Cytotoxic effect of amide derivatives of trifluoromethionine against the enteric protozoan parasite Entamoeba histolytica

Dan Sato, Seiki Kobayashi, Hiroyuki Yasui, Norio Shibata, Takeshi Toru, Masaichi Yamamoto, Gensuke Tokoro, Vahab Ali, Tomoyoshi Soga, Tsutomu Takeuchi, Makoto Suematsu, Tomoyoshi Nozaki

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Amoebiasis, caused by infection with the enteric protist Entamoeba histolytica, is one of the major parasitic diseases. Although metronidazole and its derivatives are currently employed in therapy, the paucity of effective drugs and potential clinical resistance necessitate the development of a novel drug. Trifluoromethionine (TFM) is a promising lead compound for antiamoebic drugs. To potentiate the antiamoebic effect of TFM, we synthesised various amide derivatives of TFM and evaluated their cytotoxicity. The amide derivatives of TFM were observed to have a superior cytotoxic effect compared with TFM and metronidazole against E. histolytica in vitro. Although TFM showed cytotoxicity following degradation by methionine γ-lyase, the derivatives were degraded by the enzyme less efficiently compared with TFM. We further demonstrated that a representative derivative was hydrolysed by the amoebic cell lysate to first yield TFM, followed by degradation similar to TFM. Hydrolysis was partially inhibited by protease inhibitors. A single subcutaneous or oral administration of TFM and its amide derivatives also effectively prevented the formation of amoebic liver abscess in a rodent model. These data demonstrate the improved effectiveness of TFM derivatives against E. histolytica infection and elucidate the mechanisms underlining the mode of action of these compounds.

Original languageEnglish
Pages (from-to)56-61
Number of pages6
JournalInternational Journal of Antimicrobial Agents
Volume35
Issue number1
DOIs
Publication statusPublished - 2010 Jan

Fingerprint

Entamoeba histolytica
Amides
Parasites
Metronidazole
trifluoromethionine
Pharmaceutical Preparations
Amoebic Liver Abscess
Amebiasis
Parasitic Diseases
Lyases
Infection
Protease Inhibitors
Methionine
Oral Administration
Rodentia
Hydrolysis

Keywords

  • Drug discovery
  • Methionine γ-lyase
  • Protozoan parasite
  • Sulphur-containing amino acid metabolism

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Cytotoxic effect of amide derivatives of trifluoromethionine against the enteric protozoan parasite Entamoeba histolytica. / Sato, Dan; Kobayashi, Seiki; Yasui, Hiroyuki; Shibata, Norio; Toru, Takeshi; Yamamoto, Masaichi; Tokoro, Gensuke; Ali, Vahab; Soga, Tomoyoshi; Takeuchi, Tsutomu; Suematsu, Makoto; Nozaki, Tomoyoshi.

In: International Journal of Antimicrobial Agents, Vol. 35, No. 1, 01.2010, p. 56-61.

Research output: Contribution to journalArticle

Sato, D, Kobayashi, S, Yasui, H, Shibata, N, Toru, T, Yamamoto, M, Tokoro, G, Ali, V, Soga, T, Takeuchi, T, Suematsu, M & Nozaki, T 2010, 'Cytotoxic effect of amide derivatives of trifluoromethionine against the enteric protozoan parasite Entamoeba histolytica', International Journal of Antimicrobial Agents, vol. 35, no. 1, pp. 56-61. https://doi.org/10.1016/j.ijantimicag.2009.08.016
Sato, Dan ; Kobayashi, Seiki ; Yasui, Hiroyuki ; Shibata, Norio ; Toru, Takeshi ; Yamamoto, Masaichi ; Tokoro, Gensuke ; Ali, Vahab ; Soga, Tomoyoshi ; Takeuchi, Tsutomu ; Suematsu, Makoto ; Nozaki, Tomoyoshi. / Cytotoxic effect of amide derivatives of trifluoromethionine against the enteric protozoan parasite Entamoeba histolytica. In: International Journal of Antimicrobial Agents. 2010 ; Vol. 35, No. 1. pp. 56-61.
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