Trypanosoma cruzi: effect and mode of action of nitroimidazole and nitrofuran derivatives.
With the aim of determining the actual target(s) of nitro-group bearing compounds considered as possible leads for the development of drugs against Chagas' disease, we studied in parallel nitrofurans and nitroimidazoles. We investigated nine representative compounds for the following properties: efficacy on different Trypanosoma cruzi strains, redox cyclers, inhibition of respiration, production of corresponding nitroso derivatives and intracellular thiol scavengers. Our results indicate that nifurtimox and related compounds act as redox cyclers, whereas the most active in the series, the 5-nitroimidazole megazol essentially acts as thiol scavenger particularly for trypanothione, the cofactor for trypanothione reductase, an essential enzyme in the detoxification process.
Maya
Juan Diego
JD
Faculty of Medicine, ICBM, Program of Molecular and Clinical Pharmacology, University of Chile, P.O. Box 70086, Santiago 7, Chile.
Bollo
Soledad
S
Nuñez-Vergara
Luis J
LJ
Squella
Juan A
JA
Repetto
Yolanda
Y
Morello
Antonio
A
Périé
Jacques
J
Chauvière
Gérard
G
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D009581:Nitrofurans / Q000737:chemistry / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D012119:Respiration / Q000187:drug effects; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects*
D000981:Antiprotozoal Agents; D009581:Nitrofurans; D009593:Nitroimidazoles; C044809:trypanothione; D005978:Glutathione; D013095:Spermidine