Skip to main content
SpringerLink
Log in

Chalcone, Acyl Hydrazide, and Related Amides Kill Cultured Trypanosoma brucei brucei

  • Original Articles
  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Background

Protozoan parasites of the genus Trypanosoma cause disease in a wide range of mammalian hosts. Trypanosoma brucei brucei, transmitted by tsetse fly to cattle, causes a disease (Nagana) of great economic importance in parts of Africa. T. b. brucei also serves as a model for related Trypanosoma species, which cause human sleeping sickness.

Materials and Methods

Chalcone and acyl hydrazide derivatives are known to retard the growth of Plasmodium falciparum in vitro and inhibit the malarial cysteine proteinase, falcipain. We tested the effects of these compounds on the growth of bloodstream forms of T. b. brucei in cell culture and in a murine trypanosomiasis model, and investigated their ability to inhibit trypanopain-Tb, the major cysteine proteinase of T. b. brucei.

Results

Several related chalcones, acyl hydrazides, and amides killed cultured bloodstream forms of T. b. brucei, with the most effective compound reducing parasite numbers by 50% relative to control populations at a concentration of 240 nM. The most effective inhibitors protected mice from an otherwise lethal T. b. brucei infection in an in vivo model of acute parasite infection. Many of the compounds also inhibited trypanopain-Tb, with the most effective inhibitor having a Ki value of 27 nM. Ki values for trypanopain-Tb inhibition were up to 50- to 100-fold lower than for inhibition of mammalian cathepsin L, suggesting the possibility of selective inhibition of the parasite enzyme.

Conclusions

Chalcones, acyl hydrazides, and amides show promise as antitrypanosomal chemotherapeutic agents, with trypanopain-Tb possibly being one of their in vivo targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hall HTB. (1977) Disease and Parasites of Livestock in the Tropics. Longman, Harlow.

    Google Scholar 

  2. International Laboratory for Research on Animal Diseases. (1994) ILRAD 1993/4: Annual Report of the International Laboratory for Research on Animal Diseases. International Laboratory for Research on Animal Diseases, Nairobi, pp. 21–29.

    Google Scholar 

  3. Troeberg L, Morty RE, Pike RN, et al. (1999) Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei brucei Exp. Parsitol. 91: 349–355.

    Article  CAS  Google Scholar 

  4. Ashall F, Angliker H, Shaw E. (1990) Lysis of trypanosomes by peptidyl fluoromethyl ketones. Biochim. Biophys. Res. Comm. 70: 923–929.

    Article  Google Scholar 

  5. Engel JC, Doyle PS, Hsieh I, McKerrow JH. (1998) Cysteine proteinase inhibitors cure an experimental Trypanosoma cruzi infection. J. Exp. Med. 188: 725–734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mbawa ZR, Gumm ID, Shaw E, Lonsdale-Eccles JD. (1992) Characterisation of a cysteine protease from bloodstream forms of Trypanosoma congolense. Eur. J. Biochem. 204: 371–379.

    Article  CAS  PubMed  Google Scholar 

  7. Wasilewski MM, Lim KC, Phillips J, McKerrow JH. (1996) Cysteine protease inhibitors block schistosome hemoglobin degradation in vitro and decrease worm burden and egg production in vivo. Mol. Biochem. Parasitol. 81: 179–189.

    Article  CAS  PubMed  Google Scholar 

  8. Rosenthal PJ, Lee GK, Smith RE. (1993) Inhibition of a Plasmodium vinckei cysteine proteinase cures murine malaria. J. Clin. Invest. 91: 1052–1056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rockett KA, Playfair JHL, Ashall F, Targett GAT, Angliker H, Shaw E. (1990) Inhibition of intraerythrocytic development of Plasmodium falciparum by proteinase inhibitors. FEBS Lett. 259: 257–259.

    Article  CAS  PubMed  Google Scholar 

  10. Selzer PM, Chen X, Chan VJ, et al. (1997) Leishmania major molecular modeling of cysteine proteases and prediction of new non-peptide inhibitors. Exp. Parasitol. 87: 212–221.

    Article  CAS  PubMed  Google Scholar 

  11. Harth G, Andrews N, Mills AA, Engel JC, Smith R, McKerrow JH. (1993) Peptide-fluoromethyl ketones arrest intracellular replication and intercellular transmission of Trypanosoma cruzi. Mol. Biochem. Parasitol. 58: 17–24.

    Article  CAS  PubMed  Google Scholar 

  12. Mierelles MNL, Juliano L, Carmona E, et al. (1992) Inhibitors of the major cysteinyl proteinase (GP57/51) impair host cell invasion and arrest the intracellular development of Trypanosoma cruzi in vitro. Mol. Biochem. Parasitol. 52: 175–184.

    Article  Google Scholar 

  13. Li R, Kenyon GL, Cohen FE, et al. (1995) In vitro antimalarial activity of chalcones and their derivatives. J. Med. Chem. 38: 5031–5037.

    Article  CAS  PubMed  Google Scholar 

  14. Torres-Santos EC, Moreira DL, Kaplan MAC, Meirelles MN, Rossi-Bergman B. (1999) Selective effect of 2′, 6′-dihydroxy-4′-methylchalcone isolated from Piper aduncum on Leishmania amazonensis. Antimicrob. Agents Chemother. 43: 1234–1241.

    CAS  Google Scholar 

  15. Ring CS, Sun E, McKerrow JH, et al. (1993) Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc. Natl. Acad. Sci. U. S. A. 90: 3583–3587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li Z, Chen X, Davidson E, et al. (1994) Anti-malarial drug development using models of enzyme structure. Chem. Biol. 1: 31–37.

    Article  CAS  PubMed  Google Scholar 

  17. Kuntz ID. (1992) Structure-based strategies for drug design and discovery. Science 257: 1078–1082.

    Article  CAS  PubMed  Google Scholar 

  18. Hansch C, Leo AJ. (1979) In: Substituent Constants for Correlation Analysis in Chemistry and Biology. Wiley Interscience, New York.

    Google Scholar 

  19. Hesse F, Selzer PM, Mühlstädt K, Duszenko M. A novel cultivation technique for long-term maintenance of bloodstream form trypanosomes in vitro. Mol. Biochem. Parasitol. 70: 157–166.

  20. Troeberg L, Pike RN, Morty RE, Berry RK, Coetzer THT, Lonsdale-Eccles JD. (1996) Proteases from Trypanosoma brucei brucei purification, characterisation and interactions with host regulatory molecules. Eur. J. Biochem. 238: 728–736.

    Article  CAS  PubMed  Google Scholar 

  21. Pike RN, Coetzer THT, Dennison C. (1992) Proteolytically active complexes of cathepsin L and a cysteine proteinase inhibitor; purification and demonstration of their formation in vitro. Arch. Biochem. Biophys. 294: 623–629.

    Article  CAS  PubMed  Google Scholar 

  22. Barrett AJ, Kirschke H. (1981). Cathepsin B, cathepsin H and cathepsin L. Methods Enzymol. 80C: 535–561.

    Article  Google Scholar 

  23. Barrett AJ, Kembhavi AA, Brown MA, et al. (1982) L-trans-epoxysuccinyl-leucylamido(4-guanidino) butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L. Biochem. J. 201: 189–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Salvesen G, Nagase K. (1989). Inhibition of proteolytic enzymes, p. 83–104. In: Benyon RJ, Bond JS (eds.) Proteolytic Enzymes: A Practical Approach. IRL Press, Oxford.

    Google Scholar 

  25. Dehrmann FM, Coetzer THT, Pike RN, Dennison C. (1995) Mature cathepsin L is substantially active in the ionic milieu of the extracellular medium. Arch. Biochem. Biophys. 324: 93–98.

    Article  CAS  PubMed  Google Scholar 

  26. Lipinski CA, Lombardo F, Dominy BW, Feeny PJ. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 23: 3–25.

    Article  CAS  Google Scholar 

  27. Zhang K, Yang EB, Tang YW, Wong KP, Mack P. (1991) Inhibition of glutathione reductase by plant polyphenols. Biochem. Pharmacol. 54: 1047–1053.

    Article  Google Scholar 

  28. McKerrow JH, McGrath ME, Engel JC. (1995) The cysteine protease of Trypanosoma cruzi as a model for antiparasitic drug design. Parasitol. Today 11: 279–282.

    Article  CAS  PubMed  Google Scholar 

  29. de Cazzulo F, MartInez BMJ, North MJ, Coombs MH, Cazzulo J–J. (1994) Effects of proteinase inhibitors on growth and differentiation of Trypanosoma cruzi. FEMS Microbiol. Lett. 124: 81–86.

    Article  CAS  PubMed  Google Scholar 

  30. Rosenthal PJ, McKerrow JH, Rasnick D, Leech JH. (1989) Plasmodium falciparum inhibitors of lysosomal cysteine proteinases inhibit a trophozoite proteinase and block parasite development. Mol. Biochem. Parasitol. 35: 177–184.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the South African Foundation for Research Development and the University of Natal Research Fund (THTC), a Tropical Disease Research Unit Grant from the U.S. National Institute of Allergy and Infectious Diseases, and the Burroughs Wellcome Molecular Parasitology Scholar Award (JHMK).

Author information

Authors and Affiliations

  1. School of Molecular and Cellular Biosciences, University of Natal (Pietermaritzburg), Scottsville, South Africa

    Linda Troeberg, Rory E. Morty, John D. Lonsdale-Eccles & Theresa H. T. Coetzer

  2. Department of Pharmaceutical Chemistry, Veterans Affairs Medical Center, University of California, San Francisco, California, USA

    Xiaowu Chen, Terrence M. Flaherty, Maosheng Cheng, Huiming Hua, Clayton Springer, James H. McKerrow & George L. Kenyon

  3. Department of Pathology, Veterans Affairs Medical Center, University of California, San Francisco, California, USA

    James H. McKerrow

  4. Departments of Biochemistry and Biophysics, University of California, San Francisco, California, USA

    Fred E. Cohen

  5. Departments of Pharmacology and Medicine, University of California, San Francisco, California, USA

    Fred E. Cohen

Authors
  1. Linda Troeberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaowu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Terrence M. Flaherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rory E. Morty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maosheng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huiming Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Clayton Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James H. McKerrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. George L. Kenyon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John D. Lonsdale-Eccles
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Theresa H. T. Coetzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fred E. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theresa H. T. Coetzer.

Additional information

Communicated by F. E. Cohen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Troeberg, L., Chen, X., Flaherty, T.M. et al. Chalcone, Acyl Hydrazide, and Related Amides Kill Cultured Trypanosoma brucei brucei. Mol Med 6, 660–669 (2000). https://doi.org/10.1007/BF03402046

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03402046

Keywords

Search

Navigation