Cytotoxic effect of amide derivatives of trifluoromethionine against the enteric protozoan parasite Entamoeba histolytica.
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 gamma-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.
Sato
Dan
D
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
Kobayashi
Seiki
S
Yasui
Hiroyuki
H
Shibata
Norio
N
Toru
Takeshi
T
Yamamoto
Masaichi
M
Tokoro
Gensuke
G
Ali
Vahab
V
Soga
Tomoyoshi
T
Takeuchi
Tsutomu
T
Suematsu
Makoto
M
Nozaki
Tomoyoshi
T
D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006224:Cricetinae; D003412:Cricetulus; D004748:Entamoeba histolytica / Q000187:drug effects*; D004749:Entamoebiasis / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008100:Liver Abscess / Q000517:prevention & control; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008795:Metronidazole / Q000494:pharmacology; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
D000577:Amides; D000981:Antiprotozoal Agents; D008795:Metronidazole; C037646:trifluoromethionine; D008715:Methionine