Synthesis and antiprotozoal activity of pyridyl analogues of pentamidine

Journal of Medicinal Chemistry

Volumn 52, Issue 15, 2009, Pages 4657-4667

  Bakunova, Svetlana M ^a   Bakunov, Stanislav A ^a   Wenzler, Tanja ^c   Barszcz, Todd ^b   Werbovetz, Karl A ^b   Brun, Reto ^c   Tidwell, Richard R ^a  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^b OHIO STATE UNIVERSITY   (United States)

^c SWISS TROPICAL AND PUBLIC HEALTH INSTITUTE   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

1,5 BIS(2 AMIDINOPYRIDINE 5 OXYPENTANE; 1,5 BIS(3 AMIDINOPYRIDINE 6 OXY)PENTANE; 1,5 BIS[2 (N HYDROXYAMIDINO)PYRIDINE 5 OXY]PENTANE; 1,5 BIS[2 (N METHOXYAMIDINO)PYRIDINE 4 OXY]PENTANE; AMIDOXIME DERIVATIVE; ANTIPROTOZOAL AGENT; ARTEMISININ; CATION; CHLOROQUINE; DIAMIDINE DERIVATIVE; DIAMIDOXIME; MELARSOPROL; METHAMIDOXIME DERIVATIVE; NITROGEN; PENTAMIDINE; PENTAMIDINE DERIVATIVE; PODOPHYLLOTOXIN; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIPROTOZOAL ACTIVITY; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG EFFICACY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; GROWTH INHIBITION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LEISHMANIA DONOVANI; MAMMAL CELL; MOUSE; MYOBLAST; NONHUMAN; PLASMODIUM FALCIPARUM; RAT; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; TRYPANOSOMA BRUCEI; TRYPANOSOMA RHODESIENSE; TRYPANOSOMIASIS;

ANIMALS; ANTIPROTOZOAL AGENTS; FEMALE; LEISHMANIA DONOVANI; MICE; PENTAMIDINE; PLASMODIUM FALCIPARUM; PYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 68549090813     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900805v     Document Type: Article

References (87)

1. Wongsrichanalai, C.; Pickard, A. L.; Wernsdorfer, W. H.; Meshnick, S. R. Epidemiology of drug-resistant malaria. Lancet Infect. Dis. 2002, 2, 209-218.
2. Le Bras, J.; Durand, R. The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum. Fundam. Clin. Pharmacol. 2003, 17, 147-153.
3. Arav-Boger, R.; Shapiro, T. A. Molecular mechanisms of resistance in antimalarial chemotherapy: the unmet challenge. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 565-585.
4. Hyde, J. E. Drug-resistant malaria. Trends Parasitol. 2005, 21, 494-498.
5. Platteeuw, J. J. Resistance to sulpha drug-based antifolate therapy in malaria: are we looking in the right place? Trop. Med. Int. Health 2006, 11, 804-808.
6. Woodrow, C. J.; Krishna, S. Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance. Cell. Mol. Life Sci. 2006, 63, 1586-1596.
7. Brun, R.; Schumacher, R.; Schmid, C.; Kunz, C.; Burri, C. The phenomenon of treatment failures in human African trypanosomiasis. Trop. Med. Int. Health 2001, 6, 906-914.
8. Fairlamb, A. H. Chemotherapy of human African trypanosomiasis: current and future prospects. Trends Parasitol. 2003, 19, 488-494.
9. Brun, R.; Balmer, O. New developments in human African trypanosomiasis. Curr. Opin. Infect. Dis. 2006, 19, 415-420.
10. Burri, C.; Brun, R. Human African trypanosomiasis. In Manson's Tropical Diseases; Cook, G. C., Zumla, A., Eds.; W. B. Saunders: London, 2008; pp 1307-1325.
11. Sundar, S. Drug resistance in Indian visceral leishmaniasis. Trop. Med. Int. Health 2001, 6, 849-854.
12. Sundar, S.; Chatterjee, M. Visceral leishmaniasis; current therapeutic modalities. Indian J. Med. Res. 2006, 123, 345-352.
13. Jha, T. K. Drug unresponsiveness and combination therapy for kala-azar. Indian J. Med. Res. 2006, 123, 389-398.
14. Ashley, J. N.; Barber, H. J.; Ewins, A. J.; Newbery, G.; Self, A. D. H. Chemotherapeutic comparison of the trypanocidal action of some aromatic diamidines. J. Chem. Soc. 1942, 103-116.
15. 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, 1155-1171.
16. Bouteille, B.; Oukem, O.; Bisser, S.; Dumas, M. Treatment perspectives for human African trypanosomiasis. Fundam. Clin. Pharmacol. 2003, 17, 171-181.
17. Pearson, R. D.; Hewlett, E. L. Pentamidine for the treatment of Pneumocystis carinii pneumonia and other protozoal diseases. Ann. Intern. Med. 1985, 103, 782-786.
18. Goa, K. L.; Campoli-Richards, D. M. Pentamidine isethionate. A review of its antiprotozoal activity, pharmacokinetic properties and therapeutic use in Pneumocystis carinii pneumonia. Drugs 1987, 33, 242-258.
19. Monk, J. P.; Benfield, P. Inhaled pentamidine. An overview of its pharmacological properties and a review of its therapeutic use in Pneumocystis carinii pneumonia. Drugs 1990, 39, 741-756.
20. Croft, S. L.; Yardley, V. Chemotherapy of leishmaniasis. Curr. Pharm. Des. 2002, 8, 319-342.
21. Singh, S.; Sivakumar, R. Challenges and new discoveries in the treatment of leishmaniasis. J. Infect. Chemother. 2004, 10, 307-315.
22. Antinori, S.; Longhi, E.; Bestetti, G.; Piolini, R.; Acquaviva, V.; Foschi, A.; Trovati, S.; Parravicini, C.; Corbellino, M.; Meroni, L. Post-kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient with acquired immune deficiency syndrome. Br. J. Dermatol. 2007, 157, 1032-1036.
23. Manfredi, R.; Marinacci, G.; Calza, L.; Passarini, B. Diffuse cutaneous dissemination of visceral leishmaniasis during human immunodeficiency virus (HIV) infection, despite negligible immunodeficiency: repeated failure of liposomal amphotericin B administration, followed by successful long-term pentamidine and paromomycin administration. Int. J. Antimicrob. Agents 2008, 31, 590-592.
24. Bray, P. G.; Barrett, M. P.; Ward, S. A.; de Koning, H. P. Pentamidine uptake and resistance in pathogenic protozoa: past, present and future. Trends Parasitol. 2003, 19, 232-239.
25. Bell, C. A.; Hall, J. E.; Kyle, D. E.; Grogl, M.; Ohemeng, K. A.; Allen, M. A.; Tidwell, R. R. Structure-activity relationships of analogs of pentamidine against Plasmodium falciparum and Leishmania mexicana amazonensis. Antimicrob. Agents Chemother. 1990, 34, 1381-1386.
26. Stead, A. M.; Bray, P. G.; Edwards, I. G.; DeKoning, H. P.; Elford, B. C.; Stocks, P. A.; Ward, S. A. Diamidine compounds: selective uptake and targeting in Plasmodium falciparum. Mol. Pharmacol. 2001, 59, 1298-1306.
27. Docampo, R.; Moreno, S. N. Current chemotherapy of human African trypanosomiasis. Parasitol. Res. 2003, 90, Supp. 1, S10-S13.
28. Burchmore, R. J.; Ogbunude, P. O.; Enanga, B.; Barrett, M. P. Chemotherapy of human African trypanosomiasis. Curr. Pharm. Des. 2002, 8, 256-267.
29. Legros, D.; Ollivier, G.; Gastellu-Etchegorry, M.; Paquet, C.; 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.
30. Barrett, M. P.; Fairlamb, A. H. The biochemical basis of arsenical-diamidine crossresistance in African trypanosomes. Parasitol. Today 1999, 15, 136-140.
31. Carter, N. S.; Berger, B. J.; Fairlamb, A. H. Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and - resistant Trypanosoma brucei brucei. J. Biol. Chem. 1995, 270, 28153-28157.
32. Carter, N. S.; Fairlamb, A. H. Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature 1993, 361, 173-176.
33. de Koning, H. P.; Jarvis, S. M. Adenosine transporters in bloodstream forms of Trypanosoma brucei brucei: substrate recognition motifs and affinity for trypanocidal drugs. Mol. Pharmacol. 1999, 56, 1162-1170.
34. Carter, N. S.; Barrett, M. P.; de Koning, H. P. A drug resistance determinant in Trypanosoma brucei. Trends Microbiol. 1999, 7, 469-471.
35. de Koning, H. P. Transporters in African trypanosomes: role in drug action and resistance. Int. J. Parasitol. 2001, 31, 512-522.
36. de Koning, H. P. Uptake of pentamidine in Trypanosoma brucei brucei is mediated by three distinct transporters: implications for cross-resistance with arsenicals. Mol. Pharmacol. 2001, 59, 586-592.
37. Matovu, E.; Stewart, M. L.; Geiser, F.; Brun, R.; Maser, P.; Wallace, L. J.; Burchmore, R. J.; Enyaru, J. C.; Barrett, M. P.; Kaminsky, R.; Seebeck, T.; de Koning, H. P. Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei. Eukaryot. Cell 2003, 2, 1003-1008.
38. Rollo, I. M.; Williamson, J. Acquired resistance to "Melarsen", tryparsamide and amidines in pathogenic trypanosomes after treatment with "Melarsen" alone. Nature 1951, 167, 147-148.
39. Fairlamb, A. H.; Carter, N. S.; Cunningham, M.; Smith, K. Characterisation of melarsen-resistant Trypanosoma brucei brucei with respect to cross-resistance to other drugs and trypanothione metabolism. Mol. Biochem. Parasitol. 1992, 53, 213-222.
40. Pospichal, H.; Brun, R.; Kaminsky, R.; Jenni, L. Induction of resistance to melarsenoxide cysteamine (Mel Cy) in Trypanosoma brucei brucei. Acta Trop. 1994, 58, 187-197.
41. de Koning, H. P.; Jarvis, S. M. Uptake of pentamidine in Trypanosoma brucei brucei is mediated by the P2 adenosine transporter and at least one novel, unrelated transporter. Acta Trop. 2001, 80, 245-250.
42. Bridges, D. J.; Gould, M. K.; Nerima, B.; Maeser, P.; Burchmore, R. J.; De Koning, H. P. Loss of the high affinity pentamidine transporter is responsible for high levels of cross-resistance between arsenical and diamidine drugs in African trypanosomes. Mol. Pharmacol. 2007, 71, 1098-1108.
43. Soeiro, M. N.; De Souza, E. M.; Stephens, C. E.; Boykin, D. W. Aromatic diamidines as antiparasitic agents. Expert Opin. Invest. Drugs 2005, 14, 957-972.
44. Biagini, G. A.; O'Neill, P. M.; Bray, P. G.; Ward, S. A. Current drug development portfolio for antimalarial therapies. Curr. Opin. Pharmacol. 2005, 5, 473-478.
45. Zhang, X.; Berger, B. J.; Ulrich, P. Synthesis and trypanocidal activity of the bis-carba analogue of pentamidine. Bioorg. Med. Chem. Lett. 1996, 6, 1035-1036.
46. Tidwell, R. R.; Jones, S. K.; Geratz, J. D.; Ohemeng, K. A.; Cory, M.; Hall, J. E. Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia. J. Med. Chem. 1990, 33, 1252-1257.
47. Bell, C. A.; Cory, M.; Fairley, T. A.; Hall, J. E.; Tidwell, R. R. Structure-activity relationships of pentamidine analogs against Giardia lamblia and correlation of antigiardial activity with DNA-binding affinity. Antimicrob. Agents Chemother. 1991, 35, 1099-1107.
48. Bakunova, S. M.; Bakunov, S. A.; Patrick, D. A.; Kumar, S. E. V. K.; 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, 2016-2035.
49. Das, B. P.; Boykin, D. W. Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans. J. Med. Chem. 1977, 20, 531-536.
50. Ismail, M. A.; Brun, R.; Easterbrook, J. D.; Tanious, F. A.; Wilson, W. D.; Boykin, D. W. Synthesis and antiprotozoal activity of aza-analogues of furamidine. J. Med. Chem. 2003, 46, 4761-4769.
51. Mathis, A. M.; Holman, J. L.; Sturk, L. M.; Ismail, M. A.; Boykin, D. W.; Tidwell, R. R.; Hall, J. E. Accumulation and intracellular distribution of antitrypanosomal diamidine compounds DB75 and DB820 in African trypanosomes. Antimicrob. Agents Chemother. 2006, 50, 2185-2191.
52. Forrest, H. S.; Walker, J. Chemotherapeutic agents of the sulfone type. V. 2,5-Disubstituted derivatives of pyridine. J. Chem. Soc. 1948, 1939-1945.
53. Dox, A. W.; Whitmore, F. C. Acetamidine hydrochloride. In Organic Synthesis, 2nd ed.; Blatt, A. H., Ed.; John Wiley and Sons: New York, 1941; Vol. 1, pp 5-7.
54. Markovac, A.; Ash, A. B.; Stevens, C. L.; Hackley, B. E., Jr.; Steinberg, G. M. Synthesis of oximes. IV. 2-Pyridinealdoxime methiodides from 2-picoline methiodides. J. Heterocycl. Chem. 1977, 14, 19-26.
55. Ross, S. T.; Kruse, L. I.; Ohlstein, E. H.; Erickson, R. W.; Ezekiel, M.; Flaim, K. E.; Sawyer, J. L.; Berkowitz, B. A. Inhibitors of dopamine beta-hydroxylase. 3. Some 1-(pyridylmethyl)imidazole-2-thiones. J. Med. Chem. 1987, 30, 1309-1313.
56. Bose, D. S.; Goud, P. R. Bis(trichloromethyl) carbonate, an efficient activator for the one-pot conversion of aldehydes into nitriles under mild conditions. Synth. Commun. 2002, 32, 3621-3624.
57. Singh, B.; Lesher, G. Y. Three convenient and novel syntheses of 4-amino-2-arylpyrimidines. J. Heterocycl. Chem. 1977, 14, 1413-1414.
58. Matsumura, E.; Ariga, M.; Ohfuji, T. Reissert-Kaufmann-type reaction of 4-nitropyridine N-oxide and its homologs. Bull. Chem. Soc. Jpn. 1970, 43, 3210-3214.
59. Berg, S. S.; Newbery, G. The search for chemotherapeutic amidines. Part X. Substituted 4,4′-diamidino-Rω-diphenoxyalkanes and -diphenyl ethers. J. Chem. Soc. 1949, 642-648.
60. Steck, E. A.; Kinnamon, K. E.; Rane, D. S.; Hanson, W. L. Leishmania donovani, Plasmodium berghei, Trypanosoma rhodesiense: antiprotozoal effects of some amidine types. Exp. Parasitol. 1981, 52, 404-413.
61. Willson, M.; Perie, J. J.; Malecaze, F.; Opperdoes, F.; Callens, M. Biological properties of amidinium sulfinic and sulfonic acid derivatives: inhibition of glycolytic enzymes of Trypanosoma brucei and protective effect on cell growth. Eur. J. Med. Chem. 1992, 27, 799-808.
62. Bacchi, C. J.; Brun, R.; Croft, S. L.; Alicea, K.; Buhler, Y. In vivo trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors. Antimicrob. Agents Chemother. 1996, 40, 1448-1453.
63. Donkor, I. O.; Assefa, H.; Rattendi, D.; Lane, S.; Vargas, M.; Goldberg, B.; Bacchi, C. Trypanocidal activity of dicationic compounds related to pentamidine. Eur. J. Med. Chem. 2001, 36, 531-538.
64. Donkor, I. O.; Huang, T. L.; Tao, B.; Rattendi, D.; Lane, S.; Vargas, M.; Goldberg, B.; Bacchi, C. Trypanocidal activity of conformationally restricted pentamidine congeners. J. Med. Chem. 2003, 46, 1041-1048.
65. Borges, M. N.; Messeder, J. C.; Figueroa-Villar, J. D. Synthesis, anti-Trypanosoma cruzi activity and micelle interaction studies of bisguanylhydrazones analogous to pentamidine. Eur. J. Med. Chem. 2004, 39, 925-929.
66. Dardonville, C.; Brun, R. Bisguanidine, bis(2-aminoimidazoline), and polyamine derivatives as potent and selective chemotherapeutic agents against Trypanosoma brucei rhodesiense. Synthesis and in vitro evaluation. J. Med. Chem. 2004, 47, 2296-2307.
67. Huang, T. L.; Vanden Eynde, J. J.; Mayence, A.; Donkor, I. O.; Khan, S. I.; Tekwani, B. L. Antiplasmodial and antileishmanial activity of conformationally restricted pentamidine congeners. J. Pharm. Pharmacol. 2006, 58, 1033-1042.
68. Jones, S. K.; Hall, J. E.; Allen, M. A.; Morrison, S. D.; Ohemeng, K. A.; Reddy, V. V.; Geratz, J. D.; Tidwell, R. R. Novel pentamidine analogs in the treatment of experimental Pneumocystis carinii pneumonia. Antimicrob. Agents Chemother. 1990, 34, 1026-1030.
69. Donkor, I. O.; Jones, S. K.; Tidwell, R. R. Pentamidine congeners 1: Synthesis of cis- and trans-butamidine analogues as anti-Pneumocystis carinii pneumonia agents. Bioorg. Med. Chem.Lett. 1993, 3, 1137-1140.
70. Donkor, I. O.; Tidwell, R. R.; Jones, S. K. Pentamidine congeners. 2. 2-Butene-bridged aromatic diamidines and diimidazolines as potential anti-Pneumocystis carinii pneumonia agents. J. Med. Chem. 1994, 37, 4554-4557.
71. 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, 5807-5823.
72. Kaminsky, R.; Schmid, C.; Brun, R. An "in vitro selectivity index" for evaluation of cytotoxicity of antitrypanosomal compounds. In Vitro Toxicol. 1996, 9, 315-324.
73. 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, 2468-2485.
74. Ismail, M.; Brun, R.; Wenzler, T.; Tanious, F.; Wilson, W.; Boykin, D. Dicationic biphenyl benzimidazole derivatives as antiprotozoal agents. Bioorg. Med. Chem. 2004, 12, 5405-5413.
75. Arafa, R. K.; Brun, R.; Wenzler, T.; Tanious, F. A.; Wilson, W. D.; Stephens, C. E.; Boykin, D. W. Synthesis, DNA affinity, and antiprotozoal activity of fused ring dicationic compounds and their prodrugs. J. Med. Chem. 2005, 48, 5480-5488.
76. Ismail, M. A.; Arafa, R. K.; Brun, R.; Wenzler, T.; Miao, Y.; Wilson, W. D.; Generaux, C.; Bridges, A.; Hall, J. E.; Boykin, D. W. Synthesis,DNAaffinity, and antiprotozoal activity of linear dications: terphenyl diamidines and analogues. J. Med. Chem. 2006, 49, 5324-5332.
77. Clement, B.; Immel, M.; Terlinden, R.; Wingen, F. J. Reduction of amidoxime derivatives to pentamidine in vivo. Arch. Pharm. (Weinheim) 1992, 325, 61-62.
78. Kamm, W.; Hauptmann, J.; Behrens, I.; Sturzebecher, J.; Dullweber, F.; Gohlke, H.; Stubbs, M.; Klebe, G.; Kissel, T. Transport of peptidomimetic thrombin inhibitors with a 3-amidino-phenylalanine structure: permeability and efflux mechanism in monolayers of a human intestinal cell line (Caco-2). Pharm. Res. 2001, 18, 1110-1118.
79. Clement, B. Reduction of N-hydroxylated compounds: amidoximes (N-hydroxyamidines) as pro-drugs of amidines. Drug Metab. Rev. 2002, 34, 565-579.
80. Ansede, J. H.; Anbazhagan, M.; Brun, R.; Easterbrook, J. D.; Hall, J. E.; Boykin, D. W. 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. 2004, 47, 4335-4338.
81. O'Brien, J.; Wilson, I.; Orton, T.; Pognan, F. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur. J. Biochem. 2000, 267, 5421-5426.
82. Baltz, T.; Baltz, D.; Giroud, C.; Crockett, J. Cultivation in a semidefined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense. EMBO J. 1985, 4, 1273-1277.
83. Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay, J. D. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob. Agents Chemother. 1979, 16, 710-718.
84. Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C. K.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Santo Tomas, J.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 2004, 430, 900-904.
85. 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-n-propylsulfanilamide (GB-II-5) against kinetoplastid parasites. Mol. Pharmacol. 2003, 64, 1325-1333.
86. Werbovetz, K. A.; Brendle, J. J.; Sackett, D. L. Purification, characterization, and drug susceptibility of tubulin from Leishmania. Mol. Biochem. Parasitol. 1999, 98, 53-65.
87. 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, 6-10.