Platinum(II) metal complexes as potential anti-Trypanosoma cruzi agents.
In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) two series of new platinum(II) complexes with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC50 values in the muM range against two different strains of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal drug Nifurtimox. In particular, the coordination of L3 (4-ethyl-1-(5-nitrofurfurylidene)thiosemicarbazide) to Pt(II) forming [Pt(L3)2] lead to almost a five-fold activity increase in respect to the free ligand. Trying to get an insight into the trypanocidal mechanism of action of these compounds, DNA and redox metabolism (intra-parasite free radical production) were evaluated as potential parasite targets. Results suggest that the complexes could inhibit parasite growth through a dual mechanism of action involving production of toxic free radicals by bioreduction and DNA interaction.
Vieites
Marisol
M
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, CC 1157, 11800 Montevideo, Uruguay.
Otero
Lucía
L
Santos
Diego
D
Toloza
Jeannette
J
Figueroa
Roberto
R
Norambuena
Ester
E
Olea-Azar
Claudio
C
Aguirre
Gabriela
G
Cerecetto
Hugo
H
González
Mercedes
M
Morello
Antonio
A
Maya
Juan Diego
JD
Garat
Beatriz
B
Gambino
Dinorah
D
D000818:Animals; D004247:DNA / Q000737:chemistry; D005609:Free Radicals / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013059:Spectrum Analysis, Raman; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D005609:Free Radicals; D009944:Organoplatinum Compounds; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D004247:DNA