Abstract
In the search for new therapeutic tools against Chagas disease (American trypanosomiasis) palladium and platinum complexes of the bioactive ligand pyridine-2-thiol N-oxide were exhaustively characterized and evaluated in vitro. Both complexes showed high in vitro growth inhibition activity (IC50 values in the nanomolar range) against Trypanosoma cruzi, the causative agent of the disease. They were 39–115 times more active than the antitrypanosomal drug Nifurtimox. The palladium complex showed an approximately threefold enhancement of the activity compared with the parent compound. In addition, owing to their low unspecific cytotoxicity on mammalian cells, the complexes showed a highly selective antiparasite activity. To get an insight into the mechanism of action of these compounds, DNA, redox metabolism (intraparasite free-radical production) and two parasite-specific enzymes absent in the host, namely, trypanothione reductase and NADH-fumarate reductase, were evaluated as potential parasite targets. Additionally, the effect of metal coordination on the free radical scavenger capacity previously reported for the free ligand was studied. All the data strongly suggest that trypanocidal action of the complexes could mainly rely on the inhibition of the parasite-specific enzyme NADH-fumarate reductase.
References
Engels D, Savioli L (2006) Trends Parasitol 22:363–366
Urbina J (2003) Expert Opin Ther Pat 13:661–669
Cerecetto H, González M (2002) Curr Topics Med Chem 2:1185–1190
Krauth-Siegel RL, Bauer H, Schirmer RH (2005) Angew Chem Int Ed 44:690–715
Croft S, Barret M, Urbina J (2005) Trends Parasitol 21:508–512
Ceaser M (2005) Lancet Infect Dis 5(8):470–471
Yamagata Y, Nakagawa J (2006) Adv Parasitol 61:129–165
Zhang C, Lippard S (2003) Curr Opin Chem Biol 7:481–489
Farrell N (2003) Compr Coord Chem II 9:809–840
Sánchez-Delgado RA, Anzellotti A, Suárez L (2004) In: Sigel H, Sigel A (eds) Metal ions in biological systems, vol 41. Marcel Dekker, New York, pp 379–419
Sánchez-Delgado RA, Anzellotti A (2004) Mini Rev Med Chem 4:23–30
Chibale K (2002) ARKIVOC IX, pp 93–98
Urquiola C, Vieites M, Aguirre G, Marín A, Solano B, Arrambide G, Lavaggi ML, Torre MH, González M, Monge A, Gambino D, Cerecetto H (2006) Bioorg Med Chem 14:5503–5509
Otero L, Vieites M, Boiani L, Denicola A, Rigol C, Opazo L, Olea-Azar C, Maya JD, Morello A, Krauth-Siegel RL, Piro OE, Castellano E, González M, Gambino D, Cerecetto H (2006) J Med Chem 49:3322–3331
Turrens JF, Newton CL, Zhong L, Hernández FR, Whitfield J, Docampo R (1999) FEMS Microbiol Lett 175:217–221
Tobin D, Arvanitidis M, Bisby RH (2002) Biochem Biophys Res Commun 299:155–159
Cerecetto H, González M (2001) Mini Rev Med Chem 1:219–231
Gómez-Quiroga A, Navarro-Ranninger C (2004) Coord Chem Rev 248:119–133
Hall MD, Hambley TW (2002) Coord Chem Rev 232:49–67
Hambley TW (1997) Coord Chem Rev 166:181–223
Bonse S, Richards JM, Ross SA, Lowe G, Krauth-Siegel RL (2000) J Med Chem 43:4812–4821
Lowe G, Droz AS, Vilaiyan T, Weaver GW, Tweedale L, Pratt JM, Rock P, Yardley V, Croft SL (1999) J Med Chem 42:999–1006
Croft SL (1999) Mem Inst Oswaldo Cruz 94:215–220
Shames SL, Fairlamb AH, Cerami A, Walsh CT (1985) Science 227:1485–1487
Schmidt A, Krauth-Siegel RL (2002) Curr Top Med Chem 2:1239–1259
Parajón-Costa BS, González-Baró AC, Baran EJ (2002) Z Anorg Allg Chem 628:1419–1424
Shi JC, Wen TB, Zheng Y, Zhong SJ, Wu DX, Liu QT, Kang BS, Wu BM, Mak TCW (1997) Polyhedron 16:369–375
Davidson JL, Preston PN, Russo MV (1983) J Chem Soc Dalton Trans 783–786
Zhou J, Li Y, Liu Z, Chen X-T (2005) Acta Crystallogr Sect E61:m195–m197
Koepp HM, Went H, Strehlow HZ (1960) Z Elektrochem 64:483–491
Gagné RR, Koval CA, Lisensky GC (1980) Inorg Chem 19:2854–2855
Rigol C, Olea-Azar C, Mendizábal F, Otero L, Gambino D, González M, Cerecetto H (2005) Spectrochim Acta A 61:2933–2938
Huang L, Lee A, Ellman JA (2002) J Med Chem 45:676–684
Arán VJ, Ochoa C, Boiani L, Buccino P, Cerecetto H, Gerpe A, González M, Montero D, Nogal JJ, Gómez-Barrio A, Azqueta A, López de Ceraín A, Piro OE, Castellano EE (2005) Bioorg Med Chem 13:3197–3207
Mahnken RE, Billadeau MA, Nikonowicz EP, Morrison H (1992) J Am Chem Soc 114:9253–9265
Otero L, Smircich P, Vieites M, Ciganda M, Cardoso Severino P, Terenzi H, Cerecetto H, Gambino D, Garat B (2007) J Inorg Biochem 101:74–79
Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (1999) Short protocols in molecular biology: a compendium of methods from current protocols in molecular biology. Wiley, New York
Ou B, Hampsch-Woodill M, Prior RL (2001) J Agric Food Chem 49:4619–4926
Dávalos A, Gómez-Cordovés C, Bartolomé B (2004) J Agric Food Chem 52:48–54
Jockers-Scherübl MC, Schirmer RH, Krauth-Siegel RL (1989) Eur J Biochem 180:267–272
Denicola A, Rubbo H, Prodanov E, Turrens JF (1992) Mol Biochem Parasitol 54:43–50
Contreras VT, Araujo-Jorge TC, Bonaldo MC, Thomaz N, Barbosa HS, Meirelles de NM, Goldenberg S (1988) Mem Inst Oswaldo Cruz 83(1):123–133
Christmas PB, Turrens JF (2000) FEMS Microbiol Lett 183:225–228
Lin-Vien D, Colthup NB, Fateley WG, Grasselli JG (1999) The handbook of infrared and Raman characteristic frequencies of organic molecules. Academic Press, Boston
Tsagkalidis W, Rodewald D, Rehder D, Vergopoulos V (1994) Inorg Chim Acta 219:213–215
Vieites M, Gambino D, González M, Cerecetto H, Tarulli SH, Quinzani OV, Baran EJ (2006) J Coord Chem 59(1):101–106
Gambino D, Otero L, Vieites M, Boiani M, González M, Baran EJ, Cerecetto H (2007) Spectrochim Acta A Mol Biomol Spect 68:341–348
Bard AJ, Faulkner LR (2001) Electrochemical methods: fundamentals and applications, 2nd edn. Wiley, New York
Nicholson RS, Shain I (1964) Anal Chem 36:706–723
Brown ER, Large RF (1971) In: Weisberger A, Rositer BW (eds) Part IIA, Chapter 6. Interscience, New York
Chen X, Hu Y, Wu D, Weng L, Kang B (1991) Polyhedron 10:2651–2657
Tyler KM, Engman DM (2001) Int J Parasitol 31:472–480
Otero L, Maya JD, Morello A, Rigol C, Barriga G, Rodriguez J, Folch C, Norambuena E, González M, Olea Azar C, Cerecetto H, Gambino D (2008) Med Chem 4:119–126
Krauth-Siegel RL. Personal communication
Acknowledgments
This work was partially supported by PEDECIBA of Uruguay, TWAS Research Grant 05-312 RG/CHE/LA and Prosul-CNPq project 490209/2005-0. B.P-C. is member of the Research Career of CONICET. We wish to thank R. Luise Krauth-Siegel, Heidelberg University, Germany, for performing the TR inhibition studies and O.E. Piro, Universidad Nacional de La Plata, Argentina, for performing helpful crystal parameter measurements of single crystals of the complexes.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Vieites, M., Smircich, P., Parajón-Costa, B. et al. Potent in vitro anti-Trypanosoma cruzi activity of pyridine-2-thiol N-oxide metal complexes having an inhibitory effect on parasite-specific fumarate reductase. J Biol Inorg Chem 13, 723–735 (2008). https://doi.org/10.1007/s00775-008-0358-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-008-0358-7