorylation, Ca(2+) transport, and fatty acid-induced uncoupling in malaria parasites mitochondria. J Biol Chem 2000; 275: 9709-15.
248. Uyemura SA, Luo S, Vieira M, Moreno SN, Docampo R. Oxida-tive phosphorylation and rotenone-insensitive malate-and NADH-quinone oxidoreductases in Plasmodium yoelii yoelii mitochondria in situ. J Biol Chem 2004; 279: 385-93.
249. Kawahara K, Mogi T, Tanaka TQ, Hata M, Miyoshi H, Kita K. Mitochondrial dehydrogenases in the aerobic respiratory chain of the rodent malaria parasite Plasmodium yoelii yoelii. J Biochem 2009; 145: 229-37.
250. Painter HJ, Morrisey JM, Mather MW, Vaidya AB. Specific role of mitochondrial electron transport in blood-stage Plasmodium falci-parum. Nature 2007; 446: 88-91.
251. Dhanasekaran M, Ren J. The emerging role of coenzyme Q-10 in aging, neurodegeneration, cardiovascular disease, cancer and diabetes mellitus. Curr Neurovasc Res 2005; 2: 447-59.
252. Malmquist NA, Gujjar R, Rathod PK, Phillips MA. Analysis of flavin oxidation and electron-transfer inhibition in Plasmodium fal-ciparum dihydroorotate dehydrogenase. Biochemistry 2008; 47: 2466-75.
253. Phillips MA, Gujjar R, Malmquist NA, et al. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falcipa-rum. J Med Chem 2008; 51: 3649-53.
254. Deng X, Gujjar R, El Mazouni F, et al. Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J Biol Chem 2009; 284: 26999-7009.
255. Gujjar R, Marwaha A, El Mazouni F, et al. Identification of a me-tabolically stable triazolopyrimidine-based dihydroorotate dehy-drogenase inhibitor with antimalarial activity in mice. J Med Chem 2009; 52: 1864-72.
256. Beeson JG, Winstanley PA, McFadden GI, Brown GV. New agents to combat malaria. Nat Med 2001; 7: 149-50.
257. Raghu Ram EV, Kumar A, Biswas S, et al. Nuclear gyrB encodes a functional subunit of the Plasmodium falciparum gyrase that is involved in apicoplast DNA replication. Mol Biochem Parasitol 2007; 154: 30-9.
258. McFadden GI, Roos DS. Apicomplexan plastids as drug targets. Trends Microbiol 1999; 7: 328-333.
259. Surolia N, Surolia A. Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmo-dium falciparum. Nat Med 2001; 7: 167-73.
260. Waller RF, Keeling PJ, Donald RG, et al. Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc Natl Acad Sci USA 1998; 95: 12352-7.
261. McMurry LM, Oethinger M, Levy SB. Overexpression of marA, soxS, or acrAB produces resistance to triclosan in laboratory and clinical strains of Escherichia coli. FEMS Microbiol Lett 1998; 166: 305-9.
262. Fan F, Yan K, Wallis NG, et al. Defining and combating the mechanisms of triclosan resistance in clinical isolates of Staphylo-coccus aureus. Antimicrob Agents Chemother 2002; 46: 3343-7.
263. Heath RJ, Rock CO. A triclosan-resistant bacterial enzyme. Nature 2000; 406: 145-6.
264. Slater-Radosti C, Van Aller G, Greenwood R, et al. Biochemical and genetic characterization of the action of triclosan on Staphylo-coccus aureus. J Antimicrob Chemother 2001; 48: 1-6.
265. Jomaa H, Wiesner J, Sanderbrand S, et al. Inhibitors of the nonme-valonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 1999; 285: 1573-6.
266. Ralph SA, van Dooren GG, Waller RF, et al. Tropical infectious diseases: metabolic maps and functions of the Plasmodium falcipa-rum apicoplast. Nat Rev Microbiol 2004; 2: 203-16.
267. Wilson RJM. Parasite plastids: approaching the endgame. Biol Rev 2005; 80: 129-153.
268. Missinou MA, Borrmann S, Schindler A, et al. Fosmidomycin for malaria. Lancet 2002; 360: 1941-2.
269. Lell B, Ruangweerayut R, Wiesner J, et al. Fosmidomycin, a novel chemotherapeutic agent for malaria. Antimicrob Agents Chemother 2003; 47: 735-8.
270. Wiesner J, Borrmann S, Jomaa H. Fosmidomycin for the treatment of malaria. Parasitol Res 2003; 90 Suppl 2: S71-6.
271. a) Borrmann S, Adegnika AA, Matsiegui PB, et al. Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children. J Infect Dis 2004; 189: 901-8.
272. (b) Borrmann S, Issifou S, Esser G, et al. Fosmidomycin-clindamy-cin for the treatment of Plasmodium falciparum malaria. J Infect Dis 2004; 190: 1534-40.
273. Borrmann S, Lundgren I, Oyakhirome S, et al. Fosmidomycin plus clindamycin for treatment of pediatric patients aged 1 to 14 years with Plasmodium falciparum malaria. Antimicrob Agents Che-mother 2006; 50: 2713-8.
274. Dharia NV, Sidhu AB, Cassera MB, et al. Use of high-density tiling microarrays to identify mutations globally and elucidate mechanisms of drug resistance in Plasmodium falciparum. Genome Biol 2009; 10: R21.
275. Padmanaban G, Nagaraj AG, Rangarajan PN. Drugs and Drug targets against malaria. Curr Sci India 2007: 1545-1555.
276. Bonday ZQ, Dhanasekaran S, Rangarajan PN, Padmanaban G. Import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target. Nat Med 2000; 6: 898-903.
277. Varadharajan S, Dhanasekaran S, Bonday ZQ, Rangarajan PN, Padmanaban G. Involvement of delta-aminolaevulinate synthase encoded by the parasite gene in de novo haem synthesis by Plas-modium falciparum. Biochem J 2002; 367: 321-7.
278. Varadharajan S, Sagar BK, Rangarajan PN, Padmanaban G. Localization of ferrochelatase in Plasmodium falciparum. Biochem J 2004; 384: 429-36.
279. Sato S, Wilson RJ. The genome of Plasmodium falciparum encodes an active delta-aminolevulinic acid dehydratase. Curr Genet 2002; 40: 391-8.
280. van Dooren GG, Su V, D'Ombrain MC, McFadden GI. Processing of an apicoplast leader sequence in Plasmodium falciparum and the identification of a putative leader cleavage enzyme. J Biol Chem 2002; 277: 23612-9.
281. Surolia N, Padmanaban G. de novo biosynthesis of heme offers a new chemotherapeutic target in the human malarial parasite. Bio-chem Biophys Res Commun 1992; 187: 744-50.
282. Sato S, Clough B, Coates L, Wilson RJ. Enzymes for heme biosynthesis are found in both the mitochondrion and plastid of the malaria parasite Plasmodium falciparum. Protist 2004; 155: 117-25.
283. Dhanasekaran S, Chandra NR, Chandrasekhar Sagar BK, Rangara-jan PN, Padmanaban G. Delta-aminolevulinic acid dehydratase from Plasmodium falciparum: indigenous versus imported. J Biol Chem 2004; 279: 6934-42.
284. Divo AA, Sartorelli AC, Patton CL, Bia FJ. Activity of fluoroquinolone antibiotics against Plasmodium falciparum in vitro. Antimicrob Agents Chemother 1988; 32: 1182-6.
285. Weissig V, Vetro-Widenhouse TS, Rowe TC. Topoisomerase II inhibitors induce cleavage of nuclear and 35-kb plastid DNAs in the malarial parasite Plasmodium falciparum. DNA Cell Biol 1997; 16: 1483-92.
286. Fichera ME, Roos DS. A plastid organelle as a drug target in api-complexan parasites. Nature 1997; 390: 407-9.
287. Williamson DH, Preiser PR, Moore PW, McCready S, Strath M, Wilson RJ. The plastid DNA of the malaria parasite Plasmodium falciparum is replicated by two mechanisms. Mol Microbiol 2002; 45: 533-42.
288. Ali JA, Jackson AP, Howells AJ, Maxwell A. The 43-kilodalton N-terminal fragment of the DNA gyrase B protein hydrolyzes ATP and binds coumarin drugs. Biochemistry 1993; 32: 2717-24.
289. Rosenthal PJ, Sijwali PS, Singh A, Shenai BR. Cysteine proteases of malaria parasites: targets for chemotherapy. Curr Pharm Des 2002; 8: 1659-72.
290. a) Sijwali PS, Brinen LS, Rosenthal PJ. Systematic optimization of expression and refolding of the Plasmodium falciparum cysteine protease falcipain-2. Protein Expr Purif 2001; 22: 128-34.
291. b) Sijwali PS, Shenai BR, Gut J, Singh A, Rosenthal PJ. Expression and characterization of the Plasmodium falciparum haemoglo-binase falcipain-3. Biochem J 2001; 360: 481-9.
292. Eksi S, Czesny B, van Gemert GJ, Sauerwein RW, Eling W, Williamson KC. Inhibition of Plasmodium falciparum oocyst production by membrane-permeant cysteine protease inhibitor E64d. An-timicrob Agents Chemother 2007; 51: 1064-70.
293. Olson JE, Lee GK, Semenov A, Rosenthal PJ. Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors. Bioorg Med Chem 1999; 7: 633-8.
294. Biot C, Pradines B, Sergeant MH, Gut J, Rosenthal PJ, Chibale K. Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues. Bioorg Med Chem Lett 2007; 17: 6434-8.
295. Gupta D, Yedidi RS, Varghese S, Kovari LC, Woster PM. Mechanism-based inhibitors of the aspartyl protease plasmepsin II as potential antimalarial agents. J Med Chem 2010; 53: 4234-47.
296. Doerig C. Protein kinases as targets for anti-parasitic chemotherapy. Biochim Biophys Acta 2004; 1697: 155-68.
297. Ward P, Equinet L, Packer J, Doerig C. Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote. BMC Genomics 2004; 5: 79.
298. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298: 1912-34.
299. Anamika, Srinivasan N, Krupa A. A genomic perspective of protein kinases in Plasmodium falciparum. Proteins 2005; 58: 180-9.
300. Doerig C, Meijer L, Mottram JC. Protein kinases as drug targets in parasitic protozoa. Trends Parasitol 2002; 18: 366-71.
301. Kappes B, Doerig CD, Graeser R. An overview of Plasmodium protein kinases. Parasitol Today 1999; 15: 449-54.
302. Roach PJ, Wang YH. Identification of phosphorylation sites in peptides using a microsequencer. Methods Enzymol 1991; 201: 200-6.
303. Wek RC. eIF-2 kinases: regulators of general and gene-specific translation initiation. Trends Biochem Sci 1994; 19: 491-6.
304. Deng W, Baker DA. A novel cyclic GMP-dependent protein kinase is expressed in the ring stage of the Plasmodium falciparum life cycle. Mol Microbiol 2002; 44: 1141-51.
305. Gurnett AM, Liberator PA, Dulski PM, et al. Purification and molecular characterization of cGMP-dependent protein kinase from Apicomplexan parasites. A novel chemotherapeutic target. J Biol Chem 2002; 277: 15913-22.
306. Donald RG, Allocco J, Singh SB, et al. Toxoplasma gondii cyclic GMP-dependent kinase: chemotherapeutic targeting of an essential parasite protein kinase. Eukaryot Cell 2002; 1: 317-28.
307. Salowe SP, Wiltsie J, Liberator PA, Donald RG. The role of a parasite-specific allosteric site in the distinctive activation behavior of Eimeria tenella cGMP-dependent protein kinase. Biochemistry 2002; 41: 4385-91.
308. Canaves JM, Taylor SS. Classification and phylogenetic analysis of the cAMP-dependent protein kinase regulatory subunit family. J Mol Evol 2002; 54: 17-29.
309. Garrington TP, Johnson GL. Organization and regulation of mito-gen-activated protein kinase signaling pathways. Curr Opin Cell Biol 1999; 11: 211-8.
310. Dorin D, Alano P, Boccaccio I, et al. An atypical mitogen-activated protein kinase (MAPK) homologue expressed in gametocytes of the human malaria parasite Plasmodium falciparum. Identification of a MAPK signature. J Biol Chem 1999; 274: 29912-20.
311. Nakashima S, Wang S, Hisamoto N, et al. Molecular cloning and expression of a stress-responsive mitogen-activated protein kinase-related kinase from Tetrahymena cells. J Biol Chem 1999; 274: 9976-83.
312. Doerig C, Billker O, Haystead T, Sharma P, Tobin AB, Waters NC. Protein kinases of malaria parasites: an update. Trends Parasitol 2008; 24: 570-7.
313. Hanks SK, Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J 1995; 9: 576-96.
314. Polya GM, Chandra S, Chung R, Neumann GM, Hoj PB. Purification and characterization of wheat and pine small basic protein substrates for plant calcium-dependent protein kinase. Biochim Bio-phys Acta 1992; 1120: 273-80.
315. Satterlee JS, Sussman MR. Unusual membrane-associated protein kinases in higher plants. J Membr Biol 1998; 164: 205-13.
316. Zhao Y, Kappes B, Franklin RM. Gene structure and expression of an unusual protein kinase from Plasmodium falciparum homologous at its carboxyl terminus with the EF hand calcium-binding proteins. J Biol Chem 1993; 268: 4347-54.
317. Nunes MC, Okada M, Scheidig-Benatar C, Cooke BM, Scherf A. Plasmodium falciparum FIKK kinase members target distinct components of the erythrocyte membrane. PLoS One 2010; 5: e11747.
318. Nunes MC, Goldring JP, Doerig C, Scherf A. A novel protein kinase family in Plasmodium falciparum is differentially transcribed and secreted to various cellular compartments of the host cell. Mol Microbiol 2007; 63: 391-403.
319. Parsons M, Valentine M, Deans J, Schieven GL, Ledbetter JA. Distinct patterns of tyrosine phosphorylation during the life cycle of Trypanosoma brucei. Mol Biochem Parasitol 1991; 45: 241-8.
320. Parsons M, Valentine M, Carter V. Protein kinases in divergent eukaryotes: identification of protein kinase activities regulated during trypanosome development. Proc Natl Acad Sci USA 1993; 90: 2656-60.
321. a) Hunter T, Ikebukuro K, Bannister WH, Bannister JV, Hunter GJ. The conserved residue tyrosine 34 is essential for maximal activity of iron-superoxide dismutase from Escherichia coli. Biochemistry 1997; 36: 4925-33.
322. b) Hunter T, Plowman GD. The protein kinases of budding yeast: six score and more. Trends Biochem Sci 1997; 22: 18-22.
323. Wiese M, Wang Q, Gorcke I. Identification of mitogen-activated protein kinase homologues from Leishmania mexicana. Int J Para-sitol 2003; 33: 1577-87.
324. Doerig C, Meijer L. Antimalarial drug discovery: targeting protein kinases. Expert Opin Ther Targets 2007; 11: 279-90.
325. Gray NS, Wodicka L, Thunnissen AM, et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 1998; 281: 533-8.
326. Keenan SM, Geyer JA, Welsh WJ, Prigge ST, Waters NC. Rational inhibitor design and iterative screening in the identification of selective plasmodial cyclin dependent kinase inhibitors. Comb Chem High Throughput Screen 2005; 8: 27-38.
327. Woodard CL, Li Z, Kathcart AK, et al. Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases. J Med Chem 2003; 46: 3877-82.
328. Bhattacharjee AK, Hartell MG, Nichols DA, et al. Structure-activity relationship study of antimalarial indolo [2,1-b]quinazoline-6,12-diones (tryptanthrins). Three dimensional pharmacophore modeling and identification of new antimalarial candidates. Eur J Med Chem 2004; 39: 59-67.
329. Geyer JA, Prigge ST, Waters NC. Targeting malaria with specific CDK inhibitors. Biochim Biophys Acta 2005; 1754: 160-70.
330. Caridha D, Kathcart AK, Jirage D, Waters NC. Activity of substituted thiophene sulfonamides against malarial and mammalian cy-clin dependent protein kinases. Bioorg Med Chem Lett 2010; 20: 3863-7.
331. Atamna H, Ginsburg H. The malaria parasite supplies glutathione to its host cell--investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodium falciparum. Eur J Biochem 1997; 250: 670-9.
332. Morin C, Besset T, Moutet JC, et al. The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and GRs and of human erythrocyte GR. Org Biomol Chem 2008; 6: 2731-42.
333. Biot C, Dessolin J, Grellier P, Davioud-Charvet E. Double-drug development against antioxidant enzymes from Plasmodium falci-parum. Redox Rep 2003; 8: 280-3.
334. Deponte M, Becker K. Glutathione S-transferase from malarial parasites: structural and functional aspects. Methods Enzymol 2005; 401: 241-53.
335. Ahmad R, Srivastava AK. Effect of Plasmodium yoelii nigeriensis infection on hepatic and splenic glutathione-S-transferase(s) in Swiss albino and db/+ mice: efficacy of mefloquine and menadione in antimalarial chemotherapy. Parasitology 2007; 134: 931-8.
336. Hayes JD, Strange RC. Potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress. Free Radic Res 1995; 22: 193-207.
337. Friebolin W, Jannack B, Wenzel N, et al. Antimalarial dual drugs based on potent inhibitors of GR from Plasmodium falciparum. J Med Chem 2008; 51: 1260-77.
338. Przyborski JM, Wickert H, Krohne G, Lanzer M. Maurer's clefts--a novel secretory organelle? Mol Biochem Parasitol 2003; 132: 17-26.
339. Sahu NK, Sahu S, Kohli DV. Novel molecular targets for antima-larial drug development. Chem Biol Drug Des 2008; 71: 287-97.
340. Ancelin ML, Vial HJ. Regulation of phosphatidylcholine biosyn-thesis in Plasmodium-infected erythrocytes. Biochim Biophys Acta 1989; 1001: 82-9.
341. Biagini GA, Pasini EM, Hughes R, et al. Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial drugs. Blood 2004; 104: 3372-7.
342. Taudon N, Margout D, Wein S, Calas M, Vial HJ, Bressolle FM. Quantitative analysis of a bis-thiazolium antimalarial compound, SAR97276, in mouse plasma and red blood cell samples, using liquid chromatography mass spectrometry. J Pharm Biomed Anal 2008; 46: 148-56.
343. Schrier SL. Shape changes and deformability in human erythrocyte membranes. J Lab Clin Med 1987; 110: 791-7.
344. Vial HJ, Eldin P, Martin D, Gannoun L, Calas M, Ancelin ML. Transport of phospholipid synthesis precursors and lipid trafficking into malaria-infected erythrocytes. Novartis Found Symp 1999; 226: 74-83; discussion 82-8.
345. a) Ancelin ML, Calas M, Bonhoure A, Herbute S, Vial HJ. In vivo antimalarial activities of mono-and bis quaternary ammonium salts interfering with Plasmodium phospholipid metabolism. Antimicrob Agents Chemother 2003; 47: 2598-605.
346. b) Ancelin ML, Calas M, Vidal-Sailhan V, Herbute S, Ringwald P, Vial HJ. Potent inhibitors of Plasmodium phospholipid metabolism with a broad spectrum of in vitro antimalarial activities. Antimicrob Agents Chemother 2003; 47: 2590-7.
347. Kirk K. Membrane transport in the malaria-infected erythrocyte. Physiol Rev 2001; 81: 495-537.
348. Stead AM, Bray PG, Edwards IG, et al. Diamidine compounds: selective uptake and targeting in Plasmodium falciparum. Mol Pharmacol 2001; 59: 1298-306.
349. Biagini GA, Richier E, Bray PG, Calas M, Vial H, Ward SA. Heme binding contributes to antimalarial activity of bis-quaternary ammoniums. Antimicrob Agents Chemother 2003; 47: 2584-9.
350. Richier E, Biagini GA, Wein S, et al. Potent antihematozoan activity of novel bisthiazolium drug T16: evidence for inhibition of phosphatidylcholine metabolism in erythrocytes infected with Babesia and Plasmodium spp. Antimicrob Agents Chemother 2006; 50: 3381-8.
351. Calas M, Ancelin ML, Cordina G, et al. Antimalarial activity of compounds interfering with Plasmodium falciparum phospholipid metabolism: comparison between mono-and bisquaternary ammonium salts. J Med Chem 2000; 43: 505-16.
352. Wengelnik K, Vidal V, Ancelin ML, et al. A class of potent anti-malarials and their specific accumulation in infected erythrocytes. Science 2002; 295: 1311-4.
353. Roggero R, Zufferey R, Minca M, et al. Unraveling the mode of action of the antimalarial choline analog G25 in Plasmodium falci-parum and Saccharomyces cerevisiae. Antimicrob Agents Che-mother 2004; 48: 2816-24.
354. Pessi G, Kociubinski G, Mamoun CB. A pathway for phosphati-dylcholine biosynthesis in Plasmodium falciparum involving phos-phoethanolamine methylation. Proc Natl Acad Sci USA 2004; 101: 6206-11.
355. Vial HJ, Wein S, Farenc C, et al. Prodrugs of bisthiazolium salts are orally potent antimalarials. Proc Natl Acad Sci USA 2004; 101: 15458-63.
356. Nicolas O, Margout D, Taudon N, et al. Pharmacological properties of a new antimalarial bisthiazolium salt, T3, and a corresponding prodrug, TE3. Antimicrob Agents Chemother 2005; 49: 3631-9.
357. Wein S, Maynadier M, Tran Van Ba C, et al. Reliability of antima-larial sensitivity tests depends on drug mechanisms of action. J Clin Microbiol 2010; 48: 1651-60.
358. Margout D, Wein S, Gandon H, Gattacceca F, Vial HJ, Bressolle FM. Quantitation of SAR97276 in mouse tissues by rapid resolution liquid chromatography-mass spectrometry. J Sep Sci 2009; 32: 1808-15.
359. Sanofi Aventis. http://en.sanofi-aventis.com/research-innovation/- rd-key-figures/rd-key-figures.asp (accessed July, 2010).
360. McRobert L, Jiang S, Stead A, McConkey GA. Plasmodium falci-parum: interaction of shikimate analogues with antimalarial drugs. Exp Parasitol 2005; 111: 178-81.
361. Roberts CW, Roberts F, Lyons RE, et al. The shikimate pathway and its branches in apicomplexan parasites. J Infect Dis 2002; 185 Suppl 1: S25-36.
362. McConkey GA, Pinney JW, Westhead DR, et al. Annotating the Plasmodium genome and the enigma of the shikimate pathway. Trends Parasitol 2004; 20: 60-5.
363. McConkey GA. Targeting the shikimate pathway in the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother 1999; 43: 175-7.
364. Fitzpatrick T, Ricken S, Lanzer M, Amrhein N, Macheroux P, Kappes B. Subcellular localization and characterization of choris-mate synthase in the apicomplexan Plasmodium falciparum. Mol Microbiol 2001; 40: 65-75.
365. Roberts F, Roberts CW, Johnson JJ, et al. Evidence for the shiki-mate pathway in apicomplexan parasites. Nature 1998; 393: 801-5.
366. McRobert L, Jiang S, Stead A, McConkey GA. Plasmodium falci-parum: interaction of shikimate analogues with antimalarial drugs. Exp Parasitol 2005; 111: 178-81.
367. Sahu NK, Sahu S, Kohli DV. Novel molecular targets for antima-larial drug development. Chem Biol Drug Des 2008; 71: 287-97.
368. Stalker DM, Hiatt WR, Comai L. A single amino acid substitution in the enzyme 5-enolpyruvylshikimate-3-phosphate synthase confers resistance to the herbicide glyphosate. J Biol Chem 1985; 260: 4724-8.
369. Sost D, Amrhein N. Substitution of Gly-96 to Ala in the 5-enolpyruvylshikimate-3-phosphate synthase of Klebsiella pneumo-niae results in a greatly reduced affinity for the herbicide glypho-sate. Arch Biochem Biophys 1990; 282: 433-6.
370. Dimasi JA. Risks in new drug development: approval success rates for investigational drugs. Clin Pharmacol Ther 2001; 69: 297-307.
371. Trouiller P, Olliaro P, Torreele E, Orbinski J, Laing R, Ford N. Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 2002; 359: 2188-94.
372. Trouiller P, Torreele E, Olliaro P, et al. Drugs for neglected diseases: a failure of the market and a public health failure? Trop Med Int Health 2001; 6: 945-51.
373. DiMasi JA, Feldman L, Seckler A, Wilson A. Trends in risks associated with new drug development: success rates for investigational drugs. Clin Pharmacol Ther 2010; 87: 272-7.
374. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003; 22: 151-85.
375. DiMasi JA, Grabowski HG. The cost of biopharmaceutical R & D: is biotech different? Managerial Decision Economics 2007; 28: 469-479.
376. Honig P, Lalonde R. The economics of drug development: a grim reality and a role for clinical pharmacology. Clin Pharmacol Ther 2010; 87: 247-51.
377. Munos B. Can open-source drug R&D repower pharmaceutical innovation? Clin Pharmacol Ther 2010; 87: 534-6.
378. Sollano JA, Kirsch JM, Bala MV, Chambers MG, Harpole LH. The economics of drug discovery and the ultimate valuation of pharma-cotherapies in the marketplace. Clin Pharmacol Ther 2008; 84: 263-6.
379. Ridley RG, 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: 1846-54.
380. Mzayek F, Deng H, Mather FJ, et al. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials 2007; 2: e6.
381. ClinicalTrials.gov. Food-Effect Bioavailability Study of AQ-13, a Candidate Antimalarial. http://clinicaltrials.gov/ct2/show/NCT004- 55494 (accessed July, 2010
382. Delhaes L, Abessolo H, Biot C, et al. In vitro and in vivo antimalar-ial activity of ferrochloroquine, a ferrocenyl analogue of chloro-quine against chloroquine-resistant malaria parasites. Parasitol Res 2001; 87: 239-44.
383. Atteke C, Ndong JM, Aubouy A, et al. In vitro susceptibility to a new antimalarial organometallic analogue, ferroquine, of Plasmo-dium falciparum isolates from the Haut-Ogooue region of Gabon. J Antimicrob Chemother 2003; 51: 1021-4.
384. Barends M, Jaidee A, Khaohirun N, Singhasivanon P, Nosten F. In vitro activity of ferroquine (SSR 97193) against Plasmodium falci-parum isolates from the Thai-Burmese border. Malar J 2007; 6: 81.
385. Daher W, Biot C, Fandeur T, et al. Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure. Malar J 2006; 5: 11.
386. ClinicalTrials.gov. Food-Effect Bioavailability Study of AQ-13, a Candidate Antimalarial. Dose Ranging Study of Ferroquine With Artesunate in African Adults and Children With Uncomplicated Plasmodium falciparum Malaria (FARM). http://clinicaltrials.- gov/ct2/show/NCT00988507 (accessed July, 2010).
387. Chavain N, Davioud-Charvet E, Trivelli X, et al. Antimalarial activities of ferroquine conjugates with either GR inhibitors or glu-tathione depletors via a hydrolyzable amide linker. Bioorg Med Chem 2009; 17: 8048-59.
388. O'Neill PM, Park BK, Shone AE, et al. Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century. J Med Chem 2009; 52: 1408-15.
389. Basco LK, Dechy-Cabaret O, Ndounga M, Meche FS, Robert A, Meunier B. In vitro activities of DU-1102, a new trioxaquine derivative, against Plasmodium falciparum isolates. Antimicrob Agents Chemother 2001: 1886-8.
390. Rosenthal PJ. Antimalarial drug discovery: old and new approaches. J Exp Biol 2003; 206: 3735-44.
391. Burgess SJ, Selzer A, Kelly JX, Smilkstein MJ, Riscoe MK, Peyton DH. A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum. J Med Chem 2006; 49: 5623-5.
392. Loup C, Lelievre J, Benoit-Vical F, Meunier B. Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemo-zoin better than chloroquine. Antimicrob Agents Chemother 2007; 51: 3768-70.
393. Benoit-Vical F, Lelievre J, Berry A, et al. Trioxaquines are new antimalarial agents active on all erythrocytic forms, including ga-metocytes. Antimicrob Agents Chemother 2007; 51: 1463-72.
394. Cosledan F, Fraisse L, Pellet A, et al. Selection of a trioxaquine as an antimalarial drug candidate. Proc Natl Acad Sci USA 2008; 105: 17579-84.
395. Auparakkitanon S, Noonpakdee W, Ralph RK, Denny WA, Wilairat P. Antimalarial 9-anilinoacridine compounds directed at hematin. Antimicrob Agents Chemother 2003; 47: 3708-12.
396. Auparakkitanon S, Wilairat P. Cleavage of DNA induced by 9-anilinoacridine inhibitors of topoisomerase II in the malaria parasite Plasmodium falciparum. Biochem Biophys Res Commun 2000; 269: 406-9.
397. Murphy SC, Hiller NL, Harrison T, Lomasney JW, Mohandas N, Haldar K. Lipid rafts and malaria parasite infection of erythrocytes. Mol Membr Biol 2006; 23: 81-8.
398. Miller LH, Hudson-Taylor D, Gamain B, Saul AJ. Definition of the minimal domain of CIDR1alpha of Plasmodium falciparum PfEMP1 for binding CD36. Mol Biochem Parasitol 2002; 120: 321-3.
399. Hiller NL, Akompong T, Morrow JS, Holder AA, Haldar K. Identification of a stomatin orthologue in vacuoles induced in human erythrocytes by malaria parasites. A role for microbial raft proteins in apicomplexan vacuole biogenesis. J Biol Chem 2003; 278: 48413-21.
400. Murphy SC, Harrison T, Hamm HE, Lomasney JW, Mohandas N, Haldar K. Erythrocyte G protein as a novel target for malarial chemotherapy. PLoS Med 2006; 3: e528.
401. Miller LH. Hypothesis on the mechanism of erythrocyte invasion by malaria merozoites. Bull World Health Organ 1977; 55: 157-62.
402. Dolan SA, Proctor JL, Alling DW, Okubo Y, Wellems TE, Miller LH. Glycophorin B as an EBA-175 independent Plasmodium falci-parum receptor of human erythrocytes. Mol Biochem Parasitol 1994; 64: 55-63.
403. Fujioka H, Aikawa M. Structure and life cycle. Chem Immunol 2002; 80: 1-26.
404. Bannister L, Mitchell G. The ins, outs and roundabouts of malaria. Trends Parasitol 2003; 19: 209-13.
405. Elford BC, Cowan GM, Ferguson DJ. Parasite-regulated membrane transport processes and metabolic control in malaria-infected eryth-rocytes. Biochem J 1995; 308 (Pt 2): 361-74.
406. Murphy SC, Samuel BU, Harrison T, et al. Erythrocyte detergent-resistant membrane proteins: their characterization and selective uptake during malarial infection. Blood 2004; 103: 1920-8.
407. Samuel BU, Mohandas N, Harrison T, et al. The role of cholesterol and glycosylphosphatidylinositol-anchored proteins of erythrocyte rafts in regulating raft protein content and malarial infection. J Biol Chem 2001; 276: 29319-29.
408. Lauer S, VanWye J, Harrison T, et al. Vacuolar uptake of host components, and a role for cholesterol and sphingomyelin in malarial infection. EMBO J 2000; 19: 3556-64.
409. Harrison T, Samuel BU, Akompong T, et al. Erythrocyte G protein-coupled receptor signaling in malarial infection. Science 2003; 301: 1734-6.
410. Bannister LH, Mitchell GH. The fine structure of secretion by Plasmodium knowlesi merozoites during red cell invasion. J Proto-zool 1989; 36: 362-7.
411. Nagao E, Seydel KB, Dvorak JA. Detergent-resistant erythrocyte membrane rafts are modified by a Plasmodium falciparum infection. Exp Parasitol 2002; 102: 57-9.
412. a) Haldar K, Samuel BU, Mohandas N, Harrison T, Hiller NL. Transport mechanisms in Plasmodium-infected erythrocytes: lipid rafts and a tubovesicular network. Int J Parasitol 2001; 31: 1393-401.
413. b) Haldar K, Samuel BU, Mohandas N, Harrison T, Hiller NL. Erythrocytic vacuolar rafts induced by malaria parasites. Curr Opin Hematol 2001; 8: 92-7.
414. Neves SR, Ram PT, Iyengar R. G protein pathways. Science 2002; 296: 1636-9.
415. Hiller NL, Akompong T, Morrow JS, Holder AA, Haldar K. Identification of a stomatin orthologue in vacuoles induced in human erythrocytes by malaria parasites. A role for microbial raft proteins in apicomplexan vacuole biogenesis. J Biol Chem 2003; 278: 48413-21.
416. Madeira L, Galante PA, Budu A, Azevedo MF, Malnic B, Garcia CR. Genome-wide detection of serpentine receptor-like proteins in malaria parasites. PLoS One 2008; 3: e1889.
417. Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005; 11: 1170-2.
418. Pugach P, Ketas TJ, Michael E, Moore JP. Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors. Virology 2008; 377: 401-7.
419. a) Biswas P, Galli A, Galli L, et al. Does cyclosporin A affect CCR5 and CXCR4 expression in primary HIV-1-infected patients? Cytometry B Clin Cytom 2007; 72: 433-41.
420. b) Biswas P, Tambussi G, Lazzarin A. Access denied? The status of co-receptor inhibition to counter HIV entry. Expert Opin Phar-macother 2007; 8: 923-33.
421. Cooke BM, Lingelbach K, Bannister LH, Tilley L. Protein trafficking in Plasmodium falciparum-infected red blood cells. Trends Parasitol 2004; 20: 581-9.
422. Sargeant TJ, Marti M, Caler E, et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol 2006; 7: R12.
423. Enderle T, Ha T, Ogletree DF, Chemla DS, Magowan C, Weiss S. Membrane specific mapping and colocalization of malarial and host skeletal proteins in the Plasmodium falciparum infected eryth-rocyte by dual-color near-field scanning optical microscopy. Proc Natl Acad Sci USA 1997; 94: 520-5.
424. Taraschi TF, Trelka D, Martinez S, Schneider T, O'Donnell ME. Vesicle-mediated trafficking of parasite proteins to the host cell cy-tosol and erythrocyte surface membrane in Plasmodium falciparum infected erythrocytes. Int J Parasitol 2001; 31: 1381-91.
425. Baumgartner F, Wiek S, Paprotka K, Zauner S, Lingelbach K. A point mutation in an unusual Sec7 domain is linked to brefeldin A resistance in a Plasmodium falciparum line generated by drug selection. Mol Microbiol 2001; 41: 1151-8.
426. Muregi FW, Ishih A. Next-Generation Antimalarial Drugs: Hybrid Molecules as a New Strategy in Drug Design. Drug Devel Res 2010; 71: 20-32.
427. Thomas SL, Egee S, Lapaix F, Kaestner L, Staines HM, Ellory JC. Malaria parasite Plasmodium gallinaceum up-regulates host red blood cell channels. FEBS Lett 2001; 500: 45-51.
428. Desai SA, Bezrukov SM, Zimmerberg J. A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite. Nature 2000; 406: 1001-5.
429. Wagner MA, Andemariam B, Desai SA. A two-compartment model of osmotic lysis in Plasmodium falciparum-infected erythro-cytes. Biophys J 2003; 84: 116-23.
430. Huber S, Uhlemann A, Gamper N, Duranton C, Lang F, Kremsner P. Oxidative permeabilization? Trends Parasitol 2002; 18: 346.
431. Huber SM, Uhlemann AC, Gamper NL, Duranton C, Kremsner PG, Lang F. Plasmodium falciparum activates endogenous Cl(-) channels of human erythrocytes by membrane oxidation. EMBO J 2002; 21: 22-30.
432. Duranton C, Huber SM, Lang F. Oxidation induces a Cl(-)-dependent cation conductance in human red blood cells. J Physiol 2002; 539: 847-55.
433. Duranton C, Huber S, Tanneur V, et al. Electrophysiological properties of the Plasmodium falciparum-induced cation conductance of human erythrocytes. Cell Physiol Biochem 2003; 13: 189-98.
434. Duranton C, Huber SM, Tanneur V, et al. Organic osmolyte permeabilities of the malaria-induced anion conductances in human erythrocytes. J Gen Physiol 2004; 123: 417-26
435. Tanneur V, Ilgaz D, Duranton C, et al. Time-dependent regulation of capacitative Ca2+ entry by IGF-1 in human embryonic kidney cells. Pflugers Arch 2002; 445: 74-9.
436. Staines HM, Ellory JC, Kirk K. Perturbation of the pump-leak balance for Na(+) and K(+) in malaria-infected erythrocytes. Am J Physiol Cell Physiol 2001; 280: C1576-87.
437. Staines HM, Godfrey EM, Lapaix F, Egee S, Thomas S, Ellory JC. Two functionally distinct organic osmolyte pathways in Plasmo-dium gallinaceum-infected chicken red blood cells. Biochim Bio-phys Acta 2002; 1561: 98-108.
438. Egee S, Lapaix F, Decherf G, et al. A stretch-activated anion channel is up-regulated by the malaria parasite Plasmodium falciparum. J Physiol 2002; 542: 795-801.
439. Saliba KJ, Horner HA, Kirk K. Transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite Plasmodium falciparum. J Biol Chem 1998; 273: 10190-5.
440. Lew VL, Tiffert T, Ginsburg H. Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cells. Blood 2003; 101: 4189-94.
441. Silfen J, Yanai P, Cabantchik ZI. Bioflavonoid effects on in vitro cultures of Plasmodium falciparum. Inhibition of permeation pathways induced in the host cell membrane by the intraerythrocytic parasite. Biochem Pharmacol 1988; 37: 4269-76.
442. Kirk K, Horner HA, Elford BC, Ellory JC, Newbold CI. Transport of diverse substrates into malaria-infected erythrocytes via a pathway showing functional characteristics of a chloride channel. J Biol Chem 1994; 269: 3339-47.
443. Upston JM, Gero AM. Parasite-induced permeation of nucleosides in Plasmodium falciparum malaria. Biochim Biophys Acta 1995; 1236: 249-58.
444. Kirk K, Horner HA. In search of a selective inhibitor of the induced transport of small solutes in Plasmodium falciparum-infected erythrocytes: effects of arylaminobenzoates. Biochem J 1995; 311 (Pt 3): 761-8.
445. Wu Y, Nelson MM, Quaile A, Xia D, Wastling JM, Craig A. Identification of phosphorylated proteins in erythrocytes infected by the human malaria parasite Plasmodium falciparum. Malar J 2009; 8: 105.
446. Chishti AH, Maalouf GJ, Marfatia S, et al. Phosphorylation of protein 4.1 in Plasmodium falciparum-infected human red blood cells. Blood 1994; 83: 3339-45.
447. Wiser MF, Wood PA, Eaton JW, Sheppard JR. Membrane-associated phosphoproteins in Plasmodium berghei-infected murine erythrocytes. J Cell Biol 1983; 97: 196-201.
448. Wiser MF, Plitt B. Plasmodium berghei, P. chabaudi, and P. falci-parum: similarities in phosphoproteins and protein kinase activities and their stage specific expression. Exp Parasitol 1987; 64: 328-35.
449. Conboy JG. Structure, function, and molecular genetics of erythroid membrane skeletal protein 4.1 in normal and abnormal red blood cells. Semin Hematol 1993; 30: 58-73.
450. Takakuwa Y, Tchernia G, Rossi M, Benabadji M, Mohandas N. Restoration of normal membrane stability to unstable protein 4.1-deficient erythrocyte membranes by incorporation of purified protein 4.1. J Clin Invest 1986; 78: 80-5.
451. Barik S, Taylor RE, Chakrabarti D. Identification, cloning, and mutational analysis of the casein kinase 1 cDNA of the malaria parasite, Plasmodium falciparum. Stage-specific expression of the gene. J Biol Chem 1997; 272: 26132-8.