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Kinetoplastid Parasites

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Third World Diseases

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 7))

Abstract

Kinetoplastid parasites, most notably of the genus Trypanosoma and Leishmania, have a major impact on the quality of life in the developing world. Human African trypanosomiasis (HAT, or African sleeping sickness), Chagas disease, and Leishmaniasis typically afflict the poorest and most neglected segments of these populations, and as such have historically been of little interest to the modern pharmaceutical industry. As a consequence, the few treatments that exist for these diseases are to some extent effective, however, often toxic, and not adapted to the field conditions. More recently, however, a resurgence of interest and an increase in funding have created an environment where multi-partner consortia are applying modern drug discovery methods to kinetoplastid diseases. These efforts have already produced new potential therapies for each of the kinetoplastid diseases. Clinical evaluation of these novel drug candidates (in many cases, ongoing) will determine their potential to transform the therapeutic landscape. This review will summarize the therapeutic challenges presented by each of the kinetoplastid diseases, the “state of the art” of current treatments, and will focus on evolving opportunities, emphasizing the role of the Drugs for Neglected Diseases initiative (DNDi) as a preferred development partner Product Development Partnership (PDP) providing “the best science for the most neglected.”

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Notes

  1. 1.

    NTD statement on the inclusion of Nifurtimox–Eflornithine combination as a treatment for Stage 2T. b. gambiense human African trypanosomiasis (sleeping sickness) in the WHO Model List of Essential Medicines. 17th Expert Committee on the Selection and Use of Essential Medicines. Submitted February 2009 by the Director of NTD. Available at: http://www.who.int/selection_medicines/committees/expert/17/application/nifurtimox/en/index.html.

  2. 2.

    IFPMA Developing World Partnerships web site, http://www.ifpma.org/index.php?id=2170, referenced 10 May 2010.

References

  1. Adhikari SR, Maskay NM, Sharma BP (2009) Paying for hospital-based care of Kala azar in Nepal: assessing catastrophic, impoverishment and economic consequences. Health Policy Plan 24:129–139

    Article  Google Scholar 

  2. Anoopa Sharma D, Bern C, Varghese B, Chowdhury R, Haque R, Ali M, Amann J, Ahluwalia IB, Wagatsuma Y, Breiman RF, Maguire JH, McFarland DA (2006) The economic impact of visceral leishmaniasis on households in Bangladesh. Trop Med Int Health 11:757–764

    Article  CAS  Google Scholar 

  3. Boelaert M, Meheus F, Sanchez A, Singh SP, Vanlerberghe V, Picado A, Meessen B, Sundar S (2009) The poorest of the poor: a poverty appraisal of households affected by visceral leishmaniasis in Bihar, India. Trop Med Int Health 14:639–644

    Article  CAS  Google Scholar 

  4. Remme JHF, Feenstra P, Lever PR, Médici A, Morel C, Noma M, Ramaiah KD, Richards F, Seketeli A, Schmunis G, van Brakel WH, Vassall A (2006) Tropical diseases targeted for elimination: Chagas disease, lymphatic filariasis, onchocerciasis, and leprosy. In: Disease control priorities in developing countries, 2nd edn. Oxford University Press, New York, pp 433–450. doi: 10.1596/978-0-821-36179-5/Chpt-22

  5. Bern C, Montgomery SP, Katz L, Caglioti S, Stramer SL (2008) Chagas disease and the US blood supply. Curr Opin Infect Dis 21(5):476–482

    Article  Google Scholar 

  6. Gascon J, Bern C, Pinazo MJ (2010) Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop 115(1–2):22–27

    Article  Google Scholar 

  7. Swallow BM (2000) Impacts of trypanosomiasis on African agriculture. PAAT Technical and Scientific Series, No. 2. FAO, Rome

    Google Scholar 

  8. Brun R et al (2010) Human African trypanosomiasis. Lancet 375(9709):148–159

    Article  Google Scholar 

  9. Bonds MH, Keenan DC, Rohani P, Sachs JD (2010) Poverty trap formed by the ecology of infectious diseases. Proc Biol Sci 277(1685):1185–1192

    Article  Google Scholar 

  10. Sachs JD (2007) Breaking the poverty trap. Targeted investments can trump a region's geographic disadvantages. Sci Am 297(3):40, 42

    Article  Google Scholar 

  11. Nussbaum K, Honek J, Cadmus CM, Efferth T (2010) Trypanosomatid parasites causing neglected diseases. Curr Med Chem 17(15):1594–1617

    Article  CAS  Google Scholar 

  12. Chappuis F et al (2007) Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol 5:873–882. doi:10.1038/nrmicro1748

    Article  CAS  Google Scholar 

  13. Costa CH (2008) Characterization and speculations on the urbanization of visceral leishmaniasis in Brazil. Cad Saude Publica 24:2959–2963

    Article  Google Scholar 

  14. David CV, Craft N (2009) Cutaneous and mucocutaneous leishmaniasis. Dermatol Ther 22(6):491–502

    Article  Google Scholar 

  15. Shaw JJ (1994) Taxonomy of the genus Leishmania: present and future trends and their implications. Mem Inst Oswaldo Cruz 89:471–478

    Article  CAS  Google Scholar 

  16. Desjeux P (2004) Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis 27:305–318

    Article  CAS  Google Scholar 

  17. Bern C, Maguire JH, Alvar J (2008) Complexities of assessing the disease burden attributable to leishmaniasis. PLoS Negl Trop Dis 2:e313

    Article  Google Scholar 

  18. Mubayi A, Castillo-Chavez C, Chowell G, Kribs-Zaleta C, Ali Siddiqui N, Kumar N, Das P (2009) Transmission dynamics and underreporting of Kala-azar in the Indian state of Bihar. J Theor Biol 262:177–185

    Article  Google Scholar 

  19. Herwaldt BL (1999) Leishmaniasis. Lancet 354(9185):1191–1199

    Article  CAS  Google Scholar 

  20. Murray HW, Berman JD, Davies CR, Saravia NG (2005) Advances in leishmaniasis. Lancet 366(9496):1561–1577

    Article  CAS  Google Scholar 

  21. Rittig MG, Bogdan C (2000) Leishmania–host-cell interaction: complexities and alternative views. Parasitol Today 16:292–297

    Article  CAS  Google Scholar 

  22. van Griensven J, Balasegaram M, Meheus F, Alvar J, Lynen L, Boelaert M (2010) Combination therapy for visceral leishmaniasis. Lancet Infect Dis 10:184–194

    Article  Google Scholar 

  23. Shankar EM, Vignesh R, Murugavel KG, Balakrishnan P, Ponmalar E, Rao UA, Velu V, Solomon S (2009) Common protozoans as an uncommon cause of respiratory ailments in HIV-associated immunodeficiency. FEMS Immunol Med Microbiol 57(2):93–103

    Article  CAS  Google Scholar 

  24. Chappuis F, Rijal S, Soto A, Menten J, Boelaert M (2006) A meta-analysis of the diagnostic performance of the direct agglutination test and rK39 dipstick for visceral leishmaniasis. BMJ 333(7571):723

    Article  Google Scholar 

  25. Goto H, Lindoso JA (2010) Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther 8(4):419–433

    Article  Google Scholar 

  26. Crum NF, Aronson NE, Lederman ER, Rusnak JM, Cross JH (2005) History of U.S. military contributions to the study of parasitic diseases. Mil Med 170(4 Suppl):17–29

    Google Scholar 

  27. Kenner JR, Aronson NE, Benson PM (1999) The United States military and leishmaniasis. Dermatol Clin 17:77–92

    CAS  Google Scholar 

  28. Ross R (1903) Note on the bodies recently described by Leishman and Donovan. BMJ 2:1261–1262

    Article  CAS  Google Scholar 

  29. Kinnamon KE, Steck EA, Loizeaux PS et al (1979) Leishmaniasis: military significance and new hope for treatment. Milit Med 144:660–664

    CAS  Google Scholar 

  30. Coleman RE, Hochberg LP, Putnam JL, Swanson KI, Lee JS, McAvin JC, Chan AS, Oguinn ML, Ryan JR, Wirtz RA, Moulton JK, Dave K, Faulde MK (2009) Use of vector diagnostics during military deployments: recent experience in Iraq and Afghanistan. Mil Med 174(9):904–920

    Google Scholar 

  31. Coleman RE, Burkett DA, Putnam JL, Sherwood V, Caci JB, Jennings BT, Hochberg LP, Spradling SL, Rowton ED, Blount K, Ploch J, Hopkins G, Raymond JL, O'Guinn ML, Lee JS, Weina PJ (2006) Impact of phlebotomine sand flies on U.S. Military operations at Tallil Air Base, Iraq: 1. background, military situation, and development of a “Leishmaniasis Control Program”. J Med Entomol 43(4):647–662

    Article  CAS  Google Scholar 

  32. Aronson NE, Sanders JW, Moran KA (2006) In harm's way: infections in deployed American military forces. Clin Infect Dis 43(8):1045–1051

    Article  Google Scholar 

  33. Murray CK (2008) Infectious disease complications of combat-related injuries. Crit Care Med 36(7 Suppl):S358–S364

    Article  Google Scholar 

  34. Murray CK (2008) Epidemiology of infections associated with combat-related injuries in Iraq and Afghanistan. J Trauma 64(3 Suppl):S232–S238

    Article  Google Scholar 

  35. World Health Organization (2005) Regional strategic framework for elimination of kala-azar from the South-East Asia region (2005–2015). WHO Regional Office for South-East Asia, New Delhi

    Google Scholar 

  36. Seaman J, Mercer AJ, Sondorp E (1996) The epidemic of visceral leishmaniasis in western Upper Nile, southern Sudan: course and impact from 1984 to 1994. Int J Epidemiol 25:862–871

    Article  CAS  Google Scholar 

  37. WHO Technical Report Series 946 (2010) Control of the Leishmaniases, Report of a meeting of the WHO Expert Committee on the Control of Leishmaniases, Geneva, 22–26 March 2010

    Google Scholar 

  38. Buscaglia CA et al (2006) Trypanosoma cruzi surface mucins: host-dependent coat diversity. Nat Rev Micro 4(3):229–236

    Article  CAS  Google Scholar 

  39. Hotez PJ, Bottazzi ME, Franco-Paredes C, Ault SK, Periago MR (2008) The neglected tropical diseases of Latin America and the Caribbean: a review of disease burden and distribution and a roadmap for control and elimination. PLoS Negl Trop Dis 2:e300. doi:10.1371/journal.pntd.0000300

    Article  Google Scholar 

  40. World Health Organization (2004) World health report 2004. Changing history. World Health Organization, Geneva

    Google Scholar 

  41. Mathers CD, Ezzati M, Lopez AD (2007) Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 1:e114. doi:10.1371/journal.pntd.0000149

    Article  Google Scholar 

  42. Moncayo A, Ortiz Yanine MI (2006) An update on Chagas disease (human American trypanosomiasis). Ann Trop Med Parasitol 100:663–677

    Article  CAS  Google Scholar 

  43. Tibayrenc M, Ayala FJ (2002) The clonal theory of parasitic protozoa: 12 years on. Trends Parasitol 18:405–410

    Article  CAS  Google Scholar 

  44. Andrade LO, Andrews NW (2005) The Trypanosoma cruzi-host-cell interplay: location, invasion, retention. Nat Rev Micro 3(10):819–823

    Article  CAS  Google Scholar 

  45. Andrade LO, Andrews NW (2005) The Trypanosoma cruzi-host-cell interplay: location, invasion, retention. Nat Rev Microbiol 3(10):819–823

    Article  CAS  Google Scholar 

  46. Barrett MP et al (2003) The trypanosomiases. Lancet 362:1469–1480

    Article  Google Scholar 

  47. Ribeiro I, Sevcsik A-M, Alves F, Diap G, Don R et al (2009) New, improved treatments for Chagas disease: from the R&D pipeline to the patients. PLoS Negl Trop Dis 3(7):e484. doi:10.1371/journal.pntd.0000484

    Article  Google Scholar 

  48. Zhang L, Tarleton RL (1999) Parasite persistence correlates with disease severity and localization in chronic Chagas' disease. J Infect Dis 180:480–486

    Article  CAS  Google Scholar 

  49. Rassi A Jr, Rassi A, Marin-Neto JA (2010) Chagas disease. Lancet 375(9723):1388–1402

    Article  Google Scholar 

  50. Schofield CJ, Dias JC (1999) The Southern Cone Initiative against Chagas disease. Adv Parasitol 42:1–27

    Article  CAS  Google Scholar 

  51. Coura JR, Dias JCP (2009) Epidemiology, control and surveillance of Chagas disease - 100 years after its discovery. Mem Inst Oswaldo Cruz 104(Suppl):I31–I40

    Google Scholar 

  52. Ramsey JM, Schofield CJ (2003) Control of Chagas disease vectors. Salud pública Méx (online) 45(2):123–128. ISSN 0036–3634. doi: 10.1590/S0036-36342003000200010

  53. Franco-Paredes C, Von A, Hidron A, Rodríguez-Morales AJ, Tellez I et al (2007) Chagas disease: an impediment in achieving the Millennium Development Goals in Latin America. BMC Int Health Hum Rights 7:7

    Article  Google Scholar 

  54. Prata A (2001) Clinical and epidemiological aspects of Chagas disease. Lancet Infect Dis 1:92–100

    Article  CAS  Google Scholar 

  55. Schmunis GA (2007) Epidemiology of Chagas disease in non-endemic countries: the role of international migration. Mem Inst Oswaldo Cruz 102(Suppl 1):75–85

    Article  Google Scholar 

  56. Paulinoa M, Iribarnea F, Dubinb M, Aguilera-Moralesc S, Tapiad O, Stoppani AO (2005) Mini Rev Med Chem 5:499–519

    Article  Google Scholar 

  57. Simarro PP, Jannin J, Cattand P (2008) Eliminating human African trypanosomiasis: where do we stand and what comes next? PLoS Med 5(2):e55

    Article  Google Scholar 

  58. Kennedy PG (2008) The continuing problem of human African trypanosomiasis (sleeping sickness). Ann Neurol 64(2):116–126

    Article  Google Scholar 

  59. Kennedy PG (2008) Diagnosing central nervous system trypanosomiasis: two stage or not to stage? Trans R Soc Trop Med Hyg 102(4):306–307

    Article  Google Scholar 

  60. WHO (2004) The World Health Report 2004. Shaping history. Annex Table 3: Burden of Disease in DALYs by cause, sex and mortality stratum in WHO regions, estimates for 2002, World Health Organization, Geneva (2004)

    Google Scholar 

  61. Lutumba P, Makieya E, Shaw A, Meheus F, Boelaert M (2007) Human African trypanosomiasis in a rural community, Democratic Republic of Congo. Emerg Infect Dis 13(2):248–254

    Article  Google Scholar 

  62. Field MC, Carrington M (2009) The trypanosome flagellar pocket. Nat Rev Micro 7(11):775–786

    Article  CAS  Google Scholar 

  63. Kennedy PG (2006) Diagnostic and neuropathogenesis issues in human African trypanosomiasis. Int J Parasitol 36(5):505–512

    Article  CAS  Google Scholar 

  64. Enanga B, Burchmore RJ, Stewart ML, Barrett MP (2002) Sleeping sickness and the brain. Cell Mol Life Sci 59(5):845–858

    Article  CAS  Google Scholar 

  65. Kennedy PG (2004) Human African trypanosomiasis of the CNS: current issues and challenges. J Clin Invest 113(4):496–504

    CAS  Google Scholar 

  66. Blum J, Schmid C, Burri C (2006) Clinical aspects of 2541 patients with second stage human African trypanosomiasis. Acta Trop 97(1):55–64

    Article  Google Scholar 

  67. Checchi F, Filipe JA, Haydon DT, Chandramohan D, Chappuis F (2008) Estimates of the duration of the early and late stage of gambiense sleeping sickness. BMC Infect Dis 8:16

    Article  Google Scholar 

  68. Checchi F, Filipe JAN, Barrett MP, Chandramohan D (2008) The natural progression of Gambiense sleeping sickness: what is the evidence? PLoS Negl Trop Dis 2:e303

    Article  Google Scholar 

  69. Chappuis F, Loutan L, Simarro P, Lejon V, Büscher P (2005) Options for field diagnosis of human african trypanosomiasis. Clin Microbiol Rev 18(1):133–146

    Article  Google Scholar 

  70. Steverding D (2008) The history of African trypanosomiasis. Parasit Vectors 1(1):3

    Article  Google Scholar 

  71. de Raadt P (2005) The history of sleeping sickness. http://www.who.int/trypanosomiasis_african/country/history/en/print.html

  72. Berrang Ford L (2007) Civil conflict and sleeping sickness in Africa in general and Uganda in particular. Confl Health 1:6

    Article  Google Scholar 

  73. Kaba D, Dje NN, Courtin F, Oke E, Koffi M, Garcia A, Jamonneau V, Solano P (2006) The impact of war on the evolution of sleeping sickness in west-central Côte d'Ivoire. Trop Med Int Health 11(2):136–143

    Article  CAS  Google Scholar 

  74. Stanghellini A, Josenando T (2001) The situation of sleeping sickness in Angola: a calamity. Trop Med Int Health 6(5):330–334

    Article  CAS  Google Scholar 

  75. Fèvre EM, Picozzi K, Fyfe J, Waiswa C, Odiit M, Coleman PG, Welburn SC (2005) A burgeoning epidemic of sleeping sickness in Uganda. Lancet 366(9487):745–747

    Article  Google Scholar 

  76. Legros D, Ollivier G, Etchegorry M, Paquet C, Burri B, Jannin J, Buscher P (2002) Treatment of human African trypanosomiasis—present situation and needs for research and development. Lancet Infect Dis 2:437–440

    Article  Google Scholar 

  77. Fèvre EM, Wissmann BV, Welburn SC, Lutumba P (2008) The burden of human african trypanosomiasis. PLoS Negl Trop Dis 2(12):e333

    Article  Google Scholar 

  78. Cecchi G, Paone M, Franco JR, Fevre EM, Diarra A, Ruiz JA, Mattioli RC, Simarro PP (2009) Towards the Atlas of human African trypanosomiasis. Int J Health Geogr 8:15

    Article  Google Scholar 

  79. Jenh AM, Pham PA (2008) Zambia HIV National Guidelines, Johns Hopkins Point-of-Care IT Center. http://www.zambiahivguide.org/drugs/antimicrobial_agents/suramin.html?contentInstanceId=438701

  80. World Health Organization, Media Centre (2006) Fact sheet no. 259, “African Trypanosomiasis”

    Google Scholar 

  81. de Nazaré C, Soeiro M, de Souza EM, Boykin DW (2007) Antiparasitic activity of aromatic diamidines and their patented literature. Expert Opin Ther Pat 17(8):927–939

    Article  CAS  Google Scholar 

  82. Bacchi C (2009) Chemotherapy of human African trypanosomiasis. Interdisciplinary Perspectives on Infectious Diseases (Hindawi Publishing Corporation) 1–5

    Google Scholar 

  83. Heby O, Persson L, Rentala M (2007) Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis. Amino Acids 33:359–366, PMID: 17610127

    Article  CAS  Google Scholar 

  84. Jacobs RT, Ding C (2010) Recent advances in drug discovery for neglected tropical diseases caused by infective kinetoplastid parasites. Annual Reports in Medicinal Chemistry, Volume 45, 2010 Elsevier Inc.

    Google Scholar 

  85. Dohn M, Weinberg WG, Torres RA, Follansbee SE, Caldwell PT, Scott JD, Gathe JC Jr, Haghighat DP, Sampson JH, Spotkov J, Deresinski SC, Meyer RD, Lancaster DJ (1994) Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Int Med 121(3):174–180, PMID: 7880228

    CAS  Google Scholar 

  86. Feddersen A, Sack K (1991) Experimental studies on the nephrotoxicity of pentamidine in rats. J Antimicrob Chemother 28(3):437–446, PMID: 1960124

    Article  CAS  Google Scholar 

  87. Assan R, Perronne C, Assan D, Chotard L, Mayaud C, Matheron S, Zucman D (1995) Pentamidine-induced derangements of glucose homeostasis. Determinant roles of renal failure and drug accumulation. A study of 128 patients. Diabetes Care 18(1):47–55, PMID: 7698047

    Article  CAS  Google Scholar 

  88. Antoniou T, Gough KA (2005) Early-onset pentamidine-associated second degree heart block and sinus bradycardia: Case report and review of the literature. Pharmacotherapy 25(6):899–903, PMID: 15927910

    Article  Google Scholar 

  89. Denise H, Barrett MP (2001) Uptake and mode of action of drugs used against sleeping sickness. Biochem Pharmacol 61(1):1–5, PMID: 11137702

    Article  CAS  Google Scholar 

  90. Werbovetz K (2006) Diamidines as antitrypanosomal, antileishmanial and antimalarial agents. Curr Opin Investig Drugs 7(2):147–157, PMID: 16499285

    CAS  Google Scholar 

  91. Soeiro MN, de Castro SL, de Souza EM, Batista DG, Silva CF, Boykin DW (2008) Diamidine activity against trypanosomes: the state of the art. Curr Mol Pharmacol 1(2):151–161, PMID: 20021429

    Article  CAS  Google Scholar 

  92. de Nazaré M, Soeiro C, de Souza EM, Boykin DW (2007) Antiparasitic activity of aromatic diamidines and their patented literature. Exp Opin Ther Pat 17(8):927–939

    Article  CAS  Google Scholar 

  93. Ansede JH, Anbazhagan M, Brun R, Easterbrook JD, Hall JE, Boykin DW (2004) O-alkoxyamidine prodrugs of furamidine: In vitro transport and microsomal metabolism as indicators of in vivo efficacy in a mouse model of Trypanosoma brucei rhodesiense infection. J Med Chem 47(17):4335–4338, PMID: 15294005

    Article  CAS  Google Scholar 

  94. Das BP, Boykin DW (1977) Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans. J Med Chem 20(4):531–536, PMID: 321783

    Article  CAS  Google Scholar 

  95. Clement B, Raether W (1985) Amidoximes of pentamidine: synthesis, trypanocidal and leishmanicidal activity. Arzneimittelforschung 35(7):1009–1014, PMID: 4052136

    CAS  Google Scholar 

  96. Yeates C (2003) DB-289. IDrugs 6(11):1086–1093, PMID: 14600842

    CAS  Google Scholar 

  97. Midgley I, Fitzpatrick K, Taylor LM, Houchen TL, Henderson SJ, Wright SJ, Cybulski ZR, John BA, McBurney A, Boykin DW, Trendler KL (2007) Pharmacokinetics and metabolism of the prodrug DB289 (2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) in rat and monkey and its conversion to the antiprotozoal/antifungal drug DB75 (2,5-bis(4-guanylphenyl)furan dihydrochloride). Drug Metab Dispos 35(6):955–967, PMID: 17360833

    Article  CAS  Google Scholar 

  98. Zhou L, Thakker DR, Voyksner RD, Anbazhagan M, Boykin DW, Hall JE, Tidwell RR (2004) Metabolites of an orally active antimicrobial prodrug, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime, identified by liquid chromatography/tandem mass spectrometry. J Mass Spectrom 39(4):351–360, PMID: 15103648

    Article  CAS  Google Scholar 

  99. Wang MZ, Saulter JY, Usuki E, Cheung YL, Hall M, Bridges AS, Loewen G, Parkinson OT, Stephens CE, Allen JL, Zeldin DC, Boykin DW, Tidwell RR, Parkinson A, Paine MF, Hall JE (2006) CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime]. Drug Metab Dispos 34(12):1985–1994, PMID: 16997912

    Article  CAS  Google Scholar 

  100. Saulter JY, Kurian JR, Trepanier LA, Tidwell RR, Bridges AS, Boykin DW, Stephens CE, Anbazhagan M, Hall JE (2005) Unusual dehydroxylation of antimicrobial amidoxime prodrugsby cytochrome b5 and NADH cytochrome b5 reductase. Drug Metab Dispos 33:1886–1893, PMID: 16131524

    CAS  Google Scholar 

  101. Thuita JK, Karanja SM, Wenzler T, Mdachi RE, Ngotho JM, Kagira JM, Tidwell R, Brun R (2008) Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis. Acta Trop 108(1):6–10, PMID: 18722336

    Article  CAS  Google Scholar 

  102. Mdachi RE, Thuita JK, Kagira JM, Ngotho JM, Murilla GA, Ndung'u JM, Tidwell RR, Hall JE, Brun R (2009) Efficacy of the novel diamidine compound 2,5-Bis(4-amidinophenyl)- furan-bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense infection in vervet monkeys after oral administration. Antimicrob Agents Chemother 53(3):953–957, PMID: 19064893

    Article  CAS  Google Scholar 

  103. Sturk LM, Brock JL, Bagnell CR, Hall JE, Tidwell RR (2004) Distribution and quantitation of the anti-trypanosomal diamidine 2,5-bis(4-amidinophenyl)furan (DB75) and its N-methoxy prodrug DB289 in murine brain tissue. Acta Trop 91:131–143, PMID: 15234662

    Article  CAS  Google Scholar 

  104. Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R (2009) New treatment option for second-stage African sleeping sickness: in vitro and in vivo efficacy of aza analogs of DB289. Antimicrob Agents Chemother 53(10):4185–4192, PMID: 19620327

    Article  CAS  Google Scholar 

  105. Pholig G, Bernhard S, Blum J, Burri C, Mpanya Kabeya A, Fina Lubaki J-P, Mpoo Mpoto A, Fungula Munungu B, Kambau Manesa Deo G, Nsele Mutantu P, Mbo Kuikumbi F, Fukinsia Mintwo A, Kayeye Munungi A, Dala A, Macharia S, Miaka Mia Bilenge C, Kande Betu Ku Mesu V, Ramon Franco J, Dieyi Dituvanga N, Olson C (2008) Phase 3 trial of pafuramidine maleate (DB289), a novel, oral drug, for treatment of first stage sleeping sickness: safety and efficacy. In: 57th Meeting of the American Society of Tropical Medicine & Hygiene, Abstract No. 542, New Orleans

    Google Scholar 

  106. Nyunt MM, Hendrix CW, Bakshi RP, Kumar N, Shapiro TA (2009) Phase I/II evaluation of the prophylactic antimalarial activity of pafuramidine in healthy volunteers challenged with Plasmodium falciparum sporozoites. Am J Trop Med Hyg 80(4):528–535, PMID: 19346370

    CAS  Google Scholar 

  107. De Souza EM, Lansiaux A, Bailly C, Wilson WD, Hu Q, Boykin DW, Batista MM, Araújo-Jorge TC, Soeiro MN (2004) Phenyl substitution of furamidine markedly potentiates its antiparasitic activity against Trypanosoma cruzi and Leishmania amazonensis. Biochem Pharmacol 68:593–600, PMID: 15276066

    Article  CAS  Google Scholar 

  108. De Souza EM, Melo G, Boykin DW, Kumar A, Hu Q, De Nazaré C, Soeiro M (2006) Trypanocidal activity of the phenyl-substituted analogue of furamidine DB569 against T. cruzi infection in vivo. J Antimicrob Chemother 58(3):610–614, PMID: 16854954

    Article  Google Scholar 

  109. Brendle JJ, Outlaw A, Kumar A, Boykin DW, Patrick DA, Tidwell RR, Werbovetz KA (2002) Antileishmanial activities of several classes of aromatic dications. Antimicrob Agents Chemother 46:797–807, PMID: 11850264

    Article  CAS  Google Scholar 

  110. Stephens CE, Brun R, Salem MM, Werbovetz KA, Tanious F, Wilson WD, Boykin DW (2003) The activity of diguanidino and ‘reversed’ diamidino 2,5-diarylfurans versus Trypanosoma cruzi and Leishmania donovani. Bioorg Med Chem Lett 13(12):2065–2069, PMID: 12781196

    Article  CAS  Google Scholar 

  111. Seiler N (2003) Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors. Curr Drug Targets 4(7):537–564, PMID: 14535654

    Article  CAS  Google Scholar 

  112. Wu F, Grossenbacher D, Gehring H (2007) New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells. Mol Cancer Ther 6(6):1831–1839, PMID: 17575112

    Article  CAS  Google Scholar 

  113. Coward JK, Pegg AE (1987) Specific multisubstrate adduct inhibitors of aminopropyltransferases and their effect on polyamine biosynthesis in cultured cells. Adv Enzyme Regul 26:107–113, PMID: 3673702

    Article  CAS  Google Scholar 

  114. Singh S, Mukherjee A, Khomutov AR, Persson L, Heby O, Chatterjee M, Madhubala R (2007) Antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion. Antimicrob Agents Chemother 51(2):528–534, PMID: 17101681

    Article  CAS  Google Scholar 

  115. Bitonti AJ, Byers TL, Bush TL, Casara PJ, Bacchi CJ, Clarkson AB Jr, McCann PP, Sjoerdsma A (1990) Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase. Antimicrob Agents Chemother 34:1485–1490, PMID: 1977366

    CAS  Google Scholar 

  116. Byers T, Casarat T, Bitonti A (1992) Uptake of the antitrypanosomal drug 5'-{[(Z)-4-amino-2-butenyljmethylamino}-5'-deoxyadenosine (MDL 73811) by the purine transport system of Trypanosoma brucei brucei. Biochem J 283:755–758, PMID: 1590765

    CAS  Google Scholar 

  117. Bacchi CJ, Barker RH Jr, Rodriguez A, Hirth B, Rattendi D, Yarlett N, Hendrick CL, Sybertz E (2009) Trypanocidal activity of 8-methyl-5'-{[(Z)-4-aminobut-2-enyl]-(methylamino)}adenosine (Genz-644131), an adenosylmethionine decarboxylase inhibitor. Antimicrob Agents Chemother 53(8):3269–3272, PMID: 19451291

    Article  CAS  Google Scholar 

  118. Krauth-Siegel RL, Bauer H, Schirmer RH (2005) Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia. Angew Chem Int Ed 44:690–715, PMID: 15657967

    Article  CAS  Google Scholar 

  119. Krauth-Siegel RL, Comini MA (2008) Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta 1780:1236–1248, PMID: 18395526

    CAS  Google Scholar 

  120. Rivera G, Bocanegra-García V, Ordaz-Pichardo C, Nogueda-Torres B, Monge A (2009) New therapeutic targets for drug design against Trypanosoma cruzi, advances and perspectives. Curr Med Chem 16(25):3286–3293, PMID: 19548870

    Article  CAS  Google Scholar 

  121. Soeiro MN, de Castro SL (2009) Trypanosoma cruzi targets for new chemotherapeutic approaches. Expert Opin Ther Targets 13(1):105–121, PMID: 19063710

    Article  CAS  Google Scholar 

  122. Galarreta BC, Sifuentes R, Carrillo AK, Sanchez L, Amado Mdel R, Maruenda H (2008) The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors. Bioorg Med Chem 16:6689–6695, PMID: 18558492

    Article  CAS  Google Scholar 

  123. Bitonti AJ, Dumont JA, Bush TL, Edwards ML, Stemerick DM, McCann PP, Sjoerdsma A (1989) Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha-difluoromethylornithine cure murine malaria. Proc Natl Acad Sci USA 86:651–655, PMID: 2463635

    Article  CAS  Google Scholar 

  124. Bonnet B, Soullez D, Davioud-Charvet E, Landry V, Horvath D, Sergheraert C (1997) New spermine and spermidine derivatives as potent inhibitors of Trypanosoma cruzi trypanothione reductase. Bioorg Med Chem 5:1249–1256, PMID: 9377084

    Article  CAS  Google Scholar 

  125. Baumann RJ, Hanson WL, McCann PP, Sjoerdsma A, Bitonti AJ (1990) Suppression of both antimony-susceptible and antimony-resistant Leishmania donovani by a bis(benzyl)polyamine analog. Antimicrob Agents Chemother 34:722–727, PMID: 2360812

    CAS  Google Scholar 

  126. Baumann RJ, McCann PP, Bitonti AJ (1991) Suppression of Leishmania donovani by oral administration of a bis(benzyl)polyamine analog. Antimicrob Agents Chemother 35:1403–1407, PMID: 1929300

    CAS  Google Scholar 

  127. Obexer W, Schmid C, Barbe J, Galy JP, Brun R (1995) (1995) Activity and structure relationship of acridine derivatives against African trypanosomes. Trop Med Parasitol 46(1):49–53, PMID: 7631129

    CAS  Google Scholar 

  128. Khan MO, Austin SE, Chan C, Yin H, Marks D, Vaghjiani SN, Kendrick H, Yardley V, Croft SL, Douglas KT (2000) Use of an additional hydrophobic binding site, the Z site, in the rational drug design of a new class of stronger trypanothione reductase inhibitor, quaternary alkylammonium phenothiazines. J Med Chem 43:3148–3156, PMID: 10956223

    Article  CAS  Google Scholar 

  129. Eberle C, Burkhard JA, Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F (2009) Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds. ChemMedChem 4(12):2034–2044, PMID: 19847846

    Article  CAS  Google Scholar 

  130. Spinks D, Shanks EJ, Cleghorn LAT, McElroy S, Jones D, James D, Fairlamb AH, Frearson JA, Wyatt PG, Gilbert IH (2009) Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. ChemMedChem 4:2060–2069

    Article  CAS  Google Scholar 

  131. Patterson S, Jones DC, Shanks EJ, Frearson JA, Gilbert IH, Wyatt PG, Fairlamb AH (2009) Synthesis and evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues as inhibitors of trypanothione reductase. ChemMedChem 4:1341–1353

    Article  CAS  Google Scholar 

  132. Blumenstiel K, Schoeneck R, Yardley V, Croft SL, Krauth-Siegel RL (1999) Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase. Biochem Pharmacol 58:1791–1799, PMID: 10571254

    Article  CAS  Google Scholar 

  133. LaMontagne MP, Dagli D, Khan MS, Blumbergs P (1980) Analogs of 8-[[6-(diethylamino)hexyl]amino]-6-methoxy-4- methylquinoline as candidate antileishmanial agents. J Med Chem 23(9):981–985, PMID: 7411553

    Article  CAS  Google Scholar 

  134. Yeates C (2002) Sitamaquine. Curr Opin Investig Drugs 3:1446–1452, PMID: 12431016

    CAS  Google Scholar 

  135. Berman JD, Lee LS (1983) Activity of 8-aminoquinolines against Leishmania tropica within human macrophages in vitro. Am J Trop Med Hyg 32(4):753–759, PMID: 6881421

    CAS  Google Scholar 

  136. Jha TK, Sundar S, Thakur CP, Felton JM, Sabin AJ, Horton J (2005) A phase II dose-ranging study of sitamaquine for the treatment of visceral leishmaniasis in India. Am J Trop Med Hyg 73(6):1005–1011, PMID: 16354802

    CAS  Google Scholar 

  137. Wasunna MK, Rashid JR, Mbui J, Kirigi G, Kinoti D, Lodenyo H, Felton JM, Sabin AJ, Albert MJ, Horton J, Albert MJ (2006) A phase II dose-increasing study of sitamaquine for the treatment of visceral leishmaniasis in Kenya. Am J Trop Med Hyg 73(5):871–876, PMID: 16282296

    Google Scholar 

  138. Fournet A, Gantier JC, Gautheret A, Leysalles L, Munos MH, Mayrargue J, Moskowitz H, Cavé A, Hocquemiller R (1994) The activity of 2-substituted quinoline alkaloids in BALB/c mice infected with Leishmania donovani. J Antimicrob Chemother 33:537–544

    Article  CAS  Google Scholar 

  139. Fournet A, Barrios AA, Muñoz V, Hocquemiller R, Cavé A, Bruneton J (1993) 2-substituted quinoline alkaloids as potential antileishmanial drugs. Antimicrob Agents Chemother 37(4):859–863

    CAS  Google Scholar 

  140. Nakayama H, Loiseau PM, Bories C, Torres de Ortiz S, Schinini A, Serna E, Rojas de Arias A, Fakhfakh MA, Franck X, Figadère B, Hocquemiller R, Fournet A (2005) Efficacy of orally administered 2-substituted quinolines in experimental murine cutaneous and visceral leishmaniases. Antimicrob Agents Chemother 49(12):4950–4956

    Article  CAS  Google Scholar 

  141. Urbina JA, Vivas J, Ramos H, Larralde G, Aguilar Z, Avilan L (1988) Alterations of lipid order profile and permeability of plasma membranes from Trypanosoma cruzi epimastigotes grown in the presence of ketoconazole. Mol Biochem Parasitol 30:185–196, PMID: 2845268

    Article  CAS  Google Scholar 

  142. Urbina JA, Concepcion JL, Rangel S, Visbal G, Lira R (2002) Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana. Mol Biochem Parasitol 125(1–2):35–45, PMID: 12467972

    Article  CAS  Google Scholar 

  143. Lazardi K, Urbina JA, de Souza W (1990) Ultrastructural alterations induced by two ergosterol biosynthesis inhibitors, ketoconazole and terbinafine, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Antimicrob Agents Chemother 34:2097–2105, PMID: 2073100

    CAS  Google Scholar 

  144. Maldonado RA, Molina J, Payares G, Urbina JA (1993) Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas’ disease. Antimicrob Agents Chemother 37:1353–1359, PMID: 8328786

    CAS  Google Scholar 

  145. McCabe R (1988) Failure of ketoconazole to cure chronic murine Chagas’ disease. J Infect Dis 158:1408–1409, PMID: 3143768

    Article  CAS  Google Scholar 

  146. Brener Z (1993) An experimental and clinical assay with ketoconazole in the treatment of Chagas disease. Mem Inst Oswaldo Cruz 88:149–153, PMID: 8246750

    Article  CAS  Google Scholar 

  147. Molina J, Martins-Filho O, Brener Z, Romanha AJ, Loebenberg D, Urbina JA (2000) Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocom¬petent and immunosuppressed murine hosts. Antimicrob Agents Chemother 44:150–155, PMID: 10602737

    Article  CAS  Google Scholar 

  148. Bahia MT, Talvani A, Chang S, Ribeiro I (2009) Combination of benznidazole and nifurtimox plus posaconazole enhances activity against Trypanosoma cruzi in experimental Chagas disease. Am Soc Trop Med Hyg 58th Annual Meeting, Washington DC, #746

    Google Scholar 

  149. Olivieri BP, Molina JT, de Castro SL, Pereira MC, Calvet CM, Urbina JA, Araújo-Jorge TC (2010) A comparative study of posaconazole and benznidazole in the prevention of heart damage and promotion of trypanocidal immune response in a murine model of Chagas disease. Int J Antimicrob Agents 36(1):79–83, PMID: 20452188

    Article  CAS  Google Scholar 

  150. Merck to Initiate Proof-of-Concept Study of Posaconazole for Chronic Chagas Disease, Recognized by WHO as One of the World's Neglected Tropical Diseases (2010) Merck website. http://www.merck.com/newsroom/news-release-archive/research-and-development/2010_0624.html. Accessed 19 July 2010

  151. Szajnman SH, Montalvetti A, Wang Y, Docampo R, Rodriguez JB (2003) Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase. Bioorg Med Chem Lett 13(19):3231–3235, PMID: 12951099

    Article  CAS  Google Scholar 

  152. Garzoni LR, Caldera A, Meirelles Mde N, de Castro SL, Docampo R, Meints GA, Oldfield E, Urbina JA (2004) Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi. Int J Antimicrob Agents 23(3):273–285, PMID: 15164969

    Article  CAS  Google Scholar 

  153. Garzoni LR, Waghabi MC, Baptista MM, de Castro SL, Meirelles Mde N, Britto CC, Docampo R, Oldfield E, Urbina JA (2004) Antiparasitic activity of risedronate in a murine model of acute Chagas' disease. Int J Antimicrob Agents 23(3):286–290, PMID: 15164970

    Article  CAS  Google Scholar 

  154. Szajnman SH, García Liñares GE, Li ZH, Jiang C, Galizzi M, Bontempi EJ, Ferella M, Moreno SN, Docampo R, Rodriguez JB (2008) Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase. Bioorg Med Chem 16(6):3283–3290, PMID: 18096393

    Article  CAS  Google Scholar 

  155. Urbina JA (2010) Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop 115(1–2):55–68, PMID: 19900395

    Article  Google Scholar 

  156. Azoles E1224 (Chagas) (2010) DNDi website. http://www.dndi.org/portfolio/azoles-e1224.html. Accessed 20 July 2010

  157. Drug Combinations (Chagas) (2010) DNDi website. http://www.dndi.org/portfolio/drug-combination.html. Accessed 3 Aug 2010

  158. Zeiman E, Greenblatt CL, Elgavish S, Khozin-Goldberg I, Golenser J (2008) Mode of action of fenarimol against Leishmania spp. J Parasitol 94(1):280–286

    Article  CAS  Google Scholar 

  159. Keenan M, Best WM, Armstrong T, Thompson A, Charman S, White K, Don R, von Geldern TW (2009) Novel compounds for the treatment of Chagas disease. Am Soc Trop Med Hyg 58th Annual Meeting, Washington DC, #751

    Google Scholar 

  160. Keenan M (2010) New compounds for the treatment of Chagas disease. Internat’l Conf Parasitol (ICOPA), Melbourne, Australia, #244

    Google Scholar 

  161. Buckner FS, Griffin JH, Wilson AJ, Van Voorhis WC (2001) Potent anti-Trypanosoma cruzi activities of oxidosqualene cyclase inhibitors. Antimicrob Agents Chemother 45(4):1210–1215

    Article  CAS  Google Scholar 

  162. Sealey-Cardona M, Cammerer S, Jones S, Ruiz-Pérez LM, Brun R, Gilbert IH, Urbina JA, González-Pacanowska D (2007) Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives. Antimicrob Agents Chemother 51(6):2123–2129, PMID: 17371809

    Article  CAS  Google Scholar 

  163. Braga MV, Urbina JA, de Souza W (2004) Effects of squalene synthase inhibitors on the growth and ultrastructure of Trypanosoma cruzi. Int J Antimicrob Agents 24(1):72–78, PMID: 15225865

    Article  CAS  Google Scholar 

  164. Orenes Lorente S, Gómez R, Jiménez C, Cammerer S, Yardley V, de Luca-Fradley K, Croft SL, Ruiz Perez LM, Urbina J, Gonzalez Pacanowska D, Gilbert IH (2005) Biphenylquinuclidines as inhibitors of squalene synthase and growth of parasitic protozoa. Bioorg Med Chem 13(10):3519–3529, PMID: 15848765

    Article  CAS  Google Scholar 

  165. Urbina JA, Concepcion JL, Caldera A, Payares G, Sanoja C, Otomo T, Hiyoshi H (2004) In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrob Agents Chemother 48(7):2379–2387, PMID: 15215084

    Article  CAS  Google Scholar 

  166. Hucke O, Gelb MH, Verlinde CL, Buckner FS (2005) The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease. J Med Chem 48(17):5415–5418, PMID: 16107140

    Article  CAS  Google Scholar 

  167. Chennamaneni NK, Arif J, Buckner FS, Gelb MH (2009) Isoquinoline-based analogs of the cancer drug clinical candidate tipifarnib as anti-Trypanosoma cruzi agents. Bioorg Med Chem Lett 19(23):6582–6584, PMID: 19875282

    Article  CAS  Google Scholar 

  168. Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS (2009) Rational modification of a candidate cancer drug for use against Chagas disease. J Med Chem 52(6):1639–1647, PMID: 19239254. Errata in: J Med Chem (2009) 52(14): 4549, J Med Chem (2009) 52(15): 4979

    Article  CAS  Google Scholar 

  169. Price HP, Menon MR, Panethymitaki C, Goulding D, McKean PG, Smith DF (2003) Myristoyl-CoA: protein N-myristoyltransferase, an essential enzyme and potential drug target in kinetoplastid parasites. J Biol Chem 278:7206–7214

    Google Scholar 

  170. Frearson JA, Brand S, McElroy SP, Cleghorn LAT, Smid O, Stojanovski L, Price HP, Guther MLS, Torrie LS, Robinson DA, Hallyburton I, Mpamhanga CP, Brannigan JA, Wilkinosn AJ, Hodgkinson M, Hui R, Qiu W, Raimi OG, van Aalten DMF, Brenk R, Gilbert IH, Read KD, Fairlamb AH, Ferguson MAJ, Smith DF, Wyatt PG (2010) N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature 464:728–734

    Article  CAS  Google Scholar 

  171. Robello C, Navarro P, Castanys S, Gamarro F (1997) A pteridine reductase gene ptr1 contiguous to a P-glycoprotein confers resistance to antifolates in Trypanosoma cruzi. Mol Biochem Parasitol 90:525–535

    Article  CAS  Google Scholar 

  172. Bello AR, Nare B, Freedman D, Hardy LW, Beverley SM (1994) PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc Natl Acad Sci USA 91:11442–11446

    Article  CAS  Google Scholar 

  173. Nare B, Hardy LW, Beverley S (1997) The roles of pteridine reductase and dihydrofolate reductase-thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major. J Biol Chem 272(21):13883–13891

    Article  CAS  Google Scholar 

  174. Nare B, Luba J, Hardy LW, Beverley S (1997) Parasitology 114(Suppl):S101–S110

    Google Scholar 

  175. Cavazzuti A, Paglietti G, Hunter WN, Gamarro F, Piras S, Loriga M, Alleca S, Corona P, McLuskey K, Tulloch L, Gibellini F, Ferrari S, Costi MP (2008) Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development. Proc Nat Acad Sci USA 105(5):1448–1453

    Article  CAS  Google Scholar 

  176. Khabnadideh S, Pez D, Musso A, Brun R, Pérez LM, González-Pacanowska D, Gilbert IH (2005) Design, synthesis and evaluation of 2,4-diaminoquinazolines as inhibitors of trypanosomal and leishmanial dihydrofolate reductase. Bioorg Med Chem 13(7):2637–2649

    Article  CAS  Google Scholar 

  177. Sirawaraporn W, Sertsrivanich R, Booth RG, Hansch C, Neal RA, Santi DV (1988) Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines. Mol Biochem Parasitol 31:79–86

    Article  CAS  Google Scholar 

  178. Pez D, Leal I, Zuccotto F, Boussard C, Brun R, Croft SL, Yardley V, Ruiz Perez LM, Gonzalez Pacanowska D, Gilbert IH (2003) 2,4-Diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase. Bioorg Med Chem 11(22):4693–4711

    Article  CAS  Google Scholar 

  179. Berman JD, King M, Edwards N (1989) Antileishmanial activities of 2,4-diaminoquinazoline putative dihydrofolate reductase inhibitors. Antimicrob Agents Chemother 33(11):1860–1863

    CAS  Google Scholar 

  180. Schormann N, Pal B, Senkovich O, Carson M, Howard A, Smith C, Delucas L, Chattopadhyay D (2005) Crystal structure of Trypanosoma cruzi pteridine reductase 2 in complex with a substrate and an inhibitor. J Struct Biol 152(1):64–75

    Article  CAS  Google Scholar 

  181. Dawson A, Gibellini F, Sienkiewicz N, Tulloch LB, Fyfe PK, McLuskey K, Fairlamb AH, Hunter WN (2006) Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate. Mol Microb 61(6):1457–1468

    Article  CAS  Google Scholar 

  182. Schüttelkopf AW, Hardy LW, Beverley SM, Hunter WN (2005) Structures of Leishmania major pteridine reductase complexes reveal the active site features important for ligand binding and to guide inhibitor design. J Mol Biol 352(1):105–116

    Article  CAS  Google Scholar 

  183. Tulloch LB, Martini VP, Iulek J, Huggan JK, Lee JH, Gibosn CL, Smith TK, Suckling CJ, Hunter WN (2010) Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases. J Med Chem 53:221–229

    Article  CAS  Google Scholar 

  184. Renslo AR, McKerrow JH (2006) Drug discovery and development for neglected parasitic diseases. Nat Chem Biol 2:701–710, PMID: 17108988

    Article  CAS  Google Scholar 

  185. Mottram JC, Frame MJ, Brooks DR, Tetley L, Hutchison JE, Souza AE, Coombs GH (1997) The multiple Cpb cysteine proteinase genes of Leishmania mexicana encode isoenzymes that differ in their stage regulation and substrate preferences. J Biol Chem 272:14285–14293, PMID: 9162063

    Article  CAS  Google Scholar 

  186. Robertson CD, Coombs GH (1994) Multiple high activity cysteine proteases of Leishmania mexicana are encoded by the lmcpb gene array. Microbiology 140:417–424, PMID: 8180705

    Article  CAS  Google Scholar 

  187. McKerrow JH, Rosenthal PJ, Swenerton R, Doyle P (2008) Development of protease inhibitors for protozoan infections. Curr Opin Infect Dis 21:668–672, PMID: 18978536

    Article  CAS  Google Scholar 

  188. McKerrow JH, Doyle PS, Engel JC, Podust LM, Robertson SA, Ferreira R, Saxton T, Arkin M, Kerr ID, Brinen LS, Craik CS (2009) Two approaches to discovering and developing new drugs for Chagas disease. Mem Inst Oswaldo Cruz 104(S1):263–269, PMID: 19753483

    Article  CAS  Google Scholar 

  189. Jacobsen W, Christians U, Benet LZ (2000) In vitro evaluation of the disposition of a novel cysteine protease inhibitor. Drug Metab Dispos 28(11):1343–1351, PMID: 11038163

    CAS  Google Scholar 

  190. Engel JC, Doyle PS, Hsieh I, McKerrow JH (1998) Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection. J Exp Med 188:725, PMID: 9705954

    Article  CAS  Google Scholar 

  191. Doyle PS, Zhou YM, Engel JC, McKerrow JH (2007) A cysteine protease inhibitor cures Chagas’ disease in an immunodeficient-mouse model of infection. Antimicrob Agents Chemother 51(11):3932–3939, PMID: 17698625

    Article  CAS  Google Scholar 

  192. Institute for One World Health (2010) http://www.oneworldhealth.org/chagas. Accessed 10 June 2010

  193. Roush WR, Gwaltney SL II, Cheng J, Scheidt KA, McKerrow JH, Hansell E (1998) Vinyl sulfonate esters and vinyl sulfonamides: potent, irreversible inhibitors of cysteine proteases. J Am Chem Soc 120:10994–10995

    Article  CAS  Google Scholar 

  194. Roush WR, Cheng J, Knapp-Reed B, Alvarez-Hernandez A, McKerrow JH, Hansell E, Engel JC (2001) Potent second generation vinyl sulfonamide inhibitors of the trypanosomal cysteine protease cruzain. Bioorg Med Chem Lett 11:2759–2762, PMID: 11591518

    Article  CAS  Google Scholar 

  195. Du X, Guo C, Hansell E, Doyle PS, Caffrey CR, Holler TP, McKerrow JH, Cohen FE (2002) Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain. J Med Chem 45:2695–2707, PMID: 12061873

    Article  CAS  Google Scholar 

  196. Brak K, Doyle PS, McKerrow JH, Ellman JA (2008) Identification of a new class of nonpeptidic inhibitors of cruzain. J Am Chem Soc 130(20):6404–6410, PMID: 18435536

    Article  CAS  Google Scholar 

  197. Chen YT, Lira R, Hansell E, McKerrow JH, Roush WR (2008) Synthesis of macrocyclic trypanosomal cysteine protease inhibitors. Bioorg Med Chem Lett 18(22):5860–5863, PMID: 18585034

    Article  CAS  Google Scholar 

  198. Ponte-Sucre A, Vicik R, Schultheis M, Schirmeister T, Moll H (2006) Aziridine-2,3-dicarboxylates, peptidomimetic cysteine protease inhibitors with antileishmanial activity. Antimicrob Agents Chemother 50:2439–2447, PMID: 16801424

    Article  CAS  Google Scholar 

  199. St Hilaire PM, Alves LC, Herrera F, Renil M, Sanderson SJ, Mottram JC, Coombs GH, Juliano MA, Juliano L, Arevalo J, Meldal M (2002) Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B. J Med Chem 45:1971–1982, PMID: 11985465

    Article  CAS  Google Scholar 

  200. Ascenzi P, Salvati L, Bolognesi M, Colasanti M, Polticelli F, Venturini G (2001) Inhibition of cysteine protease activity by NO-donors. Curr Protein Pept Sci 2:137–153, PMID: 12370021

    Article  CAS  Google Scholar 

  201. Colasanti M, Salvati L, Venturini G, Ascenzi P, Gradoni L (2001) Cysteine protease as a target for nitric oxide in parasitic organisms. Trends Parasitol 17:575, PMID: 11756039

    Article  CAS  Google Scholar 

  202. Vespa GNR, Cunha FQ, Silva JS (1994) Nitric oxide is involved in control of Trypanosoma cruzi-induced parasitemia and directly kills the parasite in vitro. Infect Immun 62:5177–5182, PMID: 7523307

    CAS  Google Scholar 

  203. Zeina B, Banfield C, al-Assad S (1997) Topical glyceryl trinitrate: a possible treatment for cutaneous leishmaniasis. Clin Exp Dermatol 22:244–245, PMID: 9536549

    Article  CAS  Google Scholar 

  204. Lopez-Jaramillo P, Ruano C, Rivera J, Teran E, Salazar-Irigoyen R, Esplugues JV, Moncada S (1998) Treatment of cutaneous leishmaniasis with nitric-oxide donor. Lancet 351:1176–1177, PMID: 9643692

    Article  CAS  Google Scholar 

  205. Davidson RN, Yardley V, Croft SL, Konecny P, Benjamin N (2000) A topical nitric oxide-generating therapy for cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 94:319–322, PMID: 10975011

    Article  CAS  Google Scholar 

  206. Salvati L, Mattu M, Colasanti M, Scalone S, Venturini G, Gradoni L, Ascenzi P (2001) NO donors inhibit Leishmania infantum cysteine proteinase activity. Biochim Biophys Acta 1545:357–366, PMID: 11342060

    Article  CAS  Google Scholar 

  207. Ascenzi P, Bocedi A, Gentile M, Visca P, Gradoni L (2004) Inactivation of parasite cysteine proteinases by the NO-donor 4-(phenylsulfonyl)-3-((2-(dimethylamino)ethyl)thio)-furoxan oxalate. Biochim Biophys Acta 1703:69–77, PMID: 15588704

    CAS  Google Scholar 

  208. Buates S, Matlashewski GJ (1999) Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: efficacy and mode of action. Infect Dis 179:1485–1494, PMID: 10228071

    Article  CAS  Google Scholar 

  209. Arevalo I, Ward B, Miller R, Meng TC, Najar E, Alvarez E, Matlashewski G, Llanos-Cuentas A (2001) Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator. Clin Infect Dis 33:1847–1851, PMID: 11692295

    Article  CAS  Google Scholar 

  210. Miranda-Verástegui C, Llanos-Cuentas A, Arévalo I, Ward BJ, Matlashewski G (2005) Randomized, double-blind clinical trial of topical imiquimod 5% with parenteral meglumine antimoniate in the treatment of cutaneous leishmaniasis in Peru. Clin Infect Dis 40(10):1395–1403, PMID: 15844060

    Article  Google Scholar 

  211. Miranda-Verastegui C, Tulliano GF, Gyorkos TW, Calderon W, Rahme E, Ward B, Cruz M, Llanos-Cuentas A, Matlashewski G (2009) First-line therapy for human cutaneous leishmaniasis in Peru using the TLR7 agonist imiquimod in combination with pentavalent antimony. PLoS 3(7):e491, PMID: 19636365

    Google Scholar 

  212. Al-Mutairi N, Alshiltawy M, El Khalawany M, Joshi A, Eassa BI, Manchanda Y, Gomaa S, Darwish I, Rijhwani M (2009) Treatment of Old World cutaneous leishmaniasis with dapsone, itraconazole, cryotherapy, and imiquimod, alone and in combination. Int J Derm 48:862–869

    Article  CAS  Google Scholar 

  213. Morgan RE, Werbovetz KA (2008) Selective lead compounds against kinetoplastid tubulin. Adv Exp Med Biol 625:33–47, PMID: 18365657

    Article  CAS  Google Scholar 

  214. Ochola DO, Prichard RK, Lubega GW (2002) Classical ligands bind tubulin of trypanosomes and inhibit their growth in vitro. J Parasitol 88:600–604, PMID: 12099434

    CAS  Google Scholar 

  215. Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, Cannova C, Meinke PT, Colletti SL, Bednarek MA, Singh SB, Goetz MA, Dombrowski AW, Polishook JD, Schmatz DM (1996) Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA 93:13143–13147, PMID: 8917558

    Article  CAS  Google Scholar 

  216. Mai A, Cerbara I, Valente S, Massa S, Walker LA, Tekwani BL (2004) Antimalarial and antileishmanial activities of aroyl-pyrrolyl-hydroxyamides, a new class of histone deacetylase inhibitors. Antimicrob Agents Chemother 48:1435–1436, PMID: 15047563

    Article  CAS  Google Scholar 

  217. Meinke PT, Colletti SL, Doss G, Myers RW, Gurnett AM, Dulski PM, Darkin-Rattray SJ, Allocco JJ, Galuska S, Schmatz DM, Wyvratt MJ, Fisher MH (2000) Synthesis of apicidin-derived quinolone derivatives: parasite-selective histone deacetylase inhibitors and antiproliferative agents. J Med Chem 43(25):4919–4922, PMID: 11124001

    Article  CAS  Google Scholar 

  218. Colletti SL, Myers RW, Darkin-Rattray SJ, Gurnett AM, Dulski PM, Galuska S, Allocco JJ, Ayer MB, Li C, Lim J, Crumley TM, Cannova C, Schmatz DM, Wyvratt MJ, Fisher MH, Meinke PT (2001) Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure-activity relationships of apicidin. Part 1. Bioorg Med Chem Lett 11(2):107–111, PMID: 11206438

    Article  CAS  Google Scholar 

  219. Colletti SL, Myers RW, Darkin-Rattray SJ, Gurnett AM, Dulski PM, Galuska S, Allocco JJ, Ayer MB, Li C, Lim J, Crumley TM, Cannova C, Schmatz DM, Wyvratt MJ, Fisher MH, Meinke PT (2001) Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure-activity relationships of apicidin. Part 2. Bioorg Med Chem Lett 11(2):113–117, PMID: 11206439

    Article  CAS  Google Scholar 

  220. Shin BS, Chang HS, Park EH, Yoon CH, Kim HY, Kim J, Ryu JK, Zee OP, Lee KC, Cao D, Yoo SD (2006) Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats. Biopharm Drug Dispos 27(2):69–75

    Article  CAS  Google Scholar 

  221. Cavalcanti DP, Fragoso SP, Goldenberg S, de Souza W, Motta MC (2004) The effect of topoisomerase II inhibitors on the kinetoplast ultrastructure. Parasitol Res 94:439–448, PMID: 15517387

    Article  Google Scholar 

  222. Das BB, Sengupta T, Ganguly A, Majumder HK (2006) Topoisomerases of kinetoplastid parasites: why so fascinating? Mol Microbiol 62(4):917–927, PMID: 17042788

    Article  CAS  Google Scholar 

  223. Das BB, Sen N, Roy A, Dasgupta SB, Ganguly A, Mohanta BC, Dinda B, Majumder HK (2006) Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I. Nucleic Acids Res 34(4):1121–1132, PMID: 16488884

    Article  CAS  Google Scholar 

  224. Sen N, Das BB, Ganguly A, Mukherjee T, Tripathi G, Bandyopadhyay S, Rakshit S, Sen T, Majumder HK (2004) Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani. Cell Death Differ 8:924–936, PMID: 15118764

    Article  CAS  Google Scholar 

  225. NECT – Nifurtimox-Eflornithine Co-Administration (HAT) (2010) DNDi website. http://www.dndi.org/portfolio/nect.html. Accessed 17 July 2010

  226. Priotto G, Kasparian S, Ngouama D, Ghorashian S, Arnold U, Ghabri S, Karunakara U (2007) Nifurtimox-eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Congo. Clin Infect Dis 45:1435–1442, PMID: 17990225

    Article  CAS  Google Scholar 

  227. Priotto G, Kasparian S, Mutombo W, Ngouama D, Gharashian S, Arnold U, Ghabri S, Baudin E, Buard V, Kazadi-Kyanza S, Ilunga M, Mutangala W, Pohlig G, Schmid C, Karunakara U, Torreele E, Kande V (2009) Nifurtomox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet 374:56–64, PMID: 19559476

    Article  CAS  Google Scholar 

  228. Checchi F, Piola P, Ayikoru H, Thomas F, Legros D, Priotto G (2007) Nifurtimox plus eflornithine for late-stage sleeping sickness in Uganda: a case series. PLoS Negl Trop Dis 1:e64, PMID: 18060083

    Article  CAS  Google Scholar 

  229. Baudin E (2008) Multicenter clinical trial of nifurtimox-eflornithine combination therapy for second-stage sleeping sickness. Am Soc Trop Med Hyg 57th Annual Meeting, New Orleans

    Google Scholar 

  230. NECT Added to WHO Essential Medicines List as Combination Treatment Against Sleeping Sickness (2010) DNDi website. http://www.dndi.org/press-releases/456-nect-added-to-who-essential-medicines-list-as-combination-treatment-against-sleeping-sickness.html. Accessed 16 July 2010

  231. Torreele E (2009) Proposal for the inclusion of Nifurtimox-Eflornithine Combination as a treatment for Stage 2 Trypanosoma Brucei Gambiense Human African Trypanosomiasis (Sleeping Sickness) in the WHO Model List of Essential Medicines. 17th Expert Committee on the Selection and Use of Essential Medicines, Geneva

    Google Scholar 

  232. Yun O, Priotto G, Tong J, Flevaud L, Chappuis F (2009) NECT is next: implementing the new drug combination therapy for trypanosoma brucei gambiense sleeping sickness. PloS Negl Trop Dis 3:1–7

    Article  CAS  Google Scholar 

  233. Chagas Disease Partnership Will Deliver Safe, Easy-to-Use Treatment for Children (2008) DNDi website. http://www.dndi.org/press-releases/2008/106-chagas-disease-partnership-will-deliver-safe-easy-to-use-treatment-for-children.html. Accessed 16 July 2010

  234. Terlouw DJ, Alves FP, Sosa-Estani S, Freilij H, Altcheh J, Brutus L, Kiechel J-R, Ribeiro I (2009) A new pediatric tablet strength of benznidazole for the treatment of Chagas disease. Am Soc Trop Med Hyg 58th Annual Meeting, Washington DC, #834

    Google Scholar 

  235. Jaime Altcheh MD (study director) (2009) Population pharmacokinetics of benznidazole in children with Chagas disease. ClinicalTrials.gov identifier NCT00699387

    Google Scholar 

  236. Sundar S, Rai M (2005) Treatment of visceral Leishmaniasis. Expert Opin Pharmacother 6:2821–2829, PMID: 16318433

    Article  CAS  Google Scholar 

  237. Berman J (2005) Clinical status of agents being developed for leishmaniasis. Expert Opin Investig Drugs 14:1337–1346, PMID: 16255674

    Article  CAS  Google Scholar 

  238. van Griensven J, Boerlaert M (2009) Combination therapy for visceral leishmaniasis: why, what and where? WorldLeish4, 4th World Congress on Leishmaniasis, Lucknow, India

    Google Scholar 

  239. Combination Therapy (VL in Asia) (2010) DNDi website. http://www.dndi.org/portfolio/combination-therapy-asia.html. Accessed 2 Aug 2010

  240. Combination Therapy (VL in Africa) (2010) DNDi website. http://www.dndi.org/portfolio/combination-therapy-africa.html. Accessed 2 Aug 2010

  241. Combination Therapy (VL in Latin America) (2010) DNDi website. http://www.dndi.org/portfolio/combination-therapy-latin-america.html. Accessed 2 Aug 2010

  242. Mudawi AM (2009) New treatments for visceral leishmaniasis in East Africa: the story so far. WorldLeish4, 4th World Congress on Leishmaniasis, Lucknow, India

    Google Scholar 

  243. Hailu A, Musa A, Wasunna M, Balasegaram M, Yifru S, Mengistu G, Hurissa Z, Hailu W, Weldegebreal T, Tesfaye S, Makonnen E, Khalil E, Ahmed O, Fadlall A, El-Hassan A, Raheem M, Mueller M, Koummuki Y, Rashid J, Mbui J, Mucee G, Njoroge S, Manduku V, Musibi A, Mutuma G, Kirui F, Lodenyo H, Mutea D, Kirigi G, Edward T, Smith P, Muthami L, Royce C, Ellis S, Alobo M, Omollo R, Kesusu J, Owiti R, Kinuthia J (2010) PLoS Negl Trop Dis 4:e709

    Article  CAS  Google Scholar 

  244. Musai AM, Younis B, Fadlalla A, Royce C, Balasegaram M, Wasunna M, Hailu A, Edward T, Omollo R, Mudawi M, Kokwaro G, El-Hassan A, Khalil E (2010) Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study. PLoS Negl Trop Dis 4:e855

    Article  CAS  Google Scholar 

  245. van Griensven J, Boelaert M (2011) Combination therapy for visceral leishmaniasis. Lancet 377(9764):443–444

    Article  Google Scholar 

  246. Sundar S, Sinha PK, Rai M et al (2011) Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 377(9764):477–486

    Article  CAS  Google Scholar 

  247. Torreele E (2008) Fexinidazole: a rediscovered compound progresses as a potential candidate for sleeping sickness. Am Soc Trop Med Hyg 57th Annual Meeting, New Orleans. http://www.youtube.com/watch?v=8QCrq99yzUc&feature=player_embedded

  248. Best WM, Sims CG, Scaffidi A, Giuseppe L, Thompson RCA, Armstrong T. Antiparasitic compounds. WO2010/009508

    Google Scholar 

  249. Bray MA, Torreele E, Mazué G, Tweats D, Sassella D (2009) Fexinidazole investigator’s brochure. DNDi

    Google Scholar 

  250. Jennings FW, Urquhart GM (1983) The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice. Z Parasitenkd 69(5):577–581

    Article  CAS  Google Scholar 

  251. Raether W, Seidenath H (1983) The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Ann Trop Med Parasitol 77(1):13–26

    CAS  Google Scholar 

  252. CEREP Study No. 14929 (2008) In vitro pharmacology – study of fexinidazole, fexinidazole sulfone and fexinidazole sulfoxide

    Google Scholar 

  253. Torreele E, Bourdin B, Tweats D, Kaiser M, Brun R, Mazué G, Bray MA, Pécoul B (2010) Fexinidazole – a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl Trop Dis 4:e923

    Article  CAS  Google Scholar 

  254. Best WM, Sims CG, Thompson RCA, Reid SA, Armson A, Reynoldson JA. Antiparasitic compounds. WO2006/108224

    Google Scholar 

  255. Wylie S, Sokolova A, Patterson S, Fairlamb AH (2010) Cross-resistance to nitro-drugs and implications for the treatment of human African trypanosomiasis. Internat’l Conf Parasitol (ICOPA), Melbourne, Australia, #197

    Google Scholar 

  256. Bourdin B, Jędrysiak R, Tweats D, Brun R, Kaiser M, Suwiński J, Torreele E (2011) 1-Aryl-2202 4-nitroimidazoles, a new promising series for the treatment of Human African Trypanosomiasis. Eur J Med Chem, 46(5):1524–1535

    Google Scholar 

  257. Freeman JC, Perales JB, Woodland A, Bacchi CJ, Bowling TS, Cleghorn L, Gamon CG, Grimaldi R, Hauser D, Mercer LT, Nare B, Nguyen TM, Noe RA, Rewerts CE, Wring SA, Wyatt PG, Yarlett NR, Jacobs RT, Don R (2009) Hit-to-lead and lead optimization of novel small molecules for the treatment of human african trypanosomiasis. Amer Chem Soc 238th National Meeting, Washington DC, #MEDI 346

    Google Scholar 

  258. Brenk R, Schipani A, James D et al (2008) Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem 3(3):435–444

    Article  CAS  Google Scholar 

  259. Martin D (2010) Identification and development of new chemical entities to treat visceral leishmaniasis: a bumpy road. Internat’l Conf Parasitol (ICOPA), Melbourne, Australia, #243

    Google Scholar 

  260. Rock FL, Mao W, Yaremchuk A, Tukalo M, Crepin T, Zhou H, Zhang YK, Hernandez V, Akama T, Baker SJ, Plattner JJ, Shapiro L, Martinis SA, Benkovic SJ, Cusack S, Alley MRK (2007) An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 316:1759–1761

    Article  CAS  Google Scholar 

  261. Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ (2009) Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 19:2129–2132

    Article  CAS  Google Scholar 

  262. Ding D, Zhao Y, Meng Q, Xie D, Nare B, Chen D, Bacchi CJ, Yarlett N, Zhang Y-K, Hernandez V, Xia Y, Freund Y, Abdulla M, Ang K-H, Ratnam J, McKerrow JH, Jacobs RT, Zhou H, Plattner JJ (2010) Discovery of novel benzoxaborole-based potent antitrypanosomal agents. ACS Med Chem Lett 1(4):165–169

    Article  CAS  Google Scholar 

  263. Xie D, Zhang YK, Hernandez V, Ding D, Xia A, Nare B, Jacobs RT, Freund Y, Don R, McKerrow J, Zhou H, Plattner J (2008) A new class of benzoxaborole-based potent antitrypanosomal agents: probing the effect of different linkage groups on trypanosoma brucei growth inhibition. Am Soc Trop Med Hyg 57th Annual Meeting, New Orleans, #162

    Google Scholar 

  264. Jacobs RT, Nare B, Wring SA, Orr MD, Chen D, Sligar JM, Jenks MX, Noe RA, Bowling TS, Mercer LT, Rewerts C, Gaukel E, Owens J, Parham R, Randolph R, Beaudet B, Bacchi CJ, Yarlett N, Plattner JJ, Freund Y, Ding C, Akama T, Zhang YK, Brun R, Kaiser M, Scandale I, Don R (2011) SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis. PLoS Negl Trop Dis. 5(6)e1151

    Google Scholar 

  265. Jacobs R, Ding C, Freund Y, Jarnagin K, Plattner J, Bacchi C, Yarlett N, Orr M, Nare B, Rewerts C, Chen D, Noe A, Sligar J, Jenks M, Wring S, Don R (2009) Lead optimization of novel boron-containing drug candidates for the treatment of human African trypanosomiasis. Am Soc Trop Med Hyg 58th Annual Meeting, Washington DC, #829

    Google Scholar 

  266. Nare B, Mercer L, Bowling T, Orr M, Chen D, Sligar J, Jenks M, Noe A, Wring S, Bacchi C, Yarlett N, Freund Y, Plattner J, Jarnagin K, Don R, Jacobs R (2009) In vitro pharmacodynamics and mechanism of action studies of oxaborole 6-carboxamides: a new class of compounds for the treatment of African trypanosomiasis. Am Soc Trop Med Hyg 58th Annual Meeting, Washington DC, #132

    Google Scholar 

  267. Wring S, Bacchi C, Beaudet B, Bowling T, Chen D, Don R, Freund Y, Gaukel E, Jarnagin K, Jenks M, Mercer L, Nare B, Noe A, Orr M, Parham R, Plattner J, Rewerts C, Sligar J, Yarlett N, Jacobs R (2009) SCYX-6759, an orally bioavailable oxaborole 6-carboxamide, achieves therapeutically relevant exposure in brain and CSF leading to 100% cures in a mouse model of CNS-stage human African trypanosomiasis. Am Soc Trop Med Hyg 58th Annual Meeting, Washington DC, #748

    Google Scholar 

  268. Nare B, Wring S, Bacchi C, Beaudet B, Bowling T, Brun R, Chen D, Ding C, Freund Y, Gaukel E, Hussain A, Jarnagin K, Jenks M, Kaiser M, Mercer L, Mejia E, Noe A, Orr M, Parham R, Plattner J, Randolph R, Rattendi D, Rewerts C, Sligar J, Yarlett N, Don R, Jacobs R (2010) Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system African trypanosomiasis. Antimicrob Agents Chemother 54(10):4379–4388

    Article  CAS  Google Scholar 

  269. Oxaboroles for HAT (2010) DNDi web site. http://www.dndi.org/portfolio/oxaborole.html. Accessed 16 July 2010

  270. Nare B, Wring S, Bacchi C et al (2010) Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system african trypanosomiasis. Antimicrob Agents Chemother 54(10):4379–4388

    Article  CAS  Google Scholar 

  271. Freund Y (2010) AN4169, a novel boron-containing small molecule with in vivo efficacy against T. cruzi in mice. Internat’l Conf Parasitol (ICOPA), Melbourne, Australia, #373

    Google Scholar 

  272. Kerfoot M (2010) Three simple, rapid in vitro assays for determining stage specificity and the cidal or static activity of anti-Typanosoma cruzi compounds. Internat’l Conf Parasitol (ICOPA), Melbourne, Australia, #508

    Google Scholar 

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Acknowledgments

The authors would like to thank Federica Givannini for critical reading of the manuscript. DNDi is grateful to its donors, public, and private, who have provided funding to DNDi since its inception in 2003. With the support of these donors, DNDi is well on its way to achieving the objectives of a robust pipeline with the aim to deliver six to eight new treatments by 2014. A full list of DNDi’s donors can be found at: http://www.dndi.org/index.php/donors.html?ids=8. The donors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Embedded Medicinal Chemistry Consultant, Richmond, IL, 60071, USA

    Tomas von Geldern

  2. Drug for Neglected Diseases initiative, Geneva, 1202, Switzerland

    Tomas von Geldern, Ivan Scandale & Robert Don

  3. Graduate Program in Public Health Studies, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Michael Oscar Harhay

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  1. Tomas von Geldern
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von Geldern, T., Harhay, M.O., Scandale, I., Don, R. (2011). Kinetoplastid Parasites. In: Elliott, R. (eds) Third World Diseases. Topics in Medicinal Chemistry, vol 7. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2011_17

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