Effect of the Metal Ion on the anti T. cruzi Activity and Mechanism of Action of 5‐Nitrofuryl‐Containing Thiosemicarbazone Metal Complexes

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a major health problem worldwide. In this work, we report the development of palladium and platinum metal complexes with 5‐nitrofuryl‐containing thiosemicarbazones (L) as bioactive ligands against T. cruzi and PTA (1,3,5‐triaza‐7‐phosphaadamantane) as co‐ligand. Eight new complexes of the formula [MCl(L)(PTA)] with M = Pd or Pt were synthesized and fully characterized. Most complexes showed similar activities against T. cruzi to those of the corresponding free thiosemicarbazone ligands. No significant differences between palladium and platinum complexes were observed. Metal compounds with the phenylthiosemicarbazone derivative were the most active ones (IC50 = 9.84 ± 0.32 and 4.94 ± 0.24 μM for Pd2+ and Pt2+, respectively). The prepared complexes were not toxic on mammalian cells, showing selective indexes of more than 10–20. The ability of the complexes to be reduced in the parasite, which leads to toxic free radical species, was confirmed by the detection of OH· and nitroanion free radical species by ESR spectroscopy experiments. Gel electrophoresis and fluorescence experiments were consistent with an intercalating‐like mode of DNA interaction for the complexes, but DNA interaction does not seem to be the main mechanism of anti T. cruzi action for these compounds. The results obtained show that complexation of the bioactive ligands with the selected metals is a valid strategy to obtain improved metal‐based antiparasitic compounds.

Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites

“…This mechanism of action seems to be retained by other previously reported metal complexes of these bioactive ligands [21][22][23]27,29,31,33]. As previously stated, the first step of this mechanism involves the one electron reduction of the nitro moiety.…”

“…Among the selected bioactive ligands a family of thiosemicarbazones containing the 5-nitrofuryl pharmacophore has been extensively studied by us [13]. We have rationally designed and developed more than sixty compounds of these ligands including palladium, platinum and ruthenium classical complexes as well as ruthenium η 6 -arene organometallic compounds and the effect of metal complexation and the presence of different co-ligands on the pharmacological profile of these bioactive ligands was evaluated [21][22][23][24][25][26][27][28][29][30][31][32][33].…”

“…ESR spectra were recorded in the X band (9.85 GHz) using a Bruker ECS 106 spectrometer with a rectangular cavity and 50-kHz field modulation. All the spectra were registered in the same scale, after 15 scans[29,49]. The ESR spectra were simulated using the program WINEPR Simfonia 1.25 version.2.6.2.…”

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

“…Thiosemicarbazones (TSCs) are sulfur-containing organic substances whose biological properties have been extensively studied [1][2][3][4][5][6][7][8], in particular their activities against microbial diseases as malaria, small-pot, influenza, leishmaniasis or chagas [9][10][11][12][13][14], neurological pathologies [15,16] and cancer [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. Different biological targets have been identified, like DNA [37][38][39], RNA [40] and several enzymes as RNA-dependent DNA polymerases [41], xanthine oxidoreductase [42], thioredoxin reductase [43,44], topoisomerase IIa [45][46][47] or s...…”

Investigação da reatividade de complexos metálicos com ligantes bases de Schiff frente a infecções parasitárias

“…Este estudo demonstrou que complexos com os mesmos ligantes, mas diferentes centros metálicos, demonstraram diferentes valores de toxicidade e os compostos de cobre(II) são significativamente mais tóxicos que os análogos de zinco(II). Na literatura é possível encontrar estudos que mostram que as propriedades biológicas de diversos ligantes estão vinculadas ao íon metálico coordenado 112,113.…”