Potent in vitro anti-Trypanosoma cruzi activity of pyridine-2-thiol N-oxide metal complexes having an inhibitory effect on parasite-specific fumarate reductase.
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 (IC(50) 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.
Vieites
Marisol
M
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, C. C. 1157, 11800, Montevideo, Uruguay.
Smircich
Pablo
P
Parajón-Costa
Beatriz
B
Rodríguez
Jorge
J
Galaz
Verónica
V
Olea-Azar
Claudio
C
Otero
Lucía
L
Aguirre
Gabriela
G
Cerecetto
Hugo
H
González
Mercedes
M
Gómez-Barrio
Alicia
A
Garat
Beatriz
B
Gambino
Dinorah
D
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000737:chemistry; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D010957:Plasmids / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D005609:Free Radicals; D009944:Organoplatinum Compounds; D011725:Pyridines; D013871:Thiones; D014344:Trypanocidal Agents; C008704:pyrithione; D004247:DNA; D013385:Succinate Dehydrogenase