State of the art in African trypanosome drug discovery

Current Topics in Medicinal Chemistry

Volumn 11, Issue 10, 2011, Pages 1255-1274

  Jacobs, Robert T ^a   Nare, Bakela ^a   Phillips, Margaret A ^b  

^a SCYNEXIS Inc   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

Drug discovery; Drug therapy; Eflornithine; Sleeping sickness; Trypanosoma brucei

Indexed keywords

6 PHOSPHOFRUCTOKINASE; CYTIDINE TRIPHOSPHATE SYNTHASE; DNA TOPOISOMERASE; EFLORNITHINE; ENOLASE; FRUCTOSE BISPHOSPHATE ALDOLASE; GLUCOSE 6 PHOSPHATE ISOMERASE; GLYCOPROTEIN P; HEXOKINASE; MELARSOPROL; NIFURTIMOX; ORNITHINE; PENTAMIDINE; PHOSPHOTRANSFERASE; PROTEIN N MYRISTOYLTRANSFERASE; PROTEINASE; SURAMIN; TRYPANOTHIONE REDUCTASE; TUBULIN; VARIANT SURFACE GLYCOPROTEIN;

ABDOMINAL CRAMP; AFRICAN TRYPANOSOMIASIS; ALLELE; ARTICLE; BIOSYNTHESIS; BRAIN DISEASE; CELL ACTIVITY; CELL ASSAY; CELL CYCLE; CELL GROWTH; CELL SCREENING; CEREBROSPINAL FLUID; CLINICAL FEATURE; CLINICAL TRIAL (TOPIC); DIARRHEA; DISEASE COURSE; DNA MODIFICATION; DRUG ACTIVITY; DRUG EFFICACY; DRUG FATALITY; DRUG SAFETY; DRUG TRANSPORT; DRUG WITHDRAWAL; ENDOCYTOSIS; ENERGY METABOLISM; FATIGUE; FATTY ACID SYNTHESIS; FEVER; FOLLOW UP; GENE EXPRESSION; HEADACHE; HEART INJURY; HUMAN; HYPERTENSION; HYPOGLYCEMIA; IMMUNE RESPONSE; INFECTION; LIPOGENESIS; LYSIS; MEDICAL CARE; MICROTUBULE ASSEMBLY; MONOTHERAPY; MULTIDRUG RESISTANCE; MULTIPLE CYCLE TREATMENT; NAUSEA; NEPHROTOXICITY; NEUROLOGICAL COMPLICATION; NEUTROPENIA; NONHUMAN; PERIPHERAL NEUROPATHY; POLYAMINE METABOLISM; POLYMERASE CHAIN REACTION; PRENYLATION; PROTEIN MODIFICATION; PURINE METABOLISM; PYRIMIDINE METABOLISM; RASH; RURAL HEALTH CARE; SEIZURE; SEPTIC SHOCK; SHOCK; SINGLE DRUG DOSE; TREATMENT FAILURE; TREATMENT INDICATION; TREMOR; TRYPANOSOMA GAMBIENSE; TRYPANOSOMA RHODESIENSE; VOMITING;

ANIMALS; DRUG DISCOVERY; DRUG THERAPY, COMBINATION; HUMANS; TRYPANOCIDAL AGENTS; TRYPANOSOMA BRUCEI GAMBIENSE; TRYPANOSOMIASIS, AFRICAN;

EID: 79960022935     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/156802611795429167     Document Type: Article

References (170)

1. Barrett, M. P.; Boykin, D.W.; Brun, R.; Tidwell, R.R. Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. Br. J. Pharmacol., 2007, 152(8), 1155-1171.
2. Kennedy, P.G. The continuing problem of human African trypanosomiasis (sleeping sickness). Ann. Neurol., 2008, 64(2), 116-126.
3. Stuart, K.; Brun, R.; Croft, S.; Fairlamb, A.; Gurtler, R. E.; McKerrow, J.; Reed, S.; Tarleton, R. Kinetoplastids: related protozoan pathogens, different diseases. J. Clin. Invest, 2008, 118(4), 1301-1310.
4. Fevre, E. M.; Wissmann, B.V.; Welburn, S.C.; Lutumba, P. The burden of human african trypanosomiasis. PLoS Negl. Trop. Dis., 2008, 2(12), e333.
5. Simarro, P.P.; Jannin, J.; Cattand, P. Eliminating human African trypanosomiasis: where do we stand and what comes next? PLoS Med., 2008, 5(2), e55.
6. Pays, E.; Vanhollebeke, B.; Vanhamme, L.; Paturiaux-Hanocq, F.; Nolan, D. P.; Perez-Morga, D. The trypanolytic factor of human serum. Nat. Rev. Microbiol., 2006, 4(6), 477-86.
7. Stockdale, C.; Swiderski, M. R.; Barry, J. D.; McCulloch, R. Antigenic variation in Trypanosoma brucei: joining the DOTs. PLoS Biol., 2008, 6(7), e185.
8. Blum, J. A.; Zellweger, M. J.; Burri, C.; Hatz, C. Cardiac involvement in African and American trypanosomiasis. Lancet Infect. Dis., 2008, 8(10), 631-41.
9. Blum, J. A.; Schmid, C.; Burri, C.; Hatz, C.; Olson, C.; Fungula, B.; Kazumba, L.; Mangoni, P.; Mbo, F.; Deo, K.; Mpanya, A.; Dala, A.; Franco, J. R.; Pohlig, G.; Zellweger, M. J. Cardiac alterations in human african trypanosomiasis (T.b. gambiense) with respect to the disease stage and antiparasitic treatment. PLoS Negl Trop. Dis., 2009, 3(2), e383.
10. Chappuis, F.; Loutan, L.; Simarro, P.; Lejon, V.; Buscher, P. Options for field diagnosis of human african trypanosomiasis. Clin. Microbiol. Rev., 2005, 18(1), 133-46.
11. Mugasa, C. M.; Laurent, T.; Schoone, G. J.; Kager, P. A.; Lubega, G.W.; Schallig, H. D. Nucleic acid sequence-based amplification with oligochromatography for detection of Trypanosoma brucei in clinical samples. J. Clin. Microbiol., 2009, 47(3), 630-635.
12. Njiru, Z. K.; Mikosza, A. S.; Armstrong, T.; Enyaru, J.C.; Ndung'u, J. M.; Thompson, A. R. Loop-mediated isothermal amplification (LAMP) method for rapid detection of trypanosoma brucei rhodesiense. PLoS Negl. Trop. Dis., 2008, 2(1), e147.
13. 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. Nifurtimoxeflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet, 2009, 374(9683), 56-64.
14. Schmid, C.; Richer, M.; Bilenge, C. M.; Josenando, T.; Chappuis, F.; Manthelot, C. R.; Nangouma, A.; Doua, F.; Asumu, P. N.; Simarro, P. P.; Burri, C. Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II). J. Infect. Dis., 2005, 191(11), 1922-1931.
15. Mdachi, R. E.; Thuita, J. K.; Kagira, J. M.; Ngotho, J. M.; Murilla, G. A.; Ndung'u, J. M.; Tidwell, R. R.; Hall, J. E.; Brun, R. 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., 2009, 53(3), 953-957.
16. Bakunova, S. M.; Bakunov, S. A.; Patrick, D. A.; Kumar, E.V.; Ohemeng, K. A.; Bridges, A. S.; Wenzler, T.; Barszcz, T.; Jones, S. K.; Werbovetz, K. A.; Brun, R.; Tidwell, R. R. Structure-activity study of pentamidine analogues as antiprotozoal agents. J. Med. Chem., 2009, 52(7), 2016-2035.
17. de Koning, H. P. Ever-increasing complexities of diamidine and arsenical crossresistance in African trypanosomes. Trends Parasitol., 2008, 24(8), 345-349.
18. Croft, S. L. Kinetoplastida: new therapeutic strategies. Parasite, 2008, 15(3), 522-527.
19. Sanderson, L.; Dogruel, M.; Rodgers, J.; De Koning, H. P.; Thomas, S. A. Pentamidine movement across the murine bloodbrain and blood-cerebrospinal fluid barriers: effect of trypanosome infection, combination therapy, P-glycoprotein, and multidrug resistance-associated protein. J. Pharmacol. Exp. Ther., 2009, 329(3), 967-977.
20. Robays, J.; Nyamowala, G.; Sese, C.; Betu Ku Mesu Kande, V.; Lutumba, P.; Van der Veken, W.; Boelaert, M. High failure rates of melarsoprol for sleeping sickness, Democratic Republic of Congo. Emerg. Infect. Dis., 2008, 14(6), 966-967.
21. Shahi, S. K.; Krauth-Siegel, R. L.; Clayton, C. E. Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei. Mol. Microbiol., 2002, 43(5), 1129-38.
22. Maina, N.; Maina, K. J.; Maser, P.; Brun, R. Genotypic and phenotypic characterization of Trypanosoma brucei gambiense isolates from Ibba, South Sudan, an area of high melarsoprol treatment failure rate. Acta Trop., 2007, 104(2-3), 84-90.
23. Pegg, A. E.; Feith, D. J. Polyamines and neoplastic growth. Biochem. Soc. Trans., 2007, 35(Pt 2), 295-299.
24. Casero, R.A. Jr.; Marton, L. J. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat. Rev., 2007, 6(5), 373-390.
25. Grishin, N.V.; Osterman, A. L.; Brooks, H. B.; Phillips, M. A.; Goldsmith, E. J. X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with alpha-difluoromethylornithine. Biochemistry, 1999, 38(46), 15174-15184.
26. Balasegaram, M.; Young, H.; Chappuis, F.; Priotto, G.; Raguenaud, M. E.; Checchi, F. Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Medecins Sans Frontieres programmes. Trans. R. Soc. Trop. Med. Hyg., 2009, 103(3), 280-290.
27. Sanderson, L.; Dogruel, M.; Rodgers, J.; Bradley, B.; Thomas, S. A. The blood-brain barrier significantly limits eflornithine entry into Trypanosoma brucei brucei infected mouse brain. J. Neurochem., 2008, 107(4), 1136-1146.
28. Ullu, E.; Tschudi, C.; Chakraborty, T. RNA interference in protozoan parasites. Cell Microbiol., 2004, 6(6), 509-519.
29. Krauth-Siegel, R. L.; Comini, M. A. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim. Biophys. Acta, 2008, 1780(11), 1236-1248.
30. Willert, E. K.; Fitzpatrick, R.; Phillips, M. A. Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog. Proc. Natl. Acad. Sci. U SA, 2007, 104(20), 8275-8280.
31. Willert, E. K.; Phillips, M. A. Regulated expression of an essential allosteric activator of polyamine biosynthesis in African trypanosomes. PLoS Pathog., 2008, 4(10), e1000183.
32. Li, F.; Hua, S.; Wang, C.; Gottesdiener, K. Trypanosoma brucei brucei: characterization of an ODC null bloodstream form mutant and the action of alpha-difluoromethylornithine. Exp. Parasitiol., 1998, 88, 255-257.
33. Xiao, Y.; McCloskey, D. E.; Phillips, M. A. RNA interferencemediated silencing of ornithine decarboxylase and spermidine synthase genes in Trypanosoma brucei provides insight into regulation of polyamine biosynthesis. Eukaryot Cell, 2009, 8(5), 747-755.
34. Taylor, M. C.; Kaur, H.; Blessington, B.; Kelly, J. M.; Wilkinson, S. R. Validation of spermidine synthase as a drug target in African trypanosomes. Biochem. J., 2008, 409(2), 563-569.
35. Huynh, T.T.; Huynh, V. T.; Harmon, M. A.; Phillips, M. A. Gene knockdown of g-glutamylcysteine synthetase by RNAi in the parasitic protozoa Trypanosoma brucei demonstrates that it is an essential enzyme. J. Biol. Chem., 2003, 278, 39794-39800.
36. 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.
37. Wyllie, S.; Oza, S. L.; Patterson, S.; Spinks, D.; Thompson, S.; Fairlamb, A.H. Dissecting the essentiality of the bifunctional trypanothione synthetase-amidase in Trypanosoma brucei using chemical and genetic methods. Mol. Microbiol., 2009, 74(3), 529-540.
38. Barker, R. H. Jr.; Liu, H.; Hirth, B.; Celatka, C.A.; Fitzpatrick, R.; Xiang, Y.; Willert, E.K.; Phillips, M. A.; Kaiser, M.; Bacchi, C. J.; Rodriguez, A.; Yarlett, N.; Klinger, J. D.; Sybertz, E. Novel Sadenosylmethionine decarboxylase inhibitors for the treatment of human African trypanosomiasis. Antimicrob. Agents Chemother., 2009, 53(5), 2052-2058.
39. Bacchi, C.J.; Barker, R.H. Jr.; Rodriguez, A.; Hirth, B.; Rattendi, D.; Yarlett, N.; Hendrick, C. L.; Sybertz, E. Trypanocidal activity of 8-methyl-5'-{[(Z)-4-aminobut-2-enyl]-(methylamino)}adenosine (Genz-644131), an adenosylmethionine decarboxylase inhibitor. Antimicrob. Agents Chemother., 2009, 53(8), 3269-3272.
40. Goldberg, B.; Rattendi, D.; Lloyd, D.; Sufrin, J. R.; Bacchi, C. J. In situ kinetic characterization of methylthioadenosine transport by the adenosine transporter (P2) of the African Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense. Biochem. Pharmacol., 2001, 61, 449-457.
41. Beswick, T.; Willert, E.; Phillips, M. Mechanisms of allosteric regulation of Trypanosoma cruzi S-adenosylmethionine decarboxylase. Biochemistry, 2006, 45(25), 7797-7807.
42. Richardson, J. L.; Nett, I. R.; Jones, D. C.; Abdille, M. H.; Gilbert, I. H.; Fairlamb, A. H. Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis. Chem Med Chem, 2009, 4(8), 1333-1340.
43. 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(6), 1670-1680.
44. 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(8), 1341-1353.
45. Holloway, G. A.; Charman, W. N.; Fairlamb, A. H.; Brun, R.; Kaiser, M.; Kostewicz, E.; Novello, P. M.; Parisot, J. P.; Richardson, J.; Street, I. P.; Watson, K. G.; Baell, J. B. Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with anti-parasitic activity. Antimicrob. Agents Chemother., 2009, 53(7), 72824-2833.
46. Stump, B.; Eberle, C.; Schweizer, W. B.; Kaiser, M.; Brun, R.; Krauth-Siegel, R. L.; Lentz, D.; Diederich, F. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines. ChemBioChem, 2009, 10(1), 79-83.
47. 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. Biorg. Med. Chem. Lett., 2009, 19, 3031-3035.
48. Verlinde, C. L. M. J.; Hannaert, V.; Blonski, C.; Willson, M.; Périé, J. J.; Fothergill-Gilmore, L. A.; Opperdoes, F. R.; Gelb, M. H.; Hol, W. G. J.; Michels, P. A. M. Glycolysis as a target for the design of new anti-trypanosome drugs. Drug Resist. Updates, 2001, 4(1), 50-65.
49. Lakhdar-Ghazal, F.; Blonski, C.; Willson, M.; Michels, P.; Perie, J. Glycolysis and proteases as targets for the design of new antitrypanosome drugs. Curr. Top. Med. Chem., 2002, 2(5), 439-456.
50. Albert, M. A.; Haanstra, J. R.; Hannaert, V.; Van Roy, J.; Opperdoes, F. R.; Bakker, B. M.; Michels, P. A. Experimental and in silico analyses of glycolytic flux control in bloodstream form Trypanosoma brucei. J. Biol. Chem., 2005, 280(31), 28306-28315.
51. Morris, M. T.; DeBruin, C.; Yang, Z.; Chambers, J.W.; Smith, K. S.; Morris, J. C. Activity of a second Trypanosoma brucei hexokinase is controlled by an 18-amino-acid C-terminal tail. Eukaryot Cell, 2006, 5(12), 2014-2023.
52. Chambers, J. W.; Kearns, M. T.; Morris, M. T.; Morris, J. C. Assembly of heterohexameric trypanosome hexokinases reveals that hexokinase 2 is a regulable enzyme. J. Biol. Chem., 2008, 283(22), 14963-14970.
53. Chambers, J. W.; Fowler, M. L.; Morris, M. T.; Morris, J. C. The anti-trypanosomal agent lonidamine inhibits Trypanosoma brucei hexokinase 1. Mol. Biochem. Parasitol., 2008, 158(2), 202-207.
54. Arsenieva, D.; Appavu, B. L.; Mazock, G. H.; Jeffery, C. J. Crystal structure of phosphoglucose isomerase from Trypanosoma brucei complexed with glucose-6-phosphate at 1.6 A resolution. Proteins, 2009, 74(1), 72-80.
55. Abell, L.; Schineller, J.; Keck, P.; Villafranca, J. Effect of metalligand mutations on phosphoryl transfer reactions catalyzed by E. coli glutamine synthetase. Biochemistry, 1995, 34, 16695-16702.
56. McNae, I. W.; Martinez-Oyanedel, J.; Keillor, J. W.; Michels, P. A.; Fothergill-Gilmore, L. A.; Walkinshaw, M. D. The crystal structure of ATP-bound phosphofructokinase from Trypanosoma brucei reveals conformational transitions different from those of other phosphofructokinases. J. Mol. Biol., 2009, 385(5), 1519-1533.
57. Nowicki, M. W.; Tulloch, L. B.; Worralll, L.; McNae, I. W.; Hannaert, V.; Michels, P. A.; Fothergill-Gilmore, L. A.; Walkinshaw, M. D.; Turner, N. J. Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis. Bioorg. Med. Chem., 2008, 16(9), 5050-5061.
58. Chudzik, D. M.; Michels, P. A.; de Walque, S.; Hol, W. G. Structures of type 2 peroxisomal targeting signals in two trypanosomatid aldolases. J. Mol. Biol., 2000, 300(4), 697-707.
59. Dax, C.; Duffieux, F.; Chabot, N.; Coincon, M.; Sygusch, J.; Michels, P. A. M.; Blonski, C. Selective Irreversible Inhibition of Fructose 1,6-Bisphosphate Aldolase from Trypanosoma brucei. J. Med. Chem., 2006, 49(5), 1499-1502.
60. Azema, L.; Lherbet, C.; Baudoin, C.; Blonski, C. Cell permeation of a Trypanosoma brucei aldolase inhibitor: evaluation of different enzyme-labile phosphate protecting groups. Bioorg. Med. Chem. Lett., 2006, 16(13), 3440-3443.
61. Drew, M. E.; Morris, J. C.; Wang, Z.; Wells, L.; Sanchez, M.; Landfear, S. M.; Englund, P. T. The adenosine analog tubercidin inhibits glycolysis in trypanosoma brucei as revealed by an RNA interference library. J. Biol. Chem., 2003, 278(47), 46596-46600.
62. de A S Navarro, M. V.; Gomes Dias, S. M.; Mello, L.V.; da Silva Giotto, M. T.; Gavalda, S.; Blonski, C.; Garratt, R. C.; Rigden, D. J. Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics. FEBS J., 2007, 274(19), 5077-5089.
63. Elkouni, H. Potential chemotherapeutic targets in the purine metabolism of parasites. Pharmacol. Ther., 2003, 99, 283-309.
64. Luscher, A.; Onal, P.; Schweingruber, A. M.; Maser, P. Adenosine kinase of Trypanosoma brucei and its role in susceptibility to adenosine antimetabolites. Antimicrob. Agents Chemother., 2007, 51(11), 3895-3901.
65. Rottenberg ME, M.W., Ferella M, Petitto-Assis F, Goto H, Kristensson K, McCaffrey R, Wigzell H. Treatment of African trypanosomiasis with cordycepin and adenosine deaminase inhibitors in a mouse model. J. Infect. Dis., 2005, 192(9), 1658-1665.
66. Vodnala, M.; Fijolek, A.; Rofougaran, R.; Mosimann, M.; Maser, P.; Hofer, A. Adenosine kinase mediates high affinity adenosine salvage in Trypanosoma brucei. J. Biol. Chem., 2008, 283(9), 5380-5388.
67. Pettitt, A. Mechanism of action of purine analogues in chronic lymphocytic leukaemia. Br. J. Hematol., 2003, 121, 670-692.
68. Baliani, A.; Peal, V.; Gros, L.; Brun, R.; Kaiser, M.; Barrett, M. P.; Gilbert, I. H. Novel functionalized melamine-based nitroheterocycles: synthesis and activity against trypanosomatid parasites. Org. Biomol. Chem., 2009, 7(6), 1154-1166.
69. Barrett, M. P.; Gilbert, I. H. Targeting of toxic compounds to the trypanosome's interior. Adv. Parasitol., 2006, 63, 125-183.
70. Chollet, C. B. A. Wong, P. E.; Barrett, M. P.; Gilbert, I. H. Targeted delivery of compounds to Trypanosoma brucei using the melamine motif. Bioorg. Med. Chem. Lett., 2009, 17(6), 2512-2523.
71. Wenzel, I. N.; Wong, P. E.; Maes, L.; Muller, T. J.; Krauth-Siegel, R. L.; Barrett, M. P.; Davioud-Charvet, E. Unsaturated Mannich bases active against multidrug-resistant Trypanosoma brucei brucei strains. ChemMedChem, 2009, 4(3), 339-3351.
72. Baliani, A.; Bueno, G. J.; Stewart, M. L.; Yardley, V.; Brun, R.; Barrett, M. P.; Gilbert, I. H. Design and synthesis of a series of melamine-based nitroheterocycles with activity against Trypanosomatid parasites. J. Med. Chem., 2005, 48(17), 5570-5579.
73. Landfear, S. M. Drugs and transporters in kinetoplastid protozoa. Adv. Exp. Med. Biol., 2008, 625, 22-32.
74. Lanteri, C. A.; Stewart, M. L.; Brock, J. M.; Alibu, V. P.; Meshnick, S. R.; Tidwell, R. R.; Barrett, M. P. Roles for the Trypanosoma brucei P2 transporter in DB75 uptake and resistance. Mol. Pharmacol., 2006, 70(5), 1585-1592.
75. Chollet, C.; Baliani, A.; Wong, P. E.; Barrett, M. P.; Gilbert, I. H. Targeted delivery of compounds to Trypanosoma brucei using the melamine motif. Bioorg. Med. Chem., 2009, 17(6), 2512-2523.
76. Arakaki, T. L.; Buckner, F. S.; Gillespie, J. R.; Malmquist, N. A.; Phillips, M. A.; Kalyuzhniy, O.; Luft, J. R.; Detitta, G. T.; Verlinde, C. L.; Van Voorhis, W. C.; Hol, W. G.; Merritt, E. A. Characterization of Trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target; structural, kinetic and RNAi studies. Mol. Microbiol., 2008, 68(1), 37-50.
77. Hofer, A.; Steverding, D.; Chabes, A.; Brun, R.; Thelander, L. Trypanosoma brucei CTP synthetase: a target for the treatment of African sleeping sickness. Proc. Natl. Acad. Sci. USA, 2001, 98(11), 6412-6416.
78. Fijolek, A.; Hofer, A.; Thelander, L. Expression, purification, characterization, and in vivo targeting of trypanosome CTP synthetase for treatment of African sleeping sickness. J. Biol. Chem., 2007, 282(16), 11858-18865.
79. Beck, J. T.; Ullman, B. Nutritional requirements of wild-type and folate transport-deficient Leishmania donovani for pterins and folates. Mol. Biochem. Parasitol., 1990, 43(2), 221-230.
80. Gamarro, F.; Yu, P. L.; Zhao, J.; Edman, U.; Greene, P. J.; Santi, D. Addendum to "Trypanosoma brucei dihydrofolate reductasethymidylate synthase: gene isolation and expression and characterization of the enzyme" [Mol. Biochem. Parasitol. 72(1995) 11-22]. Mol. Biochem. Parasitol., 1995, 75(1), 127.
81. Moreira, W.; Leblanc, E.; Ouellette, M. The role of reduced pterins in resistance to reactive oxygen and nitrogen intermediates in the protozoan parasite Leishmania. Free Radic. Biol. Med., 2009, 46(3), 367-375.
82. Nare, B.; Garraway, L. A.; Vickers, T. J.; Beverley, S. M. PTR1-dependent synthesis of tetrahydrobiopterin contributes to oxidant susceptibility in the trypanosomatid protozoan parasite Leishmania major. Curr. Genet., 2009, 55(3), 287-299.
83. Bello, A. R.; Nare, B.; Freedman, D.; Hardy, L.; Beverley, S. M. PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc. Natl. Acad. Sci. USA, 1994, 91(24), 11442-11446.
84. El Fadili, A.; Kundig, C.; Roy, G.; Ouellette, M. Inactivation of the Leishmania tarentolae pterin transporter (BT1) and reductase (PTR1) genes leads to viable parasites with changes in folate metabolism and hypersensitivity to the antifolate methotrexate. J. Biol. Chem., 2004, 279(18), 18575-18582.
85. Sienkiewicz, N.; Jaroslawski, S.; Wyllie, S.; Fairlamb, A. H. Chemical and genetic validation of dihydrofolate reductasethymidylate synthase as a drug target in African trypanosomes. Mol. Microbiol., 2008, 69(2), 520-533.
86. Mpamhanga, C. P.; Spinks, D.; Tulloch, L. B.; Shanks, E. J.; Robinson, D. A.; Collie, I.T.; Fairlamb, A. H.; Wyatt, P. G.; Frearson, J. A.; Hunter, W. N.; Gilbert, I. H.; Brenk, R. One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening. J. Med. Chem., 2009, 52(14), 4454-4465.
87. Chowdhury, A. R.; Majumdar, H. K. DNA topoisomerases in life and death: implications in kinetoplastid protozoa. Curr. Mol. Med., 2004, 4(6), 711-722.
88. Balaña-Fouce, R. R. C.; Pérez-Pertejo, Y.; Díaz-González, R.; Reguera, R. M. Targeting atypical trypanosomatid DNA topoisomerase I. Drug Discov. Today, 2006, 11(15), 733-740.
89. Deterding, A. D. F.; Thompson, K. A.; Steverding, D. Antitrypanosomal activities of DNA topoisomerase inhibitors. Acta Tropica, 2005, 93(3), 311-316.
90. Bakshi, R. P.; Shapiro, T. A. RNA interference of Trypanosoma brucei topoisomerase IB: both subunits are essential. Mol. Biochem. Parasitol., 2004, 136(2), 249-255.
91. Steverding, D.; Wang, X. Evaluation of anti-sleeping-sickness drugs and topoisomerase inhibitors in combination on Trypanosoma brucei. J. Antimicrob. Chemother., 2009, 63(6), 1293-1295.
92. Nenortas, E.; Burri, C.; Shapiro, T. A. Antitrypanosomal activity of fluoroquinolones. Antimicrob. Agents Chemother., 1999, 43(8), 2066-2068.
93. Nenortas, E.; Kulikowicz, T.; Burri, C.; Shapiro, T. A. Antitrypanosomal activities of fluoroquinolones with pyrrolidinyl substitutions. Antimicrob. Agents Chemother., 2003, 47(9), 3015-3017.
94. Bakshi, R. P.; Sang, D.; Morrell, A.; Cushman, M.; Shapiro, T. A. Activity of indenoisoquinolines against African trypanosomes. Antimicrob. Agents Chemother., 2009, 53(1), 123-128.
95. Lee, S.H.; Stephens, J. L.; Englund, P. T. A fatty-acid synthesis mechanism specialized for parasitism. Nat. Rev. Microbiol., 2007, 5(4), 287-297.
96. van Hellemond, J. J.; Tielens, A.G. Adaptations in the lipid metabolism of the protozoan parasite Trypanosoma brucei. FEBS Lett., 2006, 580(23), 5552-558.
97. Lee, S.H.; Stephens, J.L.; Paul, K.S.; Englund, P.T. Fatty acid synthesis by elongases in trypanosomes. Cell, 2006, 126(4), 691-699.
98. Stephens, J. L.; Lee, S. H.; Paul, K. S.; Englund, P.T. Mitochondrial fatty acid synthesis in Trypanosoma brucei. J. Biol. Chem., 2007, 282(7), 4427-4436.
99. Autio, K. J.; Guler, J. L.; Kastaniotis, A. J.; Englund, P. T.; Hiltunen, J. K. The 3-hydroxyacyl-ACP dehydratase of mitochondrial fatty acid synthesis in Trypanosoma brucei. FEBS Lett., 2008, 582(5), 729-733.
100. Guler, J. L.; Kriegova, E.; Smith, T. K.; Lukes, J.; Englund, P.T. Mitochondrial fatty acid synthesis is required for normal mitochondrial morphology and function in Trypanosoma brucei. Mol. Microbiol., 2008, 67(5), 1125-1142.
101. Tasdemir, D.; Guner, N. D.; Perozzo, R.; Brun, R.; Donmez, A. A.; Calis, I.; Ruedi, P. Anti-protozoal and plasmodial FabI enzyme inhibiting metabolites of Scrophularia lepidota roots. Phytochemistry, 2005, 66(3), 355-362.
102. Karioti, A.; Skaltsa, H.; Linden, A.; Perozzo, R.; Brun, R.; Tasdemir, D. Anthecularin: a novel sesquiterpene lactone from Anthemis auriculata with antiprotozoal activity. J. Org. Chem., 2007, 72(21), 8103-8106.
103. Tasdemir, D.; Topaloglu, B.; Perozzo, R.; Brun, R.; O'Neill, R.; Carballeira, N. M.; Zhang, X.; Tonge, P. J.; Linden, A.; Ruedi, P. Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli. Bioorg. Med. Chem., 2007, 15(21), 6834-6845.
104. Giddens, A. C.; Nielsen, L.; Boshoff, H. I.; Tasdemir, D.; Perozzo, R.; Kaiser, M.; Wang, F.; Sacchettini, J. C.; Copp, B. R. Natural product inhibitors of fatty acid biosynthesis: synthesis of the marine microbial metabolites pseudopyronines A and B and evaluation of their anti-infective activities. Tetrahedron, 2008, 64(7), 1242-1249.
105. Price, H. P.; Menon, M. R.; Panethymitaki, C.; Goulding, D.; McKean, P.G.; Smith, D.F. Myristoyl-CoA:protein Nmyristoyltransferase, an essential enzyme and potential drug target in kinetoplastid parasites. J. Biol. Chem., 2003, 278(9), 7206-7214.
106. Panethymitaki, C.; Bowyer, P. W.; Price, H. P.; Leatherbarrow, R.J.; Brown, K.A.; Smith, D.F. Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major. Biochem. J., 2006, 396(2), 277-285.
107. Bowyer, P. W.; Tate, E. W.; Leatherbarrow, R. J.; Holder, A. A.; Smith, D. F.; Brown, K. A. N-myristoyltransferase: a prospective drug target for protozoan parasites. ChemMedChem, 2008, 3(3), 402-408.
108. Sheng, C.; Ji, H.; Miao, Z.; Che, X.; Yao, J.; Wang, W.; Dong, G.; Guo, W.; Lu, J.; Zhang, W. Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design. J. Comput. Aided. Mol. Des., 2009, 23(6), 375-389.
109. Sutterwala, S. S.; Hsu, F. F.; Sevova, E. S.; Schwartz, K. J.; Zhang, K.; Key, P.; Turk, J.; Beverley, S. M.; Bangs, J. D. Developmentally regulated sphingolipid synthesis in African trypanosomes. Mol. Microbiol., 2008, 70(2), 281-296.
110. Mina, J. G.; Pan, S.Y.; Wansadhipathi, N. K.; Bruce, C. R.; Shams-Eldin, H.; Schwarz, R. T.; Steel, P. G.; Denny, P.W. The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target. Mol. Biochem. Parasitol., 2009, 168(1), 16-23.
111. Olepu, S.; Suryadevara, P.K.; Rivas, K.; Yokoyama, K.; Verlinde, C.L.; Chakrabarti, D.; Van Voorhis, W.C.; Gelb, M.H. 2-Oxotetrahydro-1,8-naphthyridines as selective inhibitors of malarial protein farnesyltransferase and as anti-malarials. Bioorg. Med. Chem. Lett., 2008, 18(2), 494-497.
112. Bendale, P.; Olepu, S.; Suryadevara, P. K.; Bulbule, V.; Rivas, K.; Nallan, L.; Smart, B.; Yokoyama, K.; Ankala, S.; Pendyala, P. R.; Floyd, D.; Lombardo, L. J.; Williams, D. K.; Buckner, F. S.; Chakrabarti, D.; Verlinde, C. L.; Van Voorhis, W. C.; Gelb, M. H. Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials. J. Med. Chem., 2007, 50(19), 4585-4605.
113. Eastman, R.T.; Buckner, F. S.; Yokoyama, K.; Gelb, M. H.; Van Voorhis, W. C. Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation. J. Lipid. Res., 2006, 47(2), 233-240.
114. Kraus, J. M.; Verlinde, C. L.; Karimi, M.; Lepesheva, G. I.; Gelb, M. H.; Buckner, F. S. Rational modification of a candidate cancer drug for use against Chagas disease. J. Med. Chem., 2009, 52(6), 1639-1647.
115. Hammarton, T. C. Cell cycle regulation in Trypanosoma brucei. Mol. Biochem. Parasitol., 2007, 153(1), 1-8.
116. Doerig, C. Protein kinases as targets for anti-parasitic chemotherapy. Biochim. Biophys. Acta, 2004, 1697(1-2), 155-168.
117. Naula, C.; Parsons, M.; Mottram, J.C. Protein kinases as drug targets in trypanosomes and Leishmania. Biochim. Biophys. Acta, 2005, 1754(1-2), 151-159.
118. Hammarton, T.C.; Kramer, S.; Tetley, L.; Boshart, M.; Mottram, J.C. Trypanosoma brucei Polo-like kinase is essential for basal body duplication, kDNA segregation and cytokinesis. Mol. Microbiol., 2007, 65(5), 1229-1248.
119. Parsons, M.; Worthey, E. A.; Ward, P. N.; Mottram, J. C. Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genom., 2005, 6, 127.
120. Brenk, R.; Schipani, A.; James, D.; Krasowski, A.; Gilbert, I.H.; Frearson, J.; Wyatt, P.G. Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem, 2008, 3(3), 435-444.
121. Meijer, L.; Flajolet, M.; Greengard, P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends in Pharmacol. Sci., 2004, 25(9), 471-480.
122. Ojo, K.K.; Gillespie, J.R.; Riechers, A.J.; Napuli, A.J.; Verlinde, C.L.; Buckner, F.S.; Gelb, M.H.; Domostoj, M.M.; Wells, S.J.; Scheer, A.; Wells, T.N.; Van Voorhis, W.C. Glycogen synthase kinase 3 is a potential drug target for African trypanosomiasis therapy. Antimicrob Agents Chemother, 2008, 52(10), 3710-3717.
123. Jetton, N.; Rothberg, K.G.; Hubbard, J.G.; Wise, J.; Li, Y.; Ball, H.L.; Ruben, L. The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms. Mol. Microbiol., 2009, 72(2), 442-458.
124. McKerrow, J.H.; Rosenthal, P.J.; Swenerton, R.; Doyle, P. Development of protease inhibitors for protozoan infections. Curr Opin Infect Dis., 2008, 21(6), 668-672.
125. Doyle, P.S.; Zhou, Y.M.; Engel, J.C.; McKerrow, J.H. A cysteine protease inhibitor cures Chagas' disease in an immunodeficientmouse model of infection. Antimicrob Agents Chemother., 2007, 51(11), 3932-3939.
126. O'Brien, T.C.; Mackey, Z.B.; Fetter, R.D.; Choe, Y.; O'Donoghue, A.J.; Zhou, M.; Craik, C.S.; Caffrey, C.R.; McKerrow, J.H. A parasite cysteine protease is key to host protein degradation and iron acquisition. J. Biol. Chem., 2008, 283(43), 28934-28943.
127. Abdulla, M.H.; O'Brien, T.; Mackey, Z.B.; Sajid, M.; Grab, D.J.; McKerrow, J.H. RNA interference of trypanosoma brucei cathepsin B and L affects disease progression in a mouse model. PLoS Negl. Trop. Dis., 2008, 2(9), e298.
128. Mallari, J.P.; Shelat, A.A.; Obrien, T.; Caffrey, C.R.; Kosinski, A.; Connelly, M.; Harbut, M.; Greenbaum, D.; McKerrow, J.H.; Guy, R.K. Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB. J. Med. Chem., 2008, 51(3), 545-552.
129. Mallari, J.P.; Shelat, A.; Kosinski, A.; Caffrey, C.R.; Connelly, M.; Zhu, F.; McKerrow, J.H.; Guy, R.K. Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB. Bioorg. Med. Chem. Lett., 2008, 18(9), 2883-2885.
130. Li, Z.; Lindsay, M.E.; Motyka, S.A.; Englund, P.T.; Wang, C.C. Identification of a bacterial-like HslVU protease in the mitochondria of Trypanosoma brucei and its role in mitochondrial DNA replication. PLoS Pathog., 2008, 4(4), e1000048.
131. Grandgenett, P. M.; Otsu, K.; Wilson, H.R.; Wilson, M. E.; Donelson, J.E. A function for a specific zinc metalloprotease of African trypanosomes. PLoS Pathog., 2007, 3(10), 1432-1445.
132. Helms, M.J.; Ambit, A.; Appleton, P.; Tetley, L.; Coombs, G.H.; Mottram, J.C. Bloodstream form Trypanosoma brucei depend upon multiple metacaspases associated with RAB11-positive endosomes. J. Cell Sci., 2006, 119(Pt 6), 1105-1117.
133. Ochola, D. O.; Prichard, R. K.; Lubega, G.W. Classical ligands bind tubulin of trypanosomes and inhibit their growth in vitro. J. Parasitol., 2002, 88(3), 600-604.
134. Bhattacharya, G.; Salem, M. M.; Werbovetz, K. A. Antileishmanial dinitroaniline sulfonamides with activity against parasite tubulin. Bioorg. Med. Chem. Lett., 2002, 12(17), 2395-2398.
135. Werbovetz, K.A.; Sackett, D.L.; Delfin, D.; Bhattacharya, G.; Salem, M.; Obrzut, T.; Rattendi, D.; Bacchi, C. Selective antimicrotubule activity of N1-phenyl-3,5-dinitro-N4, N4-di-npropylsulfanilamide (GB-II-5) against kinetoplastid parasites. Mol. Pharmacol., 2003, 64(6), 1325-1333.
136. Bhattacharya, G.; Herman, J.; Delfin, D.; Salem, M. M.; Barszcz, T.; Mollet, M.; Riccio, G.; Brun, R.; Werbovetz, K. A. Synthesis and antitubulin activity of N1-and N4-substituted 3,5-dinitro sulfanilamides against African trypanosomes and Leishmania. J. Med. Chem., 2004, 47(7), 1823-1832.
137. Wu, D.; George, T.G.; Hurh, E.; Werbovetz, K.A.; Dalton, J.T. Pre-systemic metabolism prevents antikinetoplastid activity of N1, N4-substituted 3,5-dinitro sulfanilamide, GB-II-150. Life Sci., 2006, 79(11), 1081-93.
138. George, T. G.; Johnsamuel, J.; Delfin, D. A.; Yakovich, A.; Mukherjee, M.; Phelps, M. A.; Dalton, J. T.; Sackett, D. L.; Kaiser, M.; Brun, R.; Werbovetz, K. A. Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides. Bioorg. Med. Chem., 2006, 14(16), 5699-5710.
139. George, T.G.; Endeshaw, M. M.; Morgan, R. E.; Mahasenan, K.V.; Delfin, D. A.; Mukherjee, M. S.; Yakovich, A. J.; Fotie, J.; Li, C.; Werbovetz, K. A. Synthesis, biological evaluation, and molecular modeling of 3,5-substituted-N1-phenyl-N4, N4-di-nbutylsulfanilamides as antikinetoplastid antimicrotubule agents. Bioorg. Med. Chem., 2007, 15(18), 6071-6079.
140. Giles, N.L.; Armson, A.; Reid, S.A. Characterization of trifluralin binding with recombinant tubulin from Trypanosoma brucei. Parasitol. Res., 2009, 104(4), 893-903.
141. Räz, B.; Iten, M.; Grether-Bühler, Y.; Kaminsky, R.; Brun, R. The Alamar Blue® assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro. Acta Tropica, 1997, 68(2), 139-147.
142. Mackey, Z. B.; Baca, A. M.; Mallari, J. P.; Apsel, B.; Shelat, A.; Hansell, E. J.; Chiang, P. K.; Wolff, B.; Guy, K. R.; Williams, J.; McKerrow, J. H. Discovery of trypanocidal compounds by whole cell HTS of Trypanosoma brucei. Chem. Biol. Drug Des., 2006, 67(5), 355-363.
143. Werbovetz, K. Diamidines as antitrypanosomal, antileishmanial and antimalarial agents. Curr. Opin. Investig. Drugs, 2006, 7(2), 147-157.
144. Thuita, J. K.; Karanja, S. M.; Wenzler, T.; Mdachi, R. E.; Ngotho, J. M.; Kagira, J. M.; Tidwell, R.; Brun, R. Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis. Acta Trop., 2008, 108(1), 6-10.
145. Patrick, D. A.; Bakunov, S. A.; Bakunova, S. M.; Suresh Kumar, E. V.; Chen, H.; Jones, S. K.; Wenzler, T.; Barzcz, T.; Werbovetz, K. A.; Brun, R.; Tidwell, R. R. Synthesis and antiprotozoal activities of dicationic bis(phenoxymethyl)benzenes, bis(phenoxymethyl)naphthalenes, and bis(benzyloxy)naphthalenes. Eur. J. Med. Chem., 2009, 44(9)3351-3543.
146. Bakunov, S.A.; Bakunova, S.M.; Wenzler, T.; Barszcz, T.; Werbovetz, K.A.; Brun, R.; Tidwell, R.R. Synthesis and antiprotozoal activity of cationic 2-phenylbenzofurans. J. Med. Chem., 2008, 51(21), 6927-6944.
147. Arafa, R. K.; Ismail, M. A.; Munde, M.; Wilson, W. D.; Wenzler, T.; Brun, R.; Boykin, D.W. Novel linear triaryl guanidines, Nsubstituted guanidines and potential prodrugs as antiprotozoal agents. Eur. J. Med. Chem., 2008, 43(12), 2901-2908.
148. Ismail, M. A.; Arafa, R. K.; Wenzler, T.; Brun, R.; Tanious, F. A.; Wilson, W. D.; Boykin, D.W. Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines. Bioorg. Med. Chem., 2008, 16(2), 683-691.
149. Gonzalez, J. L.; Stephens, C. E.; Wenzler, T.; Brun, R.; Tanious, F. A.; Wilson, W. D.; Barszcz, T.; Werbovetz, K. A.; Boykin, D.W. Synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl]thiophenes. Eur. J. Med. Chem., 2007, 42(4), 552-557.
150. Bakunova, S. M.; Bakunov, S. A.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.; Hall, J. E.; Tidwell, R. R. Synthesis and in vitro antiprotozoal activity of bisbenzofuran cations. J. Med. Chem., 2007, 50(23), 5807-5823.
151. Patrick, D. A.; Bakunov, S. A.; Bakunova, S. M.; Kumar, E. V.; Lombardy, R. J.; Jones, S. K.; Bridges, A. S.; Zhirnov, O.; Hall, J. E.; Wenzler, T.; Brun, R.; Tidwell, R. R. Synthesis and in vitro antiprotozoal activities of dicationic 3,5-diphenylisoxazoles. J. Med. Chem., 2007, 50(10), 2468-2485.
152. Ansede, J. H.; Voyksner, R. D.; Ismail, M. A.; Boykin, D.W.; Tidwell, R. R.; Hall, J. E. In vitro metabolism of an orally active Omethyl amidoxime prodrug for the treatment of CNS trypanosomiasis. Xenobiotica, 2005, 35(3), 211-226.
153. Faist, J.; Seebacher, W.; Schlapper, C.; Kaiser, M.; Brun, R.; Saf, R.; Weis, R. Antiplasmodial and antitrypanosomal activity of bicyclic amides and esters of dialkylamino acids. Bioorg. Med. Chem., 2009, 17(10), 3595-3603.
154. Berger, H.; Weis, R.; Kaiser, M.; Brun, R.; Saf, R.; Seebacher, W. Novel azabicyclo[3.2.2]nonane derivatives and their activities against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense. Bioorg. Med. Chem., 2008, 16(12), 6371-6378.
155. Schlapper, C.; Seebacher, W.; Kaiser, M.; Brun, R.; Saf, R.; Weis, R. Bicyclo[2.2.2]octyl esters of dialkylamino acids as antiprotozoals. Bioorg. Med. Chem., 2007, 15(16), 5543-5550.
156. Papanastasiou, I.; Tsotinis, A.; Kolocouris, N.; Prathalingam, S. R.; Kelly, J. M. Design, synthesis, and trypanocidal activity of new aminoadamantane derivatives. J. Med. Chem., 2008, 51(5), 1496-1500.
157. Weis, R.; Seebacher, W. New bicyclic amines: synthesis and SARs of their action against the causative organisms of malaria and sleeping sickness. Curr. Med. Chem., 2009, 16(11), 1426-1441.
158. Kolocouris, N.; Zoidis, G.; Foscolos, G. B.; Fytas, G.; Prathalingham, S.R.; Kelly, J.M.; Naesens, L.; De Clercq, E. Design and synthesis of bioactive adamantane spiro heterocycles. Bioorg. Med. Chem. Lett., 2007, 17(15), 4358-4362.
159. Weis, R.; Brun, R.; Saf, R.; Seebacher, W. 4-Aminobicyclo[2.2.2]octanone Derivatives with Antiprotozoal Activities. Monatshefte für Chemie / Chemical Monthly, 2003, 134(7), 1019-1026.
160. Seebacher, W.; Brun, R.; Kaiser, M.; Saf, R.; Weis, R. Synthesis and evaluation of the antitrypanosomal and antiplasmodial activities of new 4-aminobicyclo[2.2.2]octane derivatives. Eur. J. Med. Chem., 2005, 40(9), 888-896.
161. Weis, R.; Schlapper, C.; Brun, R.; Kaiser, M.; Seebacher, W. Antiplasmodial and antitrypanosomal activity of new esters and ethers of 4-dialkylaminobicyclo[2.2.2]octan-2-ols. Eur. J. Pharm. Sci., 2006, 28(5), 361-368.
162. Schlapper, C.; Seebacher, W.; Faist, J.; Kaiser, M.; Brun, R.; Saf, R.; Weis, R. Antiplasmodial and antitrypanosomal activities of aminobicyclo[2.2.2]octyl omega-aminoalkanoates. Eur. J. Med. Chem., 2009, 44(2), 736-744.
163. Seebacher, W.; Schlapper, C.; Brun, R.; Kaiser, M.; Saf, R.; Weis, R. Synthesis of new esters and oximes with 4-aminobicyclo[2.2.2]octane structure and evaluation of their antitrypanosomal and antiplasmodial activities. Eur. J. Med. Chem., 2006, 41(8), 970-977.
164. Weis, R.; Berger, H.; Kaiser, M.; Brun, R.; Saf, R.; Seebacher, W. Synthesis of bicyclic amines and their activities against Trypanosoma brucei rhodesiense and Plasmodium falciparum K1. Arch. Pharm. Res., 2008, 31(6), 688-697.
165. Seebacher, W.; Weis, R.; Kaiser, M.; Brun, R.; Saf, R. Synthesis of 2-azabicyclo[3.2.2]nonanes from bicyclo[2.2.2]octan-2-ones and their activities against Trypanosoma brucei rhodesiense and Plasmodium falciparum K1. J. Pharm. Pharm. Sci., 2005, 8(3), 578-585.
166. Paul, K.S.; Bacchi, C.J.; Englund, P.T. Multiple triclosan targets in Trypanosoma brucei. Eukaryot Cell, 2004, 3(4), 855-861.
167. Bolognesi, M.L.; Lizzi, F.; Perozzo, R.; Brun, R.; Cavalli, A. Synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing antitrypanosomal and anti-leishmanial activity. Bioorg. Med. Chem. Lett., 2008, 18(7), 2272-2276.
168. Kuettel, S.; Zambon, A.; Kaiser, M.; Brun, R.; Scapozza, L.; Perozzo, R. Synthesis and evaluation of antiparasitic activities of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives. J. Med. Chem., 2007, 50(23), 5833-5839.
169. Wilkinson, S. R.; Taylor, M. C.; Horn, D.; Kelly, J. M.; Cheeseman, I. A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proc. Natl. Acad. Sci. USA, 2008, 105(13), 5022-5027.
170. DeLano, W. L. The PyMOL Molecular Graphics System. http://www.pymol.org, 2002.