Scientific Publications - HAT

2011

Synthesis of 2H- and 14C-labeled fexinidazole and its primary metabolites labeled with 2H by E. Fontana, Alberto Pignatti, Serena Venegoni, and Michael A. Bray. The Journal of labelled compounds and radiopharmaceuticals. August 30, 2011. DOI: 10.1002/jlcr.1914
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Kinetoplastid Parasites by Tomas von Geldern, Michael Oscar Harhay, Ivan Scandale and Robert Don
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SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis by Jacobs R.T, Nare B, Wring S.A, Orr M.D, Chen D, Sligar J.M, Jenks M.X, Noe R.A, Bowling T.S, Mercer L.T, Rewerts C, Gaukel E, Owens J, Parham R, Randolph R, Beaudet B, Bacchi C.J, Yarlett N, Plattner J.J, Freund Y, Ding C, Akama T, Zhang Y-K, Brun R, Kaiser M, Scandale I, Don R. PLoS NTD. 2011 June. e1151. doi:10.1371/journal.pntd.0001151
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Challenges of controlling sleeping sickness in areas of violent conflict: experience in the Democratic Republic of Congo by Tong J, Valverde O, Mahoudeau C, Yun O, Chappuis F. Conflict and Health. May 2011, 5:7 doi:10.1186/1752-1505-5-7
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1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis by Bernadette Bourdin Trunz, Rafał Jędrysiak, David Tweats, Reto Brun, Marcel Kaiser, Jerzy Suwiński and Els Torreele, European Journal of Medicinal Chemistry, available online 5 February 2011, doi: 10.1016/j.ejmech.2011.01.071
Nitroimidazoles are a well-known class of antibacterial and antiprotozoal drugs but in spite of the widespread clinical and veterinary use of these drugs, this family has been stigmatized in part due to associated genotoxicity problems. Here we report the synthesis, the anti-trypanosomal activity and a structure–activity relationship (SAR) study of a series of about fifty 1-aryl-4-nitro-1H-imidazoles, with an emphasis on selected in vivo active molecules. Compounds 4-nitro-1-{4-(trifluoromethoxy)phenyl}-1H-imidazole and 1-(3,4-dichlorophenyl)-4-nitro-1H-imidazole are promising leads for the treatment of human African trypanosomiasis (HAT or sleeping sickness), including the fatal stage 2 of the disease, for which new treatments are urgently needed.
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2010

Fexinidazole – A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness by Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazué G, Bray M A, Pécoul B. PLoS NTD, 2010 December, Vol. 4, Issue 12, e923.
Human African trypanosomiasis (HAT) is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts, could be a short-course, safe and effective oral treatment for both acute and chronic HAT and that could be implemented at the primary health care level.
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NECT Is Next: Implementing the New Drug Combination Therapy for Trypanosoma brucei gambiense Sleeping Sickness by Yun O, Priotto G, Tong J, Flevaud L, Chappuis F. PLoS NTD, 2010 May, 4(5):e720 
In April 2009, a new treatment option for second-stage T. b. gambiense HAT, nifurtimox-eflornithine combination therapy (NECT), was added to the WHO Essential Medicines List (EML). In the current context, NECT stands as the most promising first-line treatment for second-stage T. b. gambiense HAT. The article describes the developments and challenges in rolling out and implementing NECT in HAT-endemic areas.
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2009

Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial by Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian 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. In Lancet. 2009; 374:56-64.
This pivotal Phase III study assessed the efficacy and safety of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared with the gold-standard regimen of eflornithine in 287 patients at four HAT treatments centres in the Republic of the Congo and the Democratic Republic of Congo. The results showed NECT to be comparable with eflornithine in efficacy (>90% cure in both treatment arms at 18-month follow-up) and to be well tolerated. Patient follow-up at 18 months after treatment was 93%, which is exceptionally high for these types of studies in HAT and further contributes to the robustness of the study. In comparison with eflornithine, NECT is easier to administer, more affordable and with simpler logistics, and potentially protective against the emergence of resistant parasites. The authors conclude that NECT represents an improved alternative for stage 2 HAT treatment and is suitable for first-line use in HAT control programmes.
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An accompanying Lancet editorial calls the NECT study ‘more than a small victory over sleeping sickness‘.
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Drug discovery for neglected diseases: View of a public-private partnership by Chatelain E, Don R. In Antiparasitic Antibacterial Drug Discovery by Paul M. Selzer (Ed); 2009 Apr: Wiley-Blackwell.
In answer to the lack of modern and effective drugs for diseases such as human African trypanosomiasis (HAT; sleeping sickness) and Chagas disease which present no financial viability for the pharmaceutical industry, new models of drug discovery have been developed.
The Drugs for Neglected Diseases initiative (DNDi) has adopted a model closely related to that of a virtual biotechnology company for identifying and optimizing drug leads.
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Drug Screening for Kinetoplastid Diseases: A Training Manual for Screening in Neglected Diseases by Ioset JR, Brun R, Wenzler T, Kaiser M, Yardley V. DNDi and Pan-Asian Screening Network 2009 Apr: 74pp.
The production of this research manual is one of the deliverables of the Pan-Asian Network for Drugs for Neglected Diseases from Natural Substances. This comprehensive manual is a practical and user-friendly guide for essays available to screen natural products against pathogens responsible for some of the neglected diseases. It brings recommendations and protocols related to these essays, describes the principles of good scientific practice, and lists information about materials requested for the essays, institutions using them as well as key references.
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2008

Natural Products for Neglected Diseases: A Review by Ioset JR. Current Organic Chemistry 2008 May; 12 (8): 643-666.
Neglected diseases are responsible for high mortality and morbidity each year in low-income countries. Due to the lack of vaccines and of safe, effective and affordable treatments, there is an urgent need to reinforce the existing therapeutic arsenal against these killers. One of the main opportunities is through the discovery of new molecules from natural origin. The gaps identified in the R&D process aiming to deliver new medicines for neglected diseases however also apply to natural products. A key review of the most promising antiprotozoal molecules recently discovered from natural resources is presented here together with a critical update on their current development status.

New lycorine-type alkaloid from Lycoris traubii and evaluation of antitrypanosomal and antimalarial activities of lycorine derivatives by Toriizuka Y, Kinoshita E, Kogure N, Kitajima M, Ishiyama A, Otoguro K, Yamada H, Omura S, Takayama H. Bioorg Med Chem. 2008 Dec 15; 16(24): 10182-9. Epub 2008 Oct 30.
A new lycorine derivative LT1 was isolated from the aerial part and bulbs of Lycoris traubii Hayward (Amaryllidaceae). Its structure including absolute configuration was established by spectroscopic analysis and semi-synthesis to be 1-O-(30S)-hydroxybutanoyllycorine. Some lycorine ester derivatives including LT1 were examined for their inhibitory activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and against Plasmodium falciparum, the causative agent of malaria.
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In Vitro and in Vivo Antitrypanosomal Activitiy of Two Microbial Metabolites, KS-505a and Alazopeptin by Ishiyama A, Otoguro K, Namatame M, Nishihara A, Furusawa T, Masuma R, Shiomi K, Takahashi Y, Ichimura M, Yamada H, Omura S. J Antibiot (Tokyo). 2008 Oct; 61(10): 627-32.
The group’s ongoing screening program to discover new antitrypanosomal antibiotics has been evaluating compounds isolated from soil microorganisms as well as investigating the antibiotic libraries of the Kitasato Institute for Life Sciences and BioFrontier Laboratories of Kyowa Hakko Kogyo Co. Ltd. Two compounds, KS-505a and alazopeptin, were discovered that exhibit moderate antitrypanosomal characteristics. The in vitro and in vivo antitrypanosomal activities are reported and cytotoxicities of KS-505a and alazopeptin compared with some commonly-used antitrypanosomal drugs. This is the first report of in vitro and in vivo antitrypanosomal activities of either KS-505a or alazopeptin.
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2007

Nifurtimox-Eflornithine Combination Therapy for Second-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Congo by Priotto G, Kasparian S, Ngouama D, Ghorashian S, Arnold U, Ghabri S, Karunakara U. Clinical Infectious Diseases 2007 Dec; 45: 1435-1442.
Current treatment options for patients with second-stage disease are either highly toxic or impracticable in field conditions. The article compares the efficacy and safety of the nifurtimox-eflornithine drug combination with the standard eflornithine regimen for the treatment of second-stage disease. The nifurtimox-eflornithine combination appears to be a promising first-line therapy for second-stage sleeping sickness.
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2006

New Azasterols against Trypanosoma brucei: Role of 24-Sterol Methyltransferase in Inhibitor Action by Gros L, Castillo-Acosta VM, Jimenez Jimenez C, Sealey-Cardona M, Vargas S, Manuel Estevez A, Yardley V, Rattray L, Croft SL, Ruiz-Perez LM, Urbina JA, Gilbert IH, Gonzalez-Pacanowska D. Antimicrob Agents Chemother. 2006 Aug; 50(8):2595-601.
A series of azasterol derivatives, designed as potential inhibitors of the Δ24 –sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. We conclude that the designed compounds act at sites other than 24-SMT in Trypanosoma brucei.
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Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents by Vicik R, Hoerr V, Glaser M, Schultheis M, Hansell E, McKerrow JH, Holzgrabe U, Caffrey CR, Ponte-Sucre A, Moll H, Stich A, Schirmeister T. Bioorg. Med. Chem. Lett. 2006 May 15;16(10):2753-7. Epub 2006 Mar 3.
The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new trypanocidal drugs.
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Discovery of Trypanocidal Compounds by Whole Cell HTS of Trypanosoma brucei by Mackey ZB, Baca AM, Mallari JP, Apsel B, Shelat A, Hansell EJ, Chiang PK, Wolff B, Guy KR, Williams J, McKerrow JH. Chem Biol Drug Des. 2006 May;67(5):355-63.
One potentially rapid and cost-effective approach to identifying and developing new trypanocidal drugs would be high throughput-screening of existing drugs already approved for other uses, as well as clinical candidates in late development. A screen was performed in a collection of 2160 FDA approved drugs, bioactive compounds and natural products to identify hits that were cytotoxic to cultured Trypanosoma brucei at a concentration of 1lM or less. From the screen, 35 hits from seven different drug categories were identified.
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2005

Chemotherapy of trypanosomiases and leishmaniasis by Croft SL, Barrett MP, Urbina JA. Trends Parasitol. 2005 Nov;21(11):508-12.
New formulations, therapeutic switching of the established drugs amphotericin B and paromomycin, and the serendipitous discovery of miltefosine have markedly improved leishmaniasis chemotherapy in the past 21 years. The situation for the two trypanosomiases has been less encouraging. However, the appearance of not-for-profit product-development partnerships offers a new paradigm for bringing new drugs to patients.
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2004

Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis by Lorente SO, Rodrigues JC, Jimenez Jimenez C, Joyce-Menekse M, Rodrigues C, Croft SL, Yardley V, de Luca-Fradley K, Ruiz-Perez LM, Urbina J, de Souza W, Gonzalez Pacanowska D, Gilbert IH. Antimicrob Agents Chemother. 2004 Aug;48(8):2937-50.
This paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. The compounds prepared showed activity at micromolar and nanomolar concentrations when
tested against Leishmania spp. and Trypanosoma spp. The compounds were also found to be active against the bloodstream form (trypomastigotes) of Trypanosoma brucei rhodesiense, a causative agent of African trypanosomiasis. Click here to download the full article [PDF]

Design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-Trypanosoma brucei agents by Ohkanda J, Buckner FS, Lockman JW, Yokoyama K, Carrico D, Eastman R, de Luca-Fradley K, Davies W, Croft SL, Van Voorhis WC, Gelb MH, Sebti SM, Hamilton AD. J Med Chem. 2004 Jan 15;47(2):432-45.
On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucei protein farnesyltransferase (TbPFT) was evaluated.
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2002

Treatment of human African trypanosomiasis—present situation and needs for research and development by Legros, D. et al., Lancet Infect Dis 2002 2: 437–40.
Human African trypanosomiasis (sleeping sickness) re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. Research and development efforts must be made for the development of new compounds. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.
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2001

Availability and affordability of treatment for Human African Trypanosomiasis by Etchegorry MG, Helenport JP, Pecoul B, Jannin J, Legros D. Trop Med Int Health. 2001 Nov;6(11):957-9.
Human African Trypanosomiasis (HAT) is a re-emerging disease whose usual treatments are becoming less efficient because of the increasing parasite resistance. Availability of HAT drugs is poor and their production in danger because of technical, ecological and economic constraints.
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1999

Antiparasitic agents: challenges of sleeping sickness, hopes for malaria by Croft SL. Curr Opin Infect Dis. 1999 Dec; 12(6):557-8.
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