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Electrochemical and ESR studies were carried out in this work with the aim of characterizing the reduction mechanisms of 4-substituted and 1,4-disubstituted 7-nitroquinoxalin-2-ones by means of cyclic voltammetry in DMSO as aprotic solvent. Two reduction mechanisms were found for these compounds: the first, for compounds bearing a labile hydrogen by following a self-protonation mechanism (ECE steps), and the second, for compounds without labile hydrogen, based on a purely electrochemical reduction mechanism (typical of nitroheterocycles). The electrochemical results were corroborated using ESR spectroscopy allowing us to propose the hyperfine splitting pattern of the nitro-radical, which was later corroborated by the ESR simulation spectra. All these compounds were assayed as growth inhibitors against Trypanosoma cruzi: first, on the non-proliferative (and infective) form of the parasite (trypomastigote stage), and then, the ones that displayed activity, were assayed on the non-infective form (epimastigote stage). Thus, we found four new compounds highly active against T. cruzi. Finally, molecular modeling studies suggest the inhibition of the trypanothione reductase like one of the possible mechanisms involved in the trypanocidal action., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A new series of heteroaryl nitrones, 1-7, bearing furoxanyl and thiadiazolyl moieties, were evaluated for their free radical-trapping properties. The physicochemical characterization by electron paramagnetic resonance (EPR) demonstrated its capability to trap and stabilize oxygen-, carbon-, sulfur-, and nitrogen-centered free radicals. The 4-furoxanyl nitrone 3 (FxBN), alpha(Z)-(3-methylfuroxan-4-yl)-N-tert-butylnitrone, showed appropriate solubility in aqueous solution and taking into account that this physicochemical property is very important for biological applications, we studied it deeply in terms of its trapping and kinetic behaviors. For this, kinetic studies of the hydroxyl adduct decay gave rate constants k(ST) of 1.22x10(10)dm(3)mol(-1)s(-1) and half-live up to 7200s at physiological pH, without any artifactual signals. The ability of FxBN to directly traps and stabilizes superoxide free radical, with a half-life of 1620s at physiological pH, was also demonstrated. Besides, FxBN-hydroxyl and -superoxide adducts exhibited distinct and characteristic EPR spectral patterns. Finally, we confirmed the ability of FxBN to act as spin trap in a specific biological system, that is, in the free radical production of experimental anti-trypanosomatid drugs using Trypanosoma cruzi microsomes as biological system. Moreover, previous observations of low FxBN toxicity transform it in a good candidate for in vivo spin trapping., (Crown Copyright 2009. Published by Elsevier Ltd. All rights reserved.)

In the search of new therapeutic tools for the treatment of American Trypanosomiasis, the largest parasitic disease burden in the American continent, three series of novel ruthenium complexes of the formula [RuCl(2)(HL)(2)], [RuCl(3)(dmso)(HL)] and [RuCl(PPh(3))(L)(2)] with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands (HL neutral, L monoanionic) were synthesized and characterized. Their in vitro growth inhibition activity against Trypanosoma cruzi and the effect of co-ligands in related physicochemical properties i.e. nitro moiety redox potential, lipophilicity and free radical scavenger capacity were evaluated. Results show that although a loss of activity was observed as a consequence of ruthenium complexation, lipophilicity and free radical scavenger capacity of the obtained complexes could be correlated to their trypanocidal effect.

Eight new platinum(II) complexes with 3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-trypanosomal activity were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC(50) values in the micromolar range against two different strains of Trypanosoma cruzi, causative agent of Chagas disease (American Trypanosomiasis). In addition, most of the newly developed complexes, together with the analogous platinum 5-nitrofuraldehyde containing thiosemicarbazones previously reported, resulted more active than the reference trypanocidal drug nifurtimox on the infective trypomastigote form of the parasite. Their capacity to produce free radicals that could lead to parasite death was evaluated by ESR experiments in the parasite and by respiration measurements. Compounds were tested for their DNA interaction ability. Results showed that some of the compounds could act as dual inhibitors in the parasite, through production of toxic free radicals and interaction with DNA. All the results were compared with those previously reported for the free ligands, the analogous palladium(II) compounds and the previously reported series of platinum(II) compounds.

Cyclic voltammetry (CV) and electron spin resonance (ESR) techniques were used in the investigation of novel palladium complexes with bioactive thiosemicarbazones derived from 5-nitrofurane or 5-nitrofurylacroleine. Sixteen palladium complexes grouped in two series of the formula [PdCl(2)HL] or [PdL(2)] were studied. ESR spectra of the free radicals obtained by electrolytic reduction were characterized and analyzed. The ESR spectra showed two different hyperfine patterns. The stoichiometry of the complexes does not seem to affect significantly the hyperfine constants however we observed great differences between 5-nitrofurane and 5-nitrofurylacroleine derivatives. The scavenger properties of this family of compounds were lower than Trolox.

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.

In order to get insight into the trypanocidal mechanism of action of a series of 5-nitrofuryl containing thiosemicarbazones some studies related to their bioreduction were performed. Electron spin resonance spectra of radicals generated in T. cruzi by compounds' bioreduction were analyzed. Three different patterns of ESR signals were observed for the different assayed compounds. These results were in agreement with the changes in the T. cruzi-oxygen uptake promoted by these compounds. On the other hand, free-radical scavenger properties, measured as oxygen radical absorbance capacity (ORAC), did not seem to correlate with the trypanocidal activity.

This study was undertaken to investigate the free radical-scavenging and antioxidant activities of various structurally related hydroquinones including hydroxynaphthalenones and dihydroxyanthracenones. Electron spin resonance spectroscopy and spin trapping techniques were used to evaluate the ability of hydroquinones to scavenge hydroxyl, diphenylpicrylhydrazyl, and galvinoxyl radicals. In addition, the oxygen radical absorbing capacity assay using fluorescein (ORAC-FL) was used to obtain the relative antioxidant capacity of these radicals. The rate constants of the first H atom abstraction by 2,2-diphenyl-2-picrylhydrazyl (k(2)), were obtained under pseudo-first-order conditions. The free radical-scavenging activities and k(2) values discriminate well between hydroxynaphthalenones and dihydroxyanthracenones, showing that the latter have better antioxidant properties. The aforementioned experimental data agree with quantum-chemical results demonstrating the relevance of intramolecular H bonding to radical-scavenging activities.

Successful trials with 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ) for Alzheimer's disease treatment prompted renewed interest in assessing whether its therapeutic action is related to the coordination of neurotoxic trace metals, such as Cu(II) and Zn(II). We now report conditional stability constants (K(C')) for CQ Cu(II) and Zn(II) complexes measured in a biological buffer containing Ca(II) and Mg(II) ions. UV-vis spectroscopy and polarography evidenced a 1:2 stoichiometry of Cu(II) and Zn(II) CQ complexes; the K(C')s calculated were: Cu(CQ)(2) 1.2x10(10), and Zn(CQ)(2) 7.0x10(8)M(-2); the CQ affinity for Cu(II) is at least an order of magnitude higher than for Zn(II). To test the possible functional relevance of the Cu(II) CQ complexes in the brain, we bioassayed free Cu(II) concentration by the metal-induced inhibition of ATP-gated currents of the P2X(4) receptor, a predominant brain P2X receptor. CQ reduced concentration-dependently the Cu(II) inhibition of the ATP-gated currents. In view that the stability constant of CQ for Zn(II) is similar to that of Abeta-amyloid for Zn(II), and the fact that CQ may form complexes with Cu(II), even in the presence of competing ions, the present results highlight that the formation of Cu(II) CQ complexes in the brain may act by diminishing free Cu(II) concentrations modifying thereby brain excitability, or favoring the degradation of beta-amyloid plaques or huntingtin, rather than through a specific effect of CQ itself.

In the chromophore-quencher complex fac-[Re(Aqphen)(CO)(3)(py-PTZ)](+) (Aqphen is 12,17-dihydronaphtho[2,3-h]dipyrido[3,2-a:2',3'-c]-phenazine-12,17-dione; py-PTZ is 10-(4-picolyl)phenothiazine), Aqphen is a dppz derivative, containing a pendant quinone acceptor at the terminus of a rigid ligand framework. This introduces a third, low-lying, ligand-based pi acceptor level localized largely on the quinone fragment. Laser flash excitation of fac-[Re(Aqphen)(CO)(3)(py-PTZ)](+) (354.7 nm; in 1,2-dichloroethane) results in the appearance of a relatively long-lived transient that decays with tau(298K) = 300 ns (k = 3.3 x 10(6) s(-)(1)). Application of transient absorption, time-resolved resonance Raman, and time-resolved infrared spectroscopies proves that this transient is the redox-separated state fac-[Re(I)(Aqphen(*)(-)())(CO)(3)(py-PTZ(*)(+)())](+) in which the excited electron is localized largely on the quinone portion of the Aqphen ligand.