Water-Soluble Ruthenium Complexes Bearing Activity Against Protozoan Parasites

Abstract

Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl2(HL)(HPTA)2]Cl2 with HL=bioactive 5-nitrofuryl containing thiosemicarbazones and PTA=1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl2(HL4)(HPTA)2]Cl2 complex, with HL4=N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC50)=5.2 μM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI)>38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites.

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

“…31 P NMR spectra of the complexes showed a single sharp signal for the phosphane coligand at ~52 ppm, showing a deshielding of ~13 ppm originated by the coordination of the N,S ligands, thus corroborating the existence of a significant electronic flow from the Ru center to the bidentate ligand.…”

“…All the obtained complexes were more lipophilic than the corresponding thiosemicarbazone ligands ( complexes (PTA  1,3,5-triaza-7-phosphaadamantane) [30,31]. Table 3 No correlation between lipophilicity and antiparasitic activity could be observed.…”

“…17 thiosemicarbazone ligands and their metal complexes [21][22][23]31,32,64] a quasireversible wave (couple II) at -1.1 V vs. Ag/Ag+, could be assigned to a process involving a one-electron transfer, which leads to the generation of the anion radical RNO 2 . -by reduction of the nitro moiety.…”

“…Therefore, it is a relevant physicochemical property of prospective drugs that could be correlated with the observed biological developed Ru(II) compounds with these ligands [30,31].…”

“…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].…”