No abstract

Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(η(5)-C5H5)(PPh3)L], with HL=bioactive 5-nitrofuryl containing thiosemicarbazones were synthesized and characterized in the solid state and in solution. The compounds were evaluated in vitro on the blood circulating trypomastigote form of Trypanosoma cruzi (Dm28c strain), the infective form of Trypanosoma brucei brucei (strain 427) and on J774 murine macrophages and human-derived EA.hy926 endothelial cells. The compounds were active against both parasites with IC50 values in the micromolar or submicromolar range. Interestingly, they are much more active on T. cruzi than previously developed Ru(II) classical and organometallic compounds with the same bioactive ligands. The new compounds showed moderate to very good selectivity towards the parasites in respect to mammalian cells. The global results point at [RuCp(PPh3)L2] (L2=N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp=cyclopentadienyl) as the most promising compound for further developments (IC50T. cruzi=0.41μM; IC50T. brucei brucei=3.5μM). Moreover, this compound shows excellent selectivity towards T. cruzi (SI>49) and good selectivity towards T. brucei brucei (SI>6). In order to get insight into the mechanism of antiparasitic action, the intracellular free radical production capacity of the new compounds was assessed by ESR. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and to redox cycling processes were characterized. In addition, DNA competitive binding studies with ethidium bromide by fluorescence measurements showed that the compounds interact with this biomolecule.

The synthesis of a series of ionic liquids using 1-butyl 3-methylimidazolium (Bmim+) as a cation and different amino acids (AA) as anions (Bmim[AA]) is described. These ILs were used for the first time as reaction media to achieve more eco-friendly Paraoxon degradation. The results show that the degradation of Paraoxon in these Bmim[AA]s is accomplished with great efficiency and without an extra nucleophilic agent. Therefore, we propose that all the Bmim[AA]s used in this study have a dual role in the outcome of this reaction; as a nucleophile and a solvent to carry out degradation of the organophosphorous pesticide, Paraoxon. Both kinetics and product distribution results found in this study for Paraoxon degradation turned out to be promising, because this process is achieved in a reaction medium with a better environmental profile.

A series of ionic liquids (ILs) composed by choline (Ch) as a cation and different amino acids (AA) as anions and their respective aqueous mixtures were prepared using different [Ch][AA] contents in a range of 0.4–46 mol % IL. These solvents were used for the first time to achieve an eco-friendlier Paraoxon degradation. The results show that [Ch][AA]/water mixtures are an effective reaction medium to degrade Paraoxon, even when the IL content in the mixture is low (0.4 mol % IL) and without the need of an extra nucleophile. Both the kinetics and the degradation pathways of pesticides depend on the nature of the AA on [Ch][AA] and the amount of an IL present in the mixture. We have demonstrated that in those mixtures with a low amount of [Ch][AA], the hydrolysis reaction is the main pathway for Paraoxon degradation, showing a catalytic effect of the IL. However, as the percentage of [Ch][AA] increases in the mixture, the nucleophilic attack of [Ch][AA] is evident. Finally, the aim of this study was to provide evidence of a promising and biocompatible methodology to degrade a toxic compound (Paraoxon) using a minimal quantity of an IL designed totally from natural resources.

Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted 3‐carboxamidocoumarins exerting both antioxidant and trypanocidal activities are described. Among the compounds synthesized, compound 3 (N‐(4‐hydroxyphenyl)coumarin‐3‐carboxamide) showed the most interesting antioxidant profile, presenting 53.2 % superoxide radical scavenging and the highest ORAC‐FL value (ORAC‐FL=1.87) of the series. In the trypanocidal study, compounds 9 (N‐(quinolin‐6‐yl)coumarin‐3‐carboxamide) and 10 (N‐(quinolin‐3‐yl)coumarin‐3‐carboxamide) presented high activity in epimastigote stage and low activity in trypomastigote stage, as well as low cytotoxic effects. Additionally, these compounds decreased mitochondrial transmembrane potential in epimastigote Dm28c. Based on these results, compounds 9 and 10 proved to be good candidates for further studies. Interestingly, the current study revealed that small structural changes in this scaffold allow modulating both activities, suggesting that these molecules present the desirable properties for the development of promising classes of antichagasic compounds.