In vivo anti-chagas vinylthio-, vinylsulfinyl-, and vinylsulfonylbenzofuroxan derivatives

Journal of Medicinal Chemistry

Volumn 50, Issue 24, 2007, Pages 6004-6015

  Porcal, Williams ^a   Hernández, Paola ^a   Boiani, Mariana ^a   Aguirre, Gabriela ^a   Boiani, Lucía ^a   Chidichimo, Agustina ^b   Cazzulo, Juan J ^b   Campillo, Nuria E ^c   Paez, Juan A ^c   Castro, Ana ^d   Krauth Siegel, R Luise ^e   Davies, Carolina ^f   Basombrío, Miguel Ángel ^f   González, Mercedes ^a,g   Cerecetto, Hugo ^a,g  

^a UNIVERSIDAD DE LA REPÚBLICA   (Uruguay)

^b INSTITUTO DE INVESTIGACIONES BIOTECNOLÓGICAS   (Argentina)

^c INSTITUTO DE QUÍMICA MÉDICA   (Spain)

^d Neuropharma SA   (Spain)

^e UNIVERSITY OF HEIDELBERG   (Germany)

^f UNIVERSIDAD NACIONAL DE SALTA   (Argentina)

^g FACULTAD DE CIENCIAS   (Uruguay)

Author keywords

[No Author keywords available]

Indexed keywords

5 [2 (PHENYLSULFINYL)VINYL]BENZO[1,2 C] 1,2,5 OXADIAZOLE N OXIDE; 5 [2 (PHENYLTHIO)VINYL]BENZO[1,2 C] 1,2,5 OXADIAZOLE B OXIDE; BENZOFURAN DERIVATIVE; CYSTEINE; GLUTATHIONE; N [N (3 CARBOXYOXIRANE 2 CARBONYL)LEUCYL]AGMATINE; OXIDOREDUCTASE; SULFINIC ACID DERIVATIVE; SULFONE DERIVATIVE; UNCLASSIFIED DRUG; VINYL DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHAGAS DISEASE; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG MECHANISM; DRUG SCREENING; ENZYME ACTIVE SITE; FEMALE; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; MACROPHAGE; MICROBIAL RESPIRATION; MOUSE; NONHUMAN; OXIDATION REDUCTION REACTION; PARASITEMIA; QUANTITATIVE STRUCTURE ACTIVITY RELATION; TRYPANOSOMA CRUZI;

ANIMALS; ANTIBODIES, PROTOZOAN; BENZOXAZOLES; CELL LINE; CHAGAS DISEASE; CYSTEINE ENDOPEPTIDASES; FEMALE; GLUTATHIONE; HUMANS; MACROPHAGES; MICE; MODELS, MOLECULAR; NADH, NADPH OXIDOREDUCTASES; OXIDATION-REDUCTION; OXYGEN CONSUMPTION; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES; TRYPANOCIDAL AGENTS; TRYPANOSOMA CRUZI; VINYL COMPOUNDS;

EID: 37849011377     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm070604e     Document Type: Article

References (76)

1. Cerecetto, H.; González, M. Chemotherapy of Chagas' disease: status and new development. Curr. Top. Med. Chem. 2002, 2, 1187-1213.
2. World Health Organization; Control of Chagas disease: second report of the WHO expert committee. Technical Report Series, 905, WHO, Geneva, 2002.
3. El-Sayed, N. M.; Myler, P. J.; Bartholomeu, D.C.; Nilsson, D.; Aggarwal, G.; et al. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 2005, 309, 409-415.
4. (a) Schofield, C. J.; Jannin, J.; Salvatella, R. The future of Chagas disease control. Trends Parasitol. 2006, 22, 583-588.
5. (b) Urbina, J. Chemotherapy of Chagas disease. Curr. Pharm. Des. 2002, 8, 287-295.
6. (a) Docampo, R.; Moreno, S. N. J. Free radical metabolism of antiparasitic agents. Fed. Proc. 1986, 45, 2471-2476.
7. (b) Docampo, R. Sensitivity of parasite to free radical damage by anti-parasitic drugs. Chem. Biol. Int. 1990, 73, 1-27.
8. Maya, J. D.; Cassels, B. H.; Iturriaga-Vásquez, P.; Ferreira, J.; Faúndez, M.; Galanti, N.; Ferreira, A.; Morello, A. Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comp. Biochem. Physiol. Part A 2006, 146, 601-620.
9. (a) Buckner, F. S.; Griffin, J. H.; Wilson, A. J.; Van Voorhis, W. C. Potent anti-Trypanosoma cruzi activities of oxidosqualene cyclase inhibitors. Antimicrob. Agents Chemother. 2001, 45, 1210-1215.
10. (b) Urbina, J. A.; Payares, G.; Molina, J.; Sanoja, C.; Liendo, A.; Lazardi, K.; Piras, M. M.; Piras, R.; Perez, N.; Wincker, P.; Ryley, J. F. Cure of short- and long-term experimental Chagas' disease using D0870. Science 1996, 273, 969-971.
11. (c) Nussbaumer, P.; Lietner, I.; Mraz, K.; Stütz, A. Synthesis and structure-activity relationships of side-chain-substituted analogs of the allylamine antimycotic Terbinafine lacking the central amino function. J. Med. Chem. 1995, 38, 1831-1836.
12. (d) Lazardi, K.; Urbina, J. A.; de Souza, W. Ultrastructural alterations induced by two ergosterol biosynthesis inhibitors, Keto-conazole and Terbinafine, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Antimicrob, Agents Chemother. 1990, 34, 2097-2105.
13. Turrens, J. F. Oxidative stress and antioxidant defenses: a target for the treatment of diseases caused by parasitic protozoa. Mol. Aspects Med. 2004, 25, 211-220.
14. (a) Aguirre, G.; Boiani, M.; Cerecetto, H.; Gerpe, A.; González, M.; Fernández Sainz, Y.; Denicola, A.; Ochoa de Ocáriz, C.; Nogal, J. J.; Montero, D.; Escario, J. A. Novel antiprotozoal products: Imidazole and benzimidazole N-oxide derivatives and related compounds. Arch. Pharm. 2004, 337, 259-270.
15. (b) Gerpe, A.; Aguirre, G.; Boiani, L.; Cerecetto, H.; González, M.; Olea-Azar, C.; Rigol, C.; Maya, J.D.; Morello, A.; Piro, O.E.; Aran, V.J.; Azqueta, A.; López de Ceráin, A.; Monge, A.; Rojas, M.A.; Yaluff, G. Indazole N-oxide derivatives as antiprotozoa agents. Synthesis, biological evaluation and QSAR studies. Bioorg. Med. Chem. 2006, 14, 3467-3480.
16. Cerecetto, H.; Di Maio, R.; González, M.; Risso, M.; Saenz, P.; Seoane, G.; Denicola, A.; Peluffo, G.; Quijano, C; Olea-Azar, C. 1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs. Structure-activity relationships. J. Med. Chem. 1999, 42, 1941-1950.
17. Aguirre, G.; Cerecetto, H.; Di Maio, R.; González, M.; Porcal, W.; Seoane, G.; Denicola, A.; Ortega, M. A.; Aldana, I.; Monge-Vega, A. Benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as potential antitryapanosomal drugs. Structure-activity relationships. Part II. Arch. Pharm. 2002, 335, 15-21.
18. Olea-Azar, C.; Rigol, C.; Mendizábal, F.; Cerecetto, H.; Di Maio, R.; González, M.; Porcal, W.; Morello, A.; Repetto, Y.; Maya, J. D. Novel benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as antichagasic agents: Chemical and biological studies. Lett. Drugs Des. Dev. 2005, 2, 294-301.
19. Aguirre, G.; Boiani, L.; Cerecetto, H.; Di Maio, R.; González, M.; Porcal, W.; Thomson, L.; Tórtora, V.; Denicola, A.; Möller, M. Benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as potential antitrypanosomal drugs. Part III. Substituents-clustering methodology in the search of new active compounds. Bioorg. Med. Chem. 2005, 13, 6324-6335.
20. Porcal, W.; Hernández, P.; Aguirre, G.; Boiani, L.; Boiani, M.; Merlino, A.; Ferreira, A.; Di Maio, R.; Castro, A.; González, M.; Cerecetto, H. Second generation of 5-ethenylbenzofuroxan derivatives as inhibitors of Trypanosoma cruzi growth: Synthesis, biological evaluation and structure activity relationships. Bioorg. Med. Chem. 2007, 15, 2768-2781.
21. Aguirre, G.; Boiani, L.; Boiani, M.; Cerecetto, H.; Di Maio, R.; González, M.; Porcal, W.; Denicola, A.; Piro, O. E.; Castellano, E. E.; Sant'Anna, C. M. R.; Barreiro, E. J. New potent 5-substituted benzofuroxans as inhibitors of Trypanosoma cruzi growth. Quantitative structure-activity relationships studies. Bioorg. Med. Chem. 2005, 13, 6336-6346.
22. Olea-Azar, C.; Rigol, C.; Mendizábal, F.; Briones, R.; Cerecetto, H.; Di Maio, R.; González, M.; Porcal, W.; Risso, M. Electrochemical and microsomal production of free radicals from 1,2,5-oxadiazole N-oxide as potential antiprotozoal drugs. Spectrochim. Acta Part A 2003, 59, 69-74.
23. Olea-Azar, C.; Rigol, C.; Opazo, L.; Morello, A.; Maya, J. D.; Repetto, Y.; Aguirre, G.; Cerecetto, H.; Di, Maio, R.; González, M.; Porcal, W. ESR and spin trapping studies of two new potential antitrypanosomal drugs. J. Chil. Chem. Soc. 2003, 48, 77-79.
24. Cazzulo, J. J. Proteinases of Trypanosoma cruzi: Potential targets for the chemotherapy of Chagas disease. Curr. Top. Med. Chem. 2002, 2, 1261-1271.
25. (a) Souto-Padrón, T.; Campetella, O.; Cazzulo, J. J.; de Souza, W. Cysteine proteinase in Trypanosoma cruzi: Immunocytochemical localization and involvement in parasite-host cell interaction. J. Cell Sci. 1990, 96, 485-490.
26. (b) Aparicio, I. M.; Scharfstein, J.; Lima, A. P. A new Cruzipain-mediated pathway of human cell invasion by Trypanosoma cruzi requires trypomastigote membranes. Infect. Immun. 2004, 72, 5892-5902.
27. Cazzulo J. J.; Stoka, V.; Turk, V. Cruzipain, the major cysteine proteinase from the protozoan parasite Trypanosoma cruzi. Biol. Chem. 1991, 378, 1-10.
28. Franke de Cazzulo, B. M.; Martínez, M.; North, M. J.; Coombs, G. H.; Cazzulo, J. J. Effect of proteinase inhibitors on growth and differentiation of Trypanosoma cruzi. FEMS Microbiol. Lett. 1994, 124, 81-86.
29. (a) Engel, J.C.; Doyle, P. S.; Palmer, J.; Hsieh, I.; Bainton, D.F.; McKerrow, J.H. Cysteine proteinase inhibitors alter Golgi complex ultrastructure and function in Trypanosoma cruzi. J. Cell Sci. 1998, 111, 597-606.
30. (b) McKerrow, J. H.; Engel, J. C.; Carey, C. R. Cysteine protease inhibitors as chemotherapy for parasitic infections. Bioorg. Med. Chem. 1999, 7, 639-644.
31. (c) McKerrow, J. H. Development of cysteine protease inhibitors as chemotherapy for parasitic diseases: insights on safety, target validation, and mechanism of action. Int. J. Parasitol. 1999, 29, 833-837.
32. (a) Bromme, D.; Klaus, J. L.; Okamoto, K.; Rasnick, D.; Palmer, J. T. Peptidyl vinyl sulphones; a new class of potent and selective cysteine protease inhibitors: S2P2 specificity of human cathepsin O2 in comparison with cathepsins S and L. Biochem. J. 1996, 315, 85-89.
33. (b) Roush, W. R.; Gwaltney, S. L.; Cheng, J.; Scheidt, K. A.; McKerrow, J. H.; Hansell, E. Vinyl sulfonate esters and vinyl sulfonamides: Potent, irreversible inhibitors of cysteine proteases. J. Am. Chem. Soc. 1998, 120, 10994-10995.
34. (c) Du, X.; Hansell, E.; Engel, J. C.; Caffrey, C. R.; Cohen, F. E.; McKerrow, J. H. Aryl ureas represent a new class of anti-trypanosomal agents Chem. Biol. 2000, 7, 733-742.
35. Schmidt, A.; Krauth-Siegel, R. L. Enzymes of the Trypanothione metabolism as targets for antitrypanosomal drug development. Curr. Topics Med. Chem. 2002, 2, 1239-1259.
36. Krauth-Siegel, R. L.; Inhoff, O. Parasite-specific trypanothione reductase as a drug target molecule. Parasitol Res. 2003, 90, 77-85.
37. 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.
38. (a) Henderson, G. B.; Ulrich, P.; Fairlamb, A. H.; Rosemberg, 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. U.S.A. 1988, 85, 5374-5378.
39. (b) Jockers-Scherübl, M. C.; Schirmer, R. H.; Krauth-Siegel, R. L. Trypanothione reductase from Trypanosoma cruzi. Catalytic properties of the enzyme and inhibition studies with trypanocidal compounds. Eur. J. Biochem. 1989, 180, 267-272.
40. a) Bonse, S.; Richards, J. M.; Ross, S. A.; Lowe, G.; Krauth-Siegel, R. L. (2,2′:6′,2″-Terpyridine)platinum(II) complexes are irreversible inhibitors of Trypanosoma cruzi Trypanothione reductase but not of human Glutathione reductase. J. Med. Chem. 2000, 43, 4812-4821.
41. (b) 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.
42. 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.
43. Simpkins, N. S. The chemistry of vinyl sulphones. Tetrahedron 1990, 46, 6951-6984.
44. Boden, R. M. A mild method for preparing trans-alkenes: Crown ether catalysis of the Wittig reaction. Synth. Commun. 1975, 784.
45. Enders, D.; von Berg, S.; Jandeleit, B. Diethyl [(phenylsulfonyl)-methyl] phosphonate. Org. Synth. 2002, 78, 169-176.
46. Paquette, L. A.; Carr, R. V. C. Phenyl vinyl sulfone and sulfoxide [benzene, (ethenylsulfonyl)- and benzene, (ethenylsulfinyl)-]. Organic Syntheses; Wiley: New York, 1990; Coll. Vol. 7, p 453.
47. Galli, U.; Lazzarato, L.; Bertinaria, M.; Sorba, G.; Gasco, A.; Parapini, S.; Taramelli, S. Synthesis and antimalarial activities of some furoxan sulfones and related furazans. Eur. J. Med. Chem. 2005, 40, 1335-1340.
48. Gasco, A.; Boulton, A. J. In Advances in Heterocycles Chemistry; Katritzky, A. R.; Boulton, A. J., Eds.; Wiley: New York, 1981; Vol. 29, pp 251-340.
49. Visentin, S.; Amiel, P.; Fruttero, R.; Boschi, D.; Roussel, C.; Giusta, L.; Carbone, E.; Gasco, A. Synthesis and voltage-clamp studies of methyl 1,4-dihydro-2,6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylate racemates and enantiomers and of their benzofuroxanyl analogues. J. Med. Chem. 1999, 42, 1422-1427.
50. 2+ antagonists benzofurazanyl and benzofuroxanyl-1,4-dihydropyridines. J. Mol. Struct. 2000, 523, 149-162.
51. Faucher, J. F.; Baltz, T.; Petry, K. G. Detection of an "epimastigote-like" intracellular stage of Trypanosoma cruzi. Parasitol. Res. 1995, 81, 441-443.
52. Almeida-de-Faria, M.; Freymuller, E.; Colli, W.; Alves, M. J. Trypanosoma cruzi: Characterization of an Intracellular Epimastigote-like Form. Exp. Parasitol. 1999, 92, 263-274.
53. Tyler, K. M.; Engman, D. M. The life cycle of Trypanosoma cruzi revisited. Int. J. Parasitol. 2001, 31, 472-480.
54. Molina, J.; Martins-Filho, O.; Brener, Z.; Romanha, A. J.; Loebenberg, D.; Urbina, J. A. Activity of the triazole derivative SCH 56592 (Posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrob. Agents Chemother. 2000, 44, 150-155.
55. Denicola, A.; Rubbo, H.; Rodriguez, D.; Radi, R. Peroxynitrite mediated cytotoxicity to Trypanosoma cruzi. Arch. Biochem. Biophys. 1993, 304, 279-286.
56. Muelas, S.; Di Maio, R.; Cerecetto, H.; Seoane, G.; Ochoa, C.; Escario, J. A.; Gómez-Barrio, A. New thiadiazine derivatives with activity against Trypanosoma cruzi amastigotes. Folia Parasitol. 2001, 48, 105-108.
57. Cerecetto, H.; Di Maio, R.; González, M.; Risso, M.; Sagrera, G.; Seoane, G.; Denicola, A.; Peluffo, G.; Quijano, C.; Stoppani, A. O. M.; Paulino, M.; Olea-Azar, C.; Basombrío, M. A. Synthesis and anti-trypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2- carboxaldehyde semicarbazones derivatives. Structure-activity relationships. Eur. J. Med. Chem. 2000, 35, 343-350.
58. Corrales, M.; Cardozo, R.; Segura, M. A.; Urbina, J. A.; Basombrio, M. A. Comparative efficacies of TAK-187, a long-lasting ergosterol biosynthesis inhibitor, and Benznidazole in preventing cardiac damage in a murine model of Chagas' disease. Antimicrob. Agents. Chemother. 2005, 49, 1556-1560.
59. Boiani, M.; Boiani, L.; Denicola, A.; Torres de Ortiz, S.; Serna, E.; Vera de Bilbao, N.; Sanabria, L.; Yaluff, G.; Nakayama, H.; Rojas de Arias, A.; Vega, C.; Rolan, M.; Gómez-Barrio, A.; Cerecetto, H.; González, M. 2H-Benzimidazole 1,3-dioxide derivatives: A new family of water-soluble anti-trypanosomatid. J. Med. Chem. 2006, 49, 3215-3220.
60. Brener, Z. Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Rev. Int. Med. Trop. Sao Pablo 1962, 4, 389-396.
61. Affranchino, J. L.; Schwarcz de Tarlovsky, M. N.; Stoppani, A. O. M. Terminal oxidases in the trypanosomatid Trypanosoma cruzi. Comp. Biochem. Physiol. B 1986, 85, 381-388.
62. FlexiDock. Sybyl 6.9, Tripos Inc., 1699 South Hanley Rd., St. Louis, MO 63144.
63. Sybyl 6.9, Tripos Inc., 1699 South Hanley Rd., St. Louis, MO 63144.
64. (a) Halgren, T. A. Merck Molecular Force Field. I. Basis, form, scope, parameterization and performance of MMFF94. J. Comput. Chem. 1996, 17, 490-519.
65. (b) Halgren, T. A. Merck Molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions. J. Comput. Chem. 1996, 17, 520-552.
66. (c) Halgren, T. A. Merck Molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94. J. Comput. Chem. 1996, 17, 553-586.
67. Sobolev, V.; Sorokine, A.; Prilusky, J. E.; Abola, E.; Edelman, M. Automated analysis of interatomic contacts in proteins. Bioinformatics 1999, 15, 327-332.
68. Lavigne, P.; Bagu, J. R; Boyko, R.; Willard, L.; Holmes, C. F. B.; Sykes, B. D. Structure-based thermodynamic analysis of the dissociation of protein phosphatase-1 catalytic subunit and microcystin-LR docked complexes. Protein Sci. 2000, 9, 252-264.
69. Brinen, L. S.; Hansell, E.; Cheng, J.; Roush, W. R.; McKerrow, J. H.; Fletterick, R. J. A target within the target: probing cruzain's P1′ site to define structural determinants for the Chagas' disease protease. Struct. Fold. Des. 2000, 8, 831-840.
70. Maya, J. D.; Morello, A. Inhibition of glutathione synthesis as a potencial therapeutic strategy against Chagas' disease. J. Biol. Sci. 2005, 5, 847-854.
71. Krauth-Siegel, R. L.; Meiering, S. K.; Schmidt, H. The parasite-specific trypanothione metabolism of Trypanosoma and Leishmania. Biol. Chem. 2003, 384, 539-549.
72. Steenkamp, D. J. Thiol metabolism of the trypanosomatids as potential drug targets. Life 2002, 53, 243-248.
73. Institute of Laboratory Animal Resources-National Research Council. Guide for the Care and Use of Laboratory Animals; National Academy Press: Washington, DC, 1996.
74. Morton, D. B.; Griffiths, P. H. M. Guidelines on the recognition of pain, distress and discomfort in experimental animals and a hypothesis for assessment. Vet. Rec. 1985, 116, 431-436.
75. Labriola, C.; Sousa, M.; Cazzulo, J. J. Purification of the major cysteine proteinase (cruzipain) from Trypanosoma cruzi by affinity chromatography. Biol. Res. 1993, 26, 101-107.
76. Sullivan, F. X.; Walsh, C. T. Cloning, sequencing, overproduction and purification of trypanothione reductase from Trypanosoma cruzi. Mol. Biochem. Parasitol. 1991, 44, 145-147.