Trypanosomatidae diseases: From the current therapy to the efficacious role of trypanothione reductase in drug discovery

Current Medicinal Chemistry

Volumn 20, Issue 21, 2013, Pages 2673-2696

  Bernardes, L S C ^a   Zani, C L ^b   Carvalho, I ^c  

^a FEDERAL UNIVERSITY OF SANTA CATARINA   (Brazil)

^b INSTITUTO OSWALDO CRUZ   (Brazil)

^c UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Antitrypanosomatidae drugs; Trypanosomatidae diseases; Trypanothione reductase; Trypanothione reductase inhibitors

Indexed keywords

AMITRIPTYLINE; AMPHOTERICIN B; ANTIPARASITIC AGENT; BENZNIDAZOLE; CARBONYL DERIVATIVE; CEPHARANTHINE; CHLORPROMAZINE; CLOMIPRAMINE; EFLORNITHINE; HETEROCYCLIC COMPOUND; IMIQUIMOD; ME 1B; MEGLUMINE; MELARSEN OXIDE BAL; MELARSOPROL; MEPACRINE; MILTEFOSINE; NAPHTHOQUINONE; NATURAL PRODUCT; NEUROLEPTIC AGENT; NIFURTIMOX; PAROMOMYCIN; PENTAMIDINE; PENTAMIDINE ISETHIONATE; PHENOTHIAZINE; POLYAMINE; QUINOLINE DERIVATIVE; SITAMAQUINE; STIBOGLUCONATE SODIUM; SURAMIN; TRIFLUOPERAZINE; TRYPANOTHIONE REDUCTASE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AFRICAN TRYPANOSOMIASIS; ARTICLE; CHAGAS DISEASE; DISEASE TRANSMISSION; DRUG INHIBITION; DRUG MECHANISM; HUMAN; KINETOPLASTIDA; LEISHMANIA CHAGASI; LEISHMANIA DONOVANI; LEISHMANIA INFANTUM; LEISHMANIA MEXICANA; LEISHMANIA PANAMENSIS; LEISHMANIA TROPICA; LEISHMANIASIS; NONHUMAN; PROTEIN SYNTHESIS; SKIN LEISHMANIASIS; STATIC ELECTRICITY; TRYPANOSOMA CRUZI; TRYPANOSOMA RHODESIENSE; TRYPANOSOMIASIS; VISCERAL LEISHMANIASIS;

ANIMALS; BIOLOGICAL PRODUCTS; DRUG DISCOVERY; ENZYME INHIBITORS; EUGLENOZOA INFECTIONS; HUMANS; KETONES; MOLECULAR STRUCTURE; NADH, NADPH OXIDOREDUCTASES; POLYAMINES; SULFIDES; TRYPANOSOMATINA;

EID: 84880292189     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/0929867311320210005     Document Type: Article

References (130)

1. Nwaka. S.; Ridley, R.G. Virtual drug discovery and development for neglected diseases through public-private partnerships. Nature Rev. Drug Disc., 2003, 2, 919-928.
2. Nwaka, S.; Hudson, A. Innovative lead discovery strategies for tropical diseases. Nature Rev. Drug Disc.,2006, 5, 941-955.
3. Stuart, K.; Brun, R.; Croft, S.; Fairlamb, A.H.; Gürtler, R.E.; McKerrow, J.; Reed, S.; Tarleton, R. Kinetoplastids: Related protozoan pathogens, different diseases. J. Clin. Invest., 2008, 118, 1301-1310.
4. Cavalli, A.; Bolognesi, M.L. NeglectedTropical Diseases: Multi-Target-Directed ligands in the search for novel lead candidates against Trypanosoma and Leishmania. J. Med. Chem., 2009, 52, 7339-7359.
5. WHO. World Health Organization, 2010. Available in http://www.who.int (Accessed August 11, 2012).
6. Boiani, M.; Boiani, L.; Denicola, A.; Ortiz, S.T.; Serna, E.; Bilbao, N.V.; Sanabria, L.; Yaluff, G.; Nakayama, H.; Arias, A.R.; Vega, C.; Rolan, M.; Gómez-Barrio, A.; Cerecetto, H.; González, M. 2HBenzimidazole 1,3-Dioxide derivatives: A new family of watersoluble antitrypanosomatid agents. J. Med. Chem., 2006, 49, 3215-3224.
7. Moncayo, A.; Silveira, A.C. Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemi ology, surveillance and health policy. Mem. Instit. Oswaldo Cruz, 2009, 104, Suppl 1, 17-30.
8. Trossini, G.H.G.; Guido, R.V.C.; Oliva, G.; Ferreira, E.I.; Andricopulo, A.D. Quantitative structure-activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: Molecular modeling, CoMFA and CoMSIA studies. J. Mol. Graph. Model., 2009, 28, 3-11.
9. Ibarra-Cerdeña, C.N.; Sánchez-Cordero, V.; Peterson, A.T.; Ramsey, J.M. Ecology of north american triatominae. Acta Tropica, 2009, 110, 178-186.
10. Petheric, A. Country by country. Nature Outlook, 2010, 24, S10.
11. Maya, J.D.; Bollo, S.; Nuñez-Vergara, L.J.; Squella, J.Á.; Repetto, Y.; Morello, A.; Périé, J.; Chauviére, G. Trypanosoma cruzi: Effect and mode of action of nitroimidazole and nitrofuran derivatives. Biochem. Pharmacol., 2003, 65, 999-1006.
12. Coura, J.R. Chagas disease: What is known and what is needed-A background article. Mem. Inst. Oswaldo Cruz, 2007, 102, Suppl 1, 113-122.
13. Graebin, C.S.; Uchoa, F.D.; Bernardes, L.S.C.; Campo, V.L.; Carvalho, I.; Eifler-Lima, V.L. Antiprotozoal Agents: An Overview. Anti-Inf. Agents Med. Chem., 2009, 8, 345-366.
14. Clayton, J. Chagas disease: Pushing through the pipeline. Nature Outlook, 2010, 24, S12.
15. Lazardi, K.; Urbina, J.; Souza, W. Ultrastructural alterations induced by two ergosterol biosynthesis inhibitors, ketoconazole and terbinafine, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cuzi. Antimicrob. Agents Chemother., 1990, 34, 2097-2105.
16. Vannier-Santos, M.A.; Urbina, J.A.; Martiny, A.; Neves, A.; Souza, W.J. Alterations induced by the antifungal compounds ketoconazole and terbinafine in leishmania. Eukaryot. Microbiol., 1995, 42, 337-346.
17. Porcal, W.; Hernandez, P.; Boiani, L.; Boiani, M.; Ferreira, A.; Chidichimo, A.; Cazzulo, J. J.; Olea-Azar, C.; Gonzalez, M.; Cerecetto, H. New trypanocidal hybrid compounds from the association of hydrazone moieties and benzofuroxan heterocycle. Bioorg. Med. Chem., 2008, 16, 6995-7004.
18. Urbina, J.A.; Lazardi, K.; Aguirre, T.; Piras, M.M.; Piras, R. Atiproliferative Synergismo of the allylamine SF 86-327 and ketoconazole on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Antimicrob. Agents Chemother., 1988, 32, 1237-1242.
19. Urbina, J.A.; Payares, G.; Sanoja, C.; Molina, J.; Lira, R.; Brener, Z.; Romanha, A.J. Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains. Int. J. Antimicrob. Agents, 2003, 21, 39-48.
20. Cattand, P.; Jannin, J.; Lucas, P. Sleeping sickness surveillance: An essential step towards elimination. Trop. Med. Int. Health., 2001, 6, 348-365.
21. Fevre, E.M.; Wissmann, B.V.; Welburn, S.C.; Lutumba, P. The burden of human African trypanosomiasis. PLoS Negl. Trop. Dis., 2008, 2, e333.
22. Legros, D.; Olliver, G.; Gastellu-Etchegorry, M.; Christophe, P.; Burri, C.; Jannin, J.; Buscher, P. Treatment of human African trypanosomiasis-present situation and needs for research and development. Lancet Infect. Dis., 2002, 2, 437-440.
23. Bern, C.; Maguire, J.H.; Alvar, J. Complexities of assessing the disease burden attributable to leishmaniasis. PLoS Negl. Trop. Dis., 2008, 2, e313.
24. Croft, S.L.; Coombs, G.H. Leishmaniasis-current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol., 2003, 19, 502-508.
25. Rabello, A.; Orsini, M.; Disch, J. Leishmania/HIV co-infection in Brazil: An appraisal. Ann. Trop. Med. Parasitol., 2003, 97, Suppl 1, 17-28.
26. St. George, S.; Bishop, J.V.; Titus, R.G.; Selitrennikoff, C.P. Novel compounds active against Leishmania major. Antimicrob. Agents Chemother., 2006, 50, 474-479.
27. Caryn, B.; Maguire, J.H.; Alvar, J. Complexities of assessing the disease burden attributable to leishmaniasis. PLoS Negl. Trop. Dis., 2008, 2, e313.
28. Bernardino, A.M.R.; Gomes, A.O.; Charret, K.S.; Freitas, A.C.C.; Machado, G.M.C.; Canto-Cavalheiro, M.M.; Leon, L.L.; Amaral, V.F. Synthesis and leishmanicidal activity of 1-(4-X-phenyl)-N'-[(4-Y-phenyl)methylene]-1H- pyrazole-4-carbohydrazide. Eur. J. Med. Chem., 2006, 41, 80-87.
29. Murray, H.W.; Berman, J.D.; Davies, C.R.; Saravia, N.G. Advances in leishmaniasis. Lancet, 2005, 366, 1561-1577.
30. Patel, J.A.; Shah, K.G. Leishmaniasis: A review. Pharmacology online, 2008, 2, 1-11.
31. Barrett, M.P.; Mottram, J.C.; Coombs, G.H. Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. Trends Microbiol., 1999, 7, 82-88.
32. Cerqueira, G.C.; Bartholomeu, D.C.; DaRocha, W.D.; Hou, L.; Freitas-Silva, D.M.; Machado, C.R.; El-Sayed, N.M.; Teixeira, S.M.R. Sequence diversity and evolution of multigene families in Trypanosoma cruzi. Molec. Biochem. Parasitol., 2008, 157, 65-72.
33. El-Sayed, N.M.; Myler, P.J.; Bartholomeu, D.C.; Nilsson, D.; Aggarwal, G.; Tran, A.N.; Ghedin, E.; Worthey, E.A.; Delcher, A.L.; Blandin, G.; Westenberger, S.J.; Caler, E.; Cerqueira, G.C.; Branche, C.; Haas, B.; Anupama, A.; Arner, E.; Aslund, L.; Attipoe, P.; Bontempi, E.; Bringaud, F.; Burton, P.; Cadag, E.; Campbell, D.A.; Carrington, M.; Crabtree, J.; Darban, H.; da Silveira, J.F.; De Jong, P.; Edwards, K.; Englund, P.T.; Fazelina G.; Feldblyum, T.; Ferella, M.; Frasch, A.C.; Gull, K.; Horn, D.; Hou, L.; Huang, Y.; Kindlund, E.; Klingbeil, M.; Kluge, S.; Koo, H.; Lacerda, D.; Levin, M. J.; Lorenzi, H.; Louie, T.; Machado, C.R.; McCulloch, R.; McKenna, A.; Mizuno, Y.; Mottram, J.C.; Nelson, S.; Ochaya, S.; Osoegawa, K.; Pai, G.; Parsons, M.; Pentony, M.; Pettersson, U.; Pop, M.; Ramirez, J.L.; Rinta, J.; Robertson, L.; Salzberg, S.L.; Sanchez, D.O.; Seyler, A.; Sharma, R.; Shetty, J.; Simpson, A.J.; Sisk, E.; Tammi, M.T.; Tarleton, R.; Teixeira, S.; Van Aken, S.; Vogt, C.; Ward, P.N.; Wickstead, B.; Wortman, J.; White, O.; Fraser, C.M.; Stuart, K.D.; Andersson, B. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 2005, 309, 409-415.
34. Muskavitch, M.A.; Barteneva, N.; Gubbels, M. Chemogenomics and parasitology: Small molecules and cell-based assays to study infectious processes. J. Comb. Chem. High Throughput Screen, 2008, 11, 624-646.
35. Augustyns, K.; Amssoms, K.; Yamani, A.; Rajan, P.K.; Haemers, A. Trypanothione as a target in the design of antitrypanosomal and antileishmanial agents. Curr. Pharm. Des., 2001, 7, 1117-1141.
36. Austin, S.E.; Khan, M.; Omar, F.; Douglas, K.T. Rational drug design using trypanothione reductase as a target for antitrypanosomal and anti-leishmanial drug leads. Drug Design Discov., 1999, 16, 5-23.
37. Cavalli, A.; Lizzi, F.; Bongarzone, S.; Belluti, F.; Piazzi, L.; Bolognesi, M.L. Complementary medicinal chemistry-driven strategies toward new antitrypanosomal and antileishmanial lead drug candidates. FEMS Immunol. Med. Microbiol., 2010, 58, 51-60.
38. Fairlamb, A.H.; Blackburn, P.; Ulrich, P.; Chait, B.T.; Cerami, A. Trypanothione: A novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science, 1985, 227, 1485-1487.
39. Fairlamb, A.H.; Cerami, A. Metabolism and functions of trypanothione in the kinetoplastida. Annu. Rev. Microbial., 1992, 46, 695-729.
40. Krauth-Siegel, R.L.; Inhoff, O. Parasite-specific trypanothione reductase as a drug target molecule. Parasitol. Res., 2003, 90, Suppl 2, 77-85.
41. Krauth-Siegel, R.L.; Bauer, H.; Schirmer, R.H. 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., 2005, 44, 690-715.
42. Liñares, G.E.G.; Ravaschino, E.L.; Rodriguez, J.B. Progresses in the field of drug design to combat tropical protozoan parasitic diseases. Curr. Med. Chem., 2006, 13, 335-360.
43. O'Sullivan, M.C. The battle against trypanosomiasis and leishmaniasis: Metal-based and natural product inhibitors of trypanothione reductase. Curr. Med. Chem. Anti-Infect. Agents, 2005, 4, 355-378.
44. Rivera, G.; Bocanegra-García, V.; Ordaz-Pichardo, C.; Nogueda-Torres, B.; Monge, A. New therapeutic targets for drug design against Trypanosoma cruzi, advances and perspectives. Curr. Med. Chem., 2009, 16, 3286-3293.
45. Schmidt, A.; Krauth-Siegel, R.L. Enzymes of the trypanothione metabolism as targets for antitrypanosomal drug development. Curr. Top. Med. Chem., 2002, 2, 1239-1259.
46. Werbovetz, K.A. Target-based drug discovery for malaria, leishmaniasis, and trypanosomiasis. Curr. Med. Chem., 2000, 7, 835-860.
47. Budde, H.; Flohe, L. Enzymes of the thiol-dependent hydroperoxide metabolism in pathogens as potential drug targets. BioFactors, 2003, 17, 83-92.
48. Flohé, L.; Steinert, P.; Hecht, H.J.; Hofmann, B. Tryparedoxin and Tryparedoxin Peroxidase. Methods Enzymol., 2002, 347, 244-258.
49. Nogoceke, E.; Gommel, D.U.; Kiess, M.; Kalisz, H.M.; Flohé, L. A unique cascade of oxidoreductases catalyzes trypanothionemediated peroxide metabolism in Crithidia fasciculata. Gesellschaft Biotechnologische Forschung, 1997, 378, 827-836.
50. Dormeyer, M.; Reckenfelderbaumer, N.; Ludemann, H.; Krauth-Siegel, R.L. Trypanothione-dependent synthesis of deoxyribonucleotides by Trypanosoma brucei ribonucleotide reductase. J. Biol. Chem., 2001, 276, 10602-10606.
51. Krauth-Siegel, R.L.; Comini, M.A. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim. Biophys. Acta, 2008, 1780, 1236-1248.
52. Hunter, W.N.; Bailey, S.; Habash, J.; Harrop, S.J.; Helliwell, J.R.; Aboagye-Kwarteng, T.; Smith, K.; Fairlamb, A.H. Active site of trypanothione reductase. A target for rational drug design. J. Mol. Biol., 1992, 227, 322-333.
53. Krauth-Siegel, R.L.; Sticherling, C.; Jost, I.; Walsh, C.T.; Pai, E.F.; Kabsch, W.; Lantwin, C.B. Crystallization and preliminary crystallographic analysis of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease. FEBS Lett., 1993, 317, 105-108.
54. Patterson, S.; Alphey, M.S.; Jones, D.C.; Shanks, E.J.; Street, I.P. Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: Discovery, synthesis, and characterization of their binding mode by protein crystallography. J. Med. Chem., 2011, 54, 6514-6530.
55. Zhang, Y.; Bond, C.S.; Bailey, S.; Cunningham, M.L.; Fairlamb, A.H.; Hunter, W.N. The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 Å resolution. Protein Sci., 1996, 5, 52-61.
56. Lantwin, C.B.; Schlichting, I.; Kabash, W.; Pai, E.F.; Krauth-Siegel, R.L. The structure of Trypanosoma cruzi trypanothione reductase in the oxidized and NADPH reduced state. Proteins, 1994, 18, 161-173.
57. Kuriyan, J.; Wong, L.; Guenther, B.D.; Murgolo, N.J.; Cerami, A.; Henderson, G.B. J. Mol. Biol. 1990, 215, 335.
58. Kuriyan, J.; Kong, X. P.; Krishna, T.S.; Sweet, R.M.; Murgolo, N.J.; Field, H.; Cerami, A.; Henderson, G.B. X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4 A resolution. Proc. Natl. Acad. Sci. USA, 1991, 88, 8764-8768.
59. Bailey, S.; Smith, K.; Fairlamb, A.H.; Hunter, W.N. Substrate interactions between trypanothione reductase and N1-glutathionyl spermidine disulphide at 0.28-nm resolution. Eur. J. Biochem., 1993, 213, 67-75.
60. Bond, C.S.; Zhang, Y.; Berriman, M.; Cunningham, M.L.; Fairlamb, A.H.; Hunter, W.N. Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione and the structure-based discovery of new natural product inhibitors. Structure, 1999, 7, 81-89.
61. Jacoby, E.M.; Schlichting, I.; Lantwin, C.B.; Kabsch, W.; Krauth-Siegel, R.L. Crystal structure of the Trypanosoma cruzi trypanothione reductase-mepacrine complex. Protein Struct. Funct. Genet., 1996, 24, 73-80.
62. Baiocco, P.; Colotti, G.; Franceschini, S.; Ilari, A. Molecular basis of antimony treatment in leishmaniasis. J. Med. Chem., 2009, 52, 2603-2612.
63. Gallwitz, H.; Bonse, S.; Martinez-Cruz, A.; Schlichting, I.; Schumacher, K.; Krauth-Siegel, R. L. Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: Crystallographic, kinetic and spectroscopic studies. J. Med. Chem. 1999, 42, 364-372.
64. Jones, D.C.; Ariza, A.; Chow, W.A.; Oza, S.L.; Fairlamb, A.H. Comparative Structural, Kinetic and Inhibitor Studies of Trypanosoma brucei Trypanothione Reductase with T. Cruzi. Mol. Biochem. Parasitol., 2010, 169, 12-19.
65. Borges. A.; Cunningham, M.L.; Tovar, J.; Fairlamb, A.H. Sitedirected mutagenesis of the redox-active cysteines of Trypanosoma cruzi trypanothione reductase. Eur. J. Biochem., 1995, 228, 745-752.
66. Lee, B.; Bauer, H.; Melchers, J.; Ruppert, T.; Rattray, L.; Yardley, V.; Davioud-Charvet, E.; Krauth-Siegel, R.L. Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: A divinyl ketone as key intermediate. J. Med. Chem., 2005, 48, 7400-7410.
67. Krieger, S.; Schwarz, W.; Ariyanayagam, M.R.; Fairlamb, A.H.; Krauth-Siegel, R.L.; Clayton, C. Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Mol. Microbiol. 2000, 35, 542-552.
68. Fairlamb, A.H.; Henderson, G.B.; Cerami, A. Trypanothione is the primary target for arsenical drugs against African trypanosomes. Proc. Natl. Acad. Sci., USA 1989, 86, 2607-2611.
69. Boiani, M.; Piacenza, L.; Hernández, P.; Boiani, L.; Cerecetto, H.; González, M.; Denicola, A. Mode of action of Nifurtimox and Noxide-containing heterocycles against Trypanosoma cruzi: Is oxidative stress involved? Biochem. Pharmacol., 2010, 79, 1736-1745.
70. Holloway, G.A.; Baell, J.B.; Fairlamb, A.H.; Novello, P.M.; Parisot, J.P.; Richardson, J.; Watsona, K.G.; Streeta, I.P. Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening. Bioorg. Med. Chem.Lett., 2007, 17, 1422-1427.
71. Chan, C.; Yin, H.; Garforth, J.; McKie, J.H.; Jaouhari, R.; Speers, P.; Douglas, K.T.; Rock, P.J.; Yardley, V.; Croft, S.L.; Fairlamb, A.H. Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs. J. Med. Chem., 1998, 41, 148-156.
72. Khan, M.O.; Austin, S.E.; Chan, C.; Yin, H.; Marks, D.; Vaghjiani, S.N.; Kendrick, H.; Yardley, V.; Croft, S.L.; Douglas, K.T. 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., 2000, 43, 3148-3156.
73. Benson, T.J.; McKie, J.H.; Garforth, J.; Borges, A.; Fairlamb, A.H.; Douglas, K.T. Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures. Biochem. J., 1992, 286, 9-11.
74. Borowy, N.K.; Hirumi, H.; Waithaka, H.K.; Mkoji, G. An assay for screening drugs against animal-infective blood-stream forms of Trypanosoma-brucei-brucei in vitro. Drugs Exp. Clin. Res., 1985, 11, 155-161.
75. Hammond, D.J.; Hogg, J.; Gutteridge, W.E. Trypanosoma cruzi: Possible control of parasite transmission by blood transfusion using amphiphilic cationic drugs. Exp. Parasitol., 1985, 60, 32-42.
76. Pearson, R.D.; Manian, A.A.; Harcus, J.L.; Hall, D.; Hewlett, E.L. Lethal effect of phenothiazine neuroleptics on the pathogenic protozoan Leishmania-donovani. Science, 1982, 217, 369-371.
77. Seebeck, T.; Gehr, P. Trypanocidal action of neuroleptic phenothiazines in Trypanosoma-brucei. Mol. Biochem. Parasitol., 1983, 9, 197-208.
78. Zilberstein, D.; Dwyer, D.M. Antidepressants cause lethal disruption of membrane-function in the human protozoan parasite Leishmania. Science, 1984, 226, 977-979.
79. Bonse, S.; Santelli-Rouvier, C.; Barbe, J.; Krauth-Siegel, R.L. Inhibition of Trypanosoma cruzi Trypanothione Reductase by acridines: Kinetic studies and structure-activity relationships. J. Med. Chem., 1999, 42, 5448-5454.
80. Chibale, K.; Haupt, H.; Kendrick, H.; Yardley, V.; Saravanamuthu, A.; Fairlamb, A.H.; Croft, S.L. Antiprotozoal and cytotoxicity evaluation of sulfonamide and urea analogues of quinacrine. Bioorg. Med. Chem. Lett., 2001, 11, 2655-2657.
81. Horvath, D.A. Virtual Screening Approach Applied to the Search for Trypanothione Reductase Inhibitors. J. Med. Chem., 1997, 40, 2412-2423.
82. Cavin, J.C.; Krassner, S.M.; Rodriguez, E. Plant-derived alkaloids active against Trypanosoma cruzi. J. Ethnopharmacol., 1987, 19, 89-94.
83. Galarreta, B.C.; Sifuentes, R.; Carrillo, A.K.; Sanchez, L.; Amado, M.D.R.I.; Maruenda, H. The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors. Bioorg. Med. Chem., 2008, 16, 6689-6695.
84. Perez-Pineiro, R.; Burgos, A.; Jones, D.C.; Andrew, L.C.; Rodriguez, H.; Suarez, M.; Fairlamb, A.H.; Wishart, D.S. Development of a novel virtual screening cascade protocol to identify potential Trypanothione reductase inhibitors. J. Med. Chem., 2009, 52, 1670-1680.
85. Richardson, J.L.; Nett, I.R.E.; Jones, D.C.; Abdille, M.H.; Gilbert, I.H.; Fairlamb, A.H. Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis. ChemMedChem, 2009, 4, 1333-1340.
86. Bonnet, B.; Soullez, D.; Davioud-Charvet, E.; Landry, V.; Horvath, D.; Sergheraert, C. New spermine and spermidine derivatives as potent inhibitors of Trypanosoma cruzi trypanothione reductase. Bioorg. Med. Chem., 1997, 5, 1249-1256.
87. Girault, S.; Davioud-Charvet, E.; Salmon, L.; Berecibar, A.; Debreu, M.A.; Sergheraert, C. Structure-activity relationships in 2- aminodiphenylsulfides against trypanothione reductase from Trypanosoma cruzi. Bioorg. Med. Chem. Lett., 1998, 8, 1175-1180.
88. Parveen, S.; Khan, M.O.F.; Austin, S.E.; Croft, S.L.; Yardley, V.; Rock, P.; Douglas, K.T. Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide. J. Med. Chem., 2005, 48, 8087-8097.
89. Girault, S.; Baillet, S.; Horvath, D.; Lucas, V.; Davioud-Charvet, E.; Tartar, A.; Sergheraert, C. New potent inhibitors of trypanothione reductase from Trypanosoma cruzi in the 2-aminodiphenylsulfide series. Europ. J. Med. Chem., 1997, 32, 39-52.
90. Spinks, D.; Shanks, E.J.; Cleghorn, L.A.T.; McElroy, S.; Jones, D.; James, D.; Fairlamb, A.H.; Frearson, J.A.; Wyatt, P.G.; Gilbert, I.H. Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. ChemMedChem, 2009, 4, 2060-2069.
91. Holloway, G.A.; Charman, W.N.; Fairlamb, A.H.; Brun, R.; Kaiser, M.; Kostewicz, E.; Novello, P.M.; Parisot, J.P.; Richardson, J. Trypanothione reductase High-Throughput Screening campaign identifies novel classes of inhibitors with antiparasitic activity. Antimicrob. Agents Chemother., 2009, 53, 2824-2833.
92. Bailey, S.; Fairlamb, A.H.; Hunter, W.N. Structure of trypanothione reductase from Crithidia fasciculata at 2.6 Å resolution enzyme-NADP interactions at 2.8 Å resolution. Acta Crystallogr., Sec. D, 1994, 50, 139-154.
93. Patterson, S.; Jones, D.C.; Shanks, E.J.; Frearson, J.A.; Gilbert, I.H.; Wyatt, P.G.; Fairlamb, A.H. Synthesis and evaluation of 1-(1-(benzo[b]thiophen- 2-yl)cyclohexyl)piperidine (BTCP) analogues as inhibitors of trypanothione reductase. ChemMedChem, 2009, 4, 1341-1353.
94. Walton, J.G.A.; Jones, D.C.; Kiuru, P.; Durie, A.J.; Westwood, N.J.; Fairlamb, A.H. Synthesis and Evaluation of Indatraline-Based Inhibitors for Trypanothione Reductase. ChemMedChem, 2011, 6, 321-328.
95. König, J.; Wyllie, S.; Wells, G.; Stevens, M.F.; Wyatt, P.G.; Fairlamb, A.H. Antitumor Quinol PMX464 is a cytocidal antitrypanosomal inhibitor targeting trypanothione metabolism. J. Biol. Chem., 2011, 286, 8523-8533.
96. O'Sullivan, M.C.; Zhou, Q. Novel polyamine derivatives as potent competitive inhibitors of Trypanosoma cruzi trypanothione reductase. Bioorg. Med. Chem. Lett., 1995, 5, 1957-1960.
97. Li, Z.; Fennie, M.W.; Ganem, B.; Hancock, M.T.; Kobaslija, M.; Rattendi, D.; Bacchi, C.J.; O'Sullivan, M.C. Polyamines with N-(3-phenylpropyl) substituents are effective competitive inhibitors of trypanothione reductase and trypanocidal agents. Bioorg. Med. Chem. Lett., 2001, 11, 251-254.
98. Ponasik, J.A.; Strickland, C.; Faerman, C.; Savvides, S.; Karplus, P.A.; Ganem, B. Kukoamine-A and other hydrophobic acylpolyamines-potent and selective inhibitors of crithidia-fasciculata trypanothione reductase. Biochem. J., 1995, 311, 371-375.
99. Chitkul, B.; Bradley, M. Optimising inhibitors of trypanothione reductase using solid-phase chemistry. Bioorg. Med. Chem. Lett., 2000, 10, 2367-2369.
100. Tromelin, A.; Moutiez, M.; Meziane-Cherif, D.; Aumercier, M.; Tartar, A.; Sergheraert, C. Synthesis of non-reducible inhibitors for trypanothione reductase from Trypanosoma cruzi. Bioorg. Med. Chem. Lett., 1993, 3, 1971-1976.
101. Bi, X.; Lopez, C.; Bacchi, C.J.; Rattendi, D.; Woster, P.M. Novel alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity. Bioorg. Med. Chem. Lett., 2006, 16, 3229-3232.
102. Meiering, S.; Inhoff, O.; Mies, J.; Vincek, A.; Garcia, G.; Kramer, B.; Dormeyer, M.; Krauth-Siegel, R.L. Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis. J. Med. Chem., 2005, 48, 4793-4802.
103. Cota, B.B.; Rosa, L.H.; Fagundes, S.E.M.; Martins-Filho, A.O.; Correa-Oliveira, R.; Romanha, A.J., Rosa, C.A.; Zani, C.L.A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation. Mem. Inst. Oswaldo Cruz, 2008, 103, 263-270.
104. Hamilton, C.J.; Saravanamuthu, A.; Poupat, C.; Fairlamb, A.H.; Egglestona, I.M. Time-dependent inhibitors of trypanothione reductase: Analogues of the spermidine alkaloidlunarine and related natural products. Bioorg. Med. Chem., 2005, 14, 2266-2278.
105. Fournet, A.; Ferreira, M.E.; Arias, A.R.; Schinini, A.; Nakayama, H.; Torres, S.; Sanabria, R.; Guinaudeau, H.; Bruneton, J. The effect of bisbenzylisoquinoline alkaloids on Trypanosoma cruzi infections in mice. Intern. J. Antimicrob. Agents., 1997, 8, 163-170.
106. Fournet, A.; Inchausti, A.; De Arias, A.R.; Guinaudeau, H.; Bruneton, J.; Breidenbach, M.A.; Karplus, P.A.; Faerman, C.H. Trypanocidal bisbenzylisoquinoline alkaloids are inhibitors of trypanothione reductase. J. Enzyme Inhib., 1998, 13, 1-9.
107. Fournet, A.; Muñoz, V. Natural products as trypanocidal, antileishmanial and antimalarial Drugs. Curr. Top. Med. Chem., 2002, 2, 1215-1237.
108. Lopes, N.P.; Chicaro, P.; Kato, M.J.; Albuquerque, S.; Yoshida, M. Flavonoids and lignans from Virola surinamensis twigs and their in vitro activity against Trypanosoma cruzi. Planta Med., 1998, 64, 667-669.
109. Oliveira, R.B.; Vaz, A.B.M.; Alves, R.O.; Liarte, D.B.; Donnici, C.L.; Romanha, A.J.; Zani, C.L. Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors. Mem. Instit. Oswaldo Cruz, 2006, 101, 169-173.
110. Salmon-Chemin, L.; Buisine, E.; Yardley, V.; Kohler, S.; Debreu, M.; Landry, V.; Sergheraert, C.; Croft, S.L.; Krauth-Siegel, R.L.; Davioud-Charvet, E. 2-and 3-Substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: Synthesis and correlation between redox cycling activities and in vitro cytotoxicity. J. Med. Chem., 2001, 44, 548-565.
111. Henderson, G.B.; Ulrich, P.; Fairlamb, A.H.; Rosenberg, I.; Pereira, M.; Sela, M.; Cerami, A. "Subversive" substrates for the enzyme trypanothione disulfide reductase: Alternative approach to chemotherapy of Chagas disease. Proc. Natl. Acad. Sci., USA 1988, 85, 5374-5378.
112. Henderson, G.B.; Murgolo, N.J.; Kuriyan, J.; Osapay, K.; Kominos, D.; Berry, A.; Scrutton, N.S.; Hinchliffe, N.W.; Perham, R.N.; Cerami, A. Engineering the substrate specificity of glutathione reductase toward that of trypanothione reduction. Proc. Natl. Acad. Sci. USA, 1991, 88, 8769-8773.
113. Kayser, O.; Kiderlen, A.F.; Croft, S.L. Natural products as antiparasitic drugs. Parasitol Res., 2003, 90, Suppl. 2, S55-S62.
114. Silva Júnior, E.M.; Souza, M.C.B.V.; Fernandes, M.C.; Menna-Barreto, R.F.S.; Pinto, M. C.F.R.; Lopes, F.A.; Simone, C.A.; Andrade, C.K.Z.; Pinto, A.V.; Ferreira, V.F.; Castro, S.L. Synthesis and antiTrypanosoma cruzi activity of derivatives from norlapachones and lapachones. Bioorg. Med. Chem., 2008, 16, 5030-5038.
115. Boveris, A.; Do Campo, R.; Turrens, J.F.; Stoppani, A.O. Effect of beta-lapachone on superoxide anion and hydrogen-peroxide production in Trypanosoma-cruzi. Biochem. J., 1978, 175, 431-439.
116. Croft, S.L.; Evans, A.T.; Neal, R.A. The activity of plumbagin and other electron carriers against Leishmania-donovani and Leishamnia-mexicana- amazonensis. Ann. Trop. Med. Parasitol., 1985, 79, 651-653.
117. Croft, S.L.; Hogg, J.; Gutteridge, W.E.; Hudson, A.T.; Randall, A.W.J. The activity of hydroxynaphthoquinones against Leishmania-donovani. Antimicrob. Chemother., 1992, 30, 827-832.
118. Salmon-Chemin, L.; Lemaire, A.; De Freitas, S.; Deprez, B.; Sergheraert, C.; Davioud-Charvet, E. Parallel synthesis of a library of 1,4-naphthoquinones and automated screening of potential inhibitors of trypanothione reductase from Trypanosoma cruzi. Bioorg. Med. Chem. Lett., 2000, 10, 631-635.
119. Cavalli, A.; Lizzi, F.; Bongarzone, S.; Brun, R., Krauth-Siegel, R.L.; Bolognesi, M.L. Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase. Bioorg. Med. Chem. Lett., 2009, 19, 3031-3035.
120. Carvalho, L.H.; Rocha, E.M.M.; Raslan, D.S.; Oliveira, A.B.; Krettli, A.U. In vitro activity of natural and synthetic naphthoquinones against erythrocytic stages of plasmodium-falciparum. Braz. J. Med. Biol. Res., 1988, 21, 485-487.
121. Oliveira, A.B.; Raslan, D.S.; Miraglia, M.C.M.; Mesquita, A.A.L.; Zani, C.L.; Ferreira, D.T.; Maia, J.G.S. Estrutura química e atividade biológica de naftoquinonas de Bignoniaceas brasileiras. Quim. Nova, 1990, 13, 302-307.
122. Zani, C.L.; Oliveira, A.B.; Snieckus, V. Efficient directed orthometalation-based route to cytotoxic furanonaphthoquinone naturalproducts. Tetrahedron Lett., 1987, 28, 6561-6564.
123. Zani, C.L.; Chiari, E.; Krettli, A.U.; Murta, S.M.F.; Cunningham, M.L.; Fairlamb, A.H.; Romanha, A.J. Anti-plasmodial and antitrypanosomal activity of synthetic naphtho [2,3-b] thiophen-4,9-quinones. Bioorg. Med. Chem., 1997, 5, 2185-2192.
124. Zani, C.L.; Fairlamb, A.H. 8-Methoxy-naphtho[2,3-b]thiophen-4,9-quinone, a non-competitive inhibitor of trypanothione reductase. Mem. Inst. Oswaldo Cruz, 2003, 98, 565-568.
125. Iribarne, F.; Gonzalez, M.; Cerecetto, H.; Aguilera, S.; Tapia, O.; Paulino, M. Interaction energies of nitrofurans with trypanothione reductase and glutathione reductase studied by molecular docking. J. Mol. Struc. THEOCHEM, 2007, 818, 7-22.
126. Otero. L.; Vieites, M.; Boiani, L.; Denicola, A.; Rigol, C.; Opazo, L.; Olea-Azar, C.; Maya, J.D.; Morello, A.; Krauth-Siegel, R.L.; Piro, O.E.; Castellano, E.; González, M.; Gambino, D.; Cerecetto, H. Novel Antitrypanosomal Agents Based on Palladium Nitrofurylthiosemicarbazone Complexes: DNA and Redox Metabolism as Potential Therapeutic Targets. J. Med. Chem., 2006, 49, 3322-3331.
127. Millet, R.; Maes, L.; Landry, V.; Sergheraert, C.; Davioud-Charvet, E. Antitrypanosomal activities and cytotoxicity of 5-nitro-2-furancarbohydrazides. Bioorg. Med. Chem. Lett., 2002, 12, 3601-3604.
128. Aguirre, G.; Boiani, L.; Cerecetto, H.; Fernandez, M.; Gonzalez, M.; Denicola, A.; Otero, L.; Gambino, D.; Rigol, C.; Olea-Azar, C.; Faundez, M. In vitro activity and mechanism of action against the protozoan parasite Trypanosoma cruzi of 5-nitrofurylcontaining thiosemicarbazones. Bioorg. Med. Chem., 2004, 12, 4885-4893.
129. Martyn, D.C.; Jones, D.C.; Fairlamb, A.H.; Clardy, J. Highthroughput screening affords novel and selective trypanothione reductase inhibitors with antitrypanosomal activity. Bioorg. Med. Chem Lett. 2007, 17, 1280-1283.
130. Silva, C.H.T.P.; Bernardes, L.S.C.; Da Silva, V.B.; Zani, C.L.; Carvalho, I. Novel aryl β-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: Binding mode revised by docking and GRIND2-based 3D-QSAR procedures. J. Biomol. Struct. Dyn., 2012, 29, 702-716.