Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets.
In the search for new therapeutic tools against American Trypanosomiasis palladium complexes with bioactive nitrofuran-containing thiosemicarbazones as ligands were obtained. Sixteen novel palladium (II) complexes with the formulas [PdCl2(HL)] and [Pd(L)2] were synthesized, and the crystal structure of [Pd(5-nitrofuryl-3-acroleine thiosemicarbazone)2] x 3DMSO was solved by X-ray diffraction methods. Most complexes showed higher in vitro growth inhibition activity against Trypanosoma cruzi than the standard drug Nifurtimox. In most cases, the activity of the ligand was maintained or even increased as a result of palladium complexation. In addition, the complexes' mode of antitrypanosomal action was investigated. Although the complexes showed strong DNA binding, all data strongly suggest that the main trypanocidal mechanism of action is the production of oxidative stress as a result of their bioreduction and extensive redox cycling. Moreover, the complexes were found to be irreversible inhibitors of trypanothione reductase.
Otero
Lucía
L
Departamento Estrella Campos, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Vieites
Marisol
M
Boiani
Lucía
L
Denicola
Ana
A
Rigol
Carolina
C
Opazo
Lucía
L
Olea-Azar
Claudio
C
Maya
Juan Diego
JD
Morello
Antonio
A
Krauth-Siegel
R Luise
RL
Piro
Oscar E
OE
Castellano
Eduardo
E
González
Mercedes
M
Gambino
Dinorah
D
Cerecetto
Hugo
H
D000818:Animals; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D009581:Nitrofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010165:Palladium; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism
D005609:Free Radicals; D008024:Ligands; D009581:Nitrofurans; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D010165:Palladium; D004247:DNA; C427203:calf thymus DNA; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D004121:Dimethyl Sulfoxide