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Some copper(II) and zinc(II) complexes with oxindolimine ligands were tested regarding their trypanocidal properties. These complexes have already shown good biological activity in the inhibition of tumor cell proliferation, having DNA and mitochondria as main targets, through an oxidative mechanism, and inducing apoptosis. Herein, we demonstrate that they also have significant activity against the infective trypomastigote forms and the intracellular amastigote forms of T. cruzi, modulated by the metal ion as well as by the oxindolimine ligand. Selective indexes (LC50/IC50) determined for both zinc(II) and copper(II) complexes, are higher after 24 or 48 h incubation with trypomastigotes, in comparison to traditional drugs used in clinics, such as benznidazole, and other metal-based compounds previously reported in the literature. Additionally, tests against amastigotes indicated infection index <10% (% of infected macrophages/average number of amastigotes per macrophage), after 24 or 48 h in the presence of zinc(II) (60–80 µM) or analogous copper(II) complexes (10–25 µM). The copper complexes exhibit further oxidative properties, being able to damage DNA, proteins and carbohydrates, in the presence of hydrogen peroxide, with the generation of hydroxyl radicals. This redox reactivity could explain its better performance towards the parasites in relation to the zinc analogs. However, both copper and zinc complexes display good selective indexes, indicating that the influence of the ligand is also crucial, and is probably related to the inhibition of some crucial proteins. [ABSTRACT FROM AUTHOR]

Epiisopiloturine (EPI), extracted from leaves ofPilocarpus microphyllus, a plant originally from the Amazon and Savanna regions in Brazil, was described as a potential drug against Schistosomiasis, a neglected severe disease. Herein, EPI was complexed with copper(II) or zinc(II) salts and the isolated species, [Cu(epi)4](ClO4)2(1) and [Zn(epi)2Cl2] (2), were structurally and spectroscopically characterized. By using X-ray diffraction, the crystal structures of both metal complexes were determined, indicating a square pyramidal geometry for copper for1and a tetrahedral environment around zinc for2. EPR spectra of1show a typical tetragonal environment around the central metal ion with some tetrahedral distortion, both in the solid state and in frozen acetonitrile solution, in accordance with crystallographic data. For2, NMR spectra have bands consistent with a tetrahedral species in solid state or in DMSO-d6solution. These spectroscopic characterization data were further supported by Density Functional Theory calculations, showing that these metal complexes are also stable in solution. Those metal complexes were tested against adult worms ofSchistosoma mansoni, in comparison to the free alkaloid as anthelmintic agent. Coordination with copper(II) improved the alkaloid schistosomicidal properties, while binding to zinc(II) decreased its activity. [ABSTRACT FROM AUTHOR]

Herein, we report results of calculations based on density functional theory (BP86/TZVP) of a set of isatin-Schiff base copper(II) and related complexes, 1-12, that have shown significant pro-apoptotic activity toward diverse tumor cells. The interaction of the copper(II) cation with different ligands has been investigated at the same level of theory. The strength and character of the Cu(II)-L bonding was characterized by metal-ligand bond lengths, vibrational frequencies, binding energies, ligand deformation energies, and natural population analysis. The metal-ligand bonding situation was also characterized by using two complementary topological approaches, the quantum theory of atoms-in-molecules (QTAIM) and the electron localization function (ELF). The calculated electronic g-tensor and hyperfine coupling constants present significant agreement with the EPR experimental data. The calculated parameters pointed to complex 10 as the most stable among the isatin-Schiff base copper(II) species, in good agreement with experimental data that indicate this complex as the most reactive in the series. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012 [ABSTRACT FROM AUTHOR]

Abstract: The reaction of Cu(ClO4)2·6H2O with dimethylglyoxime (H2dmg) in a 1:1 mole ratio in aqueous methanol at room temperature affords the dinuclear complex [Cu2(μ-Hdmg)4] (1). Reaction of 1 with [Cu(bpy)(H2O)2](ClO4)2 (bpy=2,2′-bipyridine) in a 1:1 mole ratio in aqueous methanol at room temperature yields the tetranuclear complex [Cu4(μ-Hdmg)2(μ-dmg)2(bpy)2(H2O)2](ClO4)2 (2). The direct reaction of Cu(ClO4)2·6H2O with H2dmg and bpy in a 2:2:1 mole ratio in aqueous methanol at room temperature also yields 2 quantitatively. The complexes 1 and 2 were structurally characterized by X-ray crystallography. Unlike the binding in Ni/Co-dmg, two different types of N−O bridging modes during the oxime based metallacycle formation and stacking of square planar units have been identified in these complexes. The neutral dinuclear complex 1 has CuN4O coordination spheres and complex 2 consists of a dicationic [Cu4(μ-Hdmg)2(μ-dmg)2(bpy)2(H2O)2]2+ unit and two uncoordinated ClO4 − anions having CuN4O and CuN2O3 coordination spheres. The two copper(II) ions are at a distance of 3.846(8)Å in 1 for the trans out of plane link and at 3.419(10) and 3.684(10)Å in 2 for the trans out of plane and cis in plane arrangements, respectively. The average Cu–Noxime distances are 1.953 and 1.935Å, respectively. The average basal and apical Cu−Ooxime distances are 1.945, 2.295 and 2.429Å. The UV–Vis spectra of 2 is similar to the spectrum of the reaction mixture of 1 and [Cu(bpy)(H2O)2]2+. Variable temperature magnetic properties measurement shows that the interaction between the paramagnetic copper centers in complex 1 is antiferromagnetic in nature. The EPR spectra of frozen solution of the complexes at 77K consist of axially symmetric fine-structure transitions (ΔM S =1) and half-field signals (ΔM S =2) at ca. 1600G, suggesting the presence of appreciable Cu–Cu interactions. [Copyright &y& Elsevier]

Some hydrazones and Schiff bases derived from isatin, an endogenous oxindole formed in the metabolism of tryptophan, were obtained to investigate their effects on in vitro aggregation of β-amyloid peptides (Aβ), macromolecules implicated in Alzheimer's disease. Some hydrazone ligands , prepared by condensation reactions of isatin with hydrazine derivatives, showed a large affinity binding to the synthetic peptides Aβ, particularly to Aβ 1 – 16. Measurements by NMR spectroscopy indicated that those interactions occur mainly at the metal binding site of the peptide, involving His6, His13, and His14 residues, and that hydrazone E -diastereoisomer interacts preferentially with the amyloid peptides. Experimental results were consistent with simulations using a docking approach, where it is demonstrated that the amino acid residues Glu3, His6, His13, and His14 are those that mostly interact with the ligands. Further, these oxindole-derived ligands can efficiently chelate copper(II) and zinc(II) ions, forming moderate stable [ML] 1:1 species. The corresponding formation constants were determined by UV/Vis spectroscopy, by titrations of the ligands with increasing amounts of metal salts, and the obtained log K values were in the range 2.74 to 5.11. Both properties, good affinity for amyloid peptides, and reasonably good capacity of chelating biometal ions, like copper and zinc, can explain the efficient inhibition of Aβ fragments aggregation, as shown by experiments carried out with the oxindole derivatives in the presence of metal ions. Synopsis: Some hydrazones and Schiff bases derived from an endogenous oxindole were obtained, and investigated about their effects on in vitro aggregation of β -amyloid peptides (Aβ), implicated in Alzheimer's disease. [Display omitted] • Schiff base and hydrazine-derivatives of isatin were synthesized. • These ligands form stable copper and zinc complexes characterized spectroscopically. • Strong interactions of a hydrazine-derivative with amyloid peptide were verified. • Interactions occur mainly through histine residues, involving E- diastereoisomer. • Noteworthy peptide aggregation inhibition was shown in the presence of such ligands. [ABSTRACT FROM AUTHOR]

Herein, the design and syntheses of two new mononuclear oxindolimine-copper(II) ( 1 and 2 ) and corresponding heterobinuclear oxindolimine Cu(II) Pt(II) complexes ( 3 and 4 ), are described. All the isolated complexes were characterized by spectroscopic techniques (UV/Vis, IR, EPR), in addition to elemental analysis and mass spectrometry. Cyclic voltammetry (CV) measurements showed that in all cases, one-electron quasi-reversible waves were observed, and ascribed to the formation of corresponding copper(I) complexes. Additionally, waves related to oxindolimine ligand reduction was verified, and confirmed using analogous oxindolimine-Zn(II) complexes. The Pt(IV/II) reduction, and corresponding oxidation, for complexes 3 and 4 occurred at very close values to those observed for cisplatin. By complementary fluorescence studies, it was shown that glutathione (GSH) cannot reduce any of these complexes, under the experimental conditions (room temperature, phosphate buffer 50 mM, pH 7.4), using an excess of 20-fold [GSH]. All these complexes showed characteristic EPR spectral profile, with parameters values g ǁ > g ⊥ suggesting an axially distorted environment around the copper(II) center. Interactions with calf thymus-DNA, monitored by circular dichroism (CD), indicated different effects modulated by the ligands. Finally, the cytotoxicity of each complex was tested toward different tumor cells, in comparison to cisplatin, and low values of IC 50 in the range 0.6 to 4.0 μM were obtained, after 24 or 48 h incubation at 37 °C. The obtained results indicate that such complexes can be promising alternative antitumor agents. [ABSTRACT FROM AUTHOR]

New ternary copper(II) complexes of sulfathiazole (SFT, C 9 H 8 N 3 O 2 S 2 ) or nimesulide (NMS, C 13 H 11 N 2 O 5 S) and 2,2′-bipyridine (bipy) were synthesized, and characterized by chemical and spectroscopic techniques. Elemental analyses indicated a 2:1:1 sulfonamide/copper/bipy composition for both complexes. Mass spectrometric measurements permitted identifying the molecular ions [Cu(SFT) 2 (bipy)+H] + and [Cu(NMS) 2 (bipy)+H] + at m / z 728 and 835, respectively, confirming the proposed compositions. Crystal structure of the [Cu(SFT) 2 (bipy)] complex was solved by powder X-ray diffraction analysis (PXRD), attesting that the Cu(II) ion is hexacoordinated in a distorted octahedral geometry. Each SFT molecule coordinates to the metal ion by the nitrogen atoms of the SO 2 –N group and of the heterocyclic ring. The coordination sphere is completed by a bipyridine. Electronic paramagnetic resonance (EPR) studies were carried out for the [Cu(NMS) 2 (bipy)] complex, indicating a tetragonal environment around the metal ion. It was suggested that NMS coordinates to Cu(II) by the nitrogen and oxygen atoms of the SO 2 –N group, which was confirmed by infrared spectroscopic studies. Biological studies showed the antibacterial activity of both Cu-SFT and Cu-NMS complexes, with the minimum inhibitory concentration (MIC) values ranging from 0.10 to 0.84 mmol L −1 against Gram-negative bacteria for [Cu(SFT) 2 (bipy)], and from 1.50 to 3.00 mmol L −1 against Gram-positive and -negative bacteria for [Cu(NMS) 2 (bipy)]. [ABSTRACT FROM AUTHOR]

This work reports on the synthesis and characterization of new complexes of the type [Cu(O–O)(N–N)X], where O–O = 4,4,4-trifluoro-1-phenyl-1,3-butanedione (HBTA), 1-(4-chlorophenyl)-4,4,4-trifluoro-1,3-butanedione (HBTACl) or 2-thenoyltrifluoroacetone (HTTA); N–N = 2,2-bipyridine (Bipy) or 1,10-phenanthroline (Phen) and X = NO 3 − or ClO 4 − . These complexes were characterized by elemental analyses, conductivity measurements, FT-IR, UV–Vis, EPR, High-resolution Electrospray Ionization Mass Spectrometry (HRESIMS) and TG/DTA. The X-ray structural analysis of two representative compounds indicates that the geometry around the copper ion is distorted square-pyramidal and it is coordinated to β-diketone via the oxygen atoms and to N -donor heterocyclic ligands via its two nitrogen atoms. A perchlorate or nitrate ion weakly bonded occupies the apical position, completing the coordination sphere. The crystal packing is stabilized by non-classical hydrogen bonds and weak interactions π–π stacking. The cytotoxic activity of compounds was investigated in a chronic myelogenous leukemia cell line. The complexes with 1,10-phenanthroline are more active than carboplatin. As example, the compound [Cu(BTACl)(Phen)NO 3 ] inhibits the growth of K562 cells with an IC 50 value equal to 2.1 μM. [ABSTRACT FROM AUTHOR]

This paper reports on the synthesis and characterization of two new ternary copper(II) complexes: [Cu(doxycycline)(1,10-phenanthroline)(H2O)(ClO4)](ClO4) (1) and [Cu(tetracycline)(1,10-phenanthroline)(H2O)(ClO4)](ClO4) (2). These compounds exhibit a distorted tetragonal geometry around copper, which is coordinated to two bidentate ligands, 1,10-phenanthroline and tetracycline or doxycyline, a water molecule, and a perchlorate ion weakly bonded in the axial positions. In both compounds, copper(II) binds to tetracyclines via the oxygen of the hydroxyl group and oxygen of the amide group at ring A and to 1,10-phenanthroline via its two heterocyclic nitrogens. We have evaluated the binding of the new complexes to DNA, their capacity to cleave it, their cytotoxic activity, and uptake in tumoral cells. The complexes bind to DNA preferentially by the major groove, and then cleave its strands by an oxidative mechanism involving the generation of ROS. The cleavage of DNA was inhibited by radical inhibitors and/or trappers such as superoxide dismutase, DMSO, and the copper(I) chelator bathocuproine. The enzyme T4 DNA ligase was not able to relegate the products of DNA cleavage, which indicates that the cleavage does not occur via a hydrolytic mechanism. Both complexes present an expressive plasmid DNA cleavage activity generating single- and double-strand breaks, under mild reaction conditions, and even in the absence of any additional oxidant or reducing agent. In the same experimental conditions, [Cu(phen)2]2+ is approximately 100-fold less active than our complexes. These complexes are among the most potent DNA cleavage agents reported so far. Both complexes inhibit the growth of K562 cells with the IC50 values of 1.93 and 2.59 μmol L-1 for compounds 1 and 2, respectively. The complexes are more active than the free ligands, and their cytotoxic activity correlates with intracellular copper concentration and the number of Cu-DNA adducts formed inside cells. [ABSTRACT FROM AUTHOR]

A series of new metal complexes, [Zn(KTZ) 2 (Ac) 2 ]·H 2 O (1) , [Zn(KTZ) 2 Cl 2 ]·0.4CH 3 OH (2), [Zn(KTZ) 2 (H 2 O)(NO 3)](NO 3) (3), [Cu(KTZ) 2 (Ac) 2 ]·H 2 O (4) , [Cu(KTZ) 2 Cl 2 ]·3.2H 2 O (5), [Cu(KTZ) 2 (H 2 O)(NO 3)](NO 3)·H 2 O (6), were synthesized by a reaction of ketoconazole (KTZ) with their respective zinc or copper salts under mild conditions. Similarly, six corresponding metal-CTZ (clotrimazole) complexes [Zn(CTZ) 2 (Ac) 2 ]·4H 2 O (7) , [Zn(CTZ) 2 Cl 2 ] (8), [Zn(CTZ) 2 (H 2 O)(NO 3)](NO 3)·4H 2 O (9), [Cu(CTZ) 2 (Ac) 2 ]·H 2 O (10) , [Cu(CTZ) 2 Cl 2 ]·2H 2 O (11), [Cu(CTZ) 2 (H 2 O)(NO 3)](NO 3)·2H 2 O (12), were obtained. These metal complexes were characterized by elemental analyses, molar conductivity, 1H and 13C{1H} nuclear magnetic resonance, UV/Vis, and infrared spectroscopies. Further, the crystal structure for complexes 7 and 10 was determined by single-crystal X-ray diffraction. The antifungal activity of these metal complexes was evaluated against three fungal species of medical relevance: Candida albicans , Cryptococcus neoformans, and Sporothrix brasiliensis. Complexes 1 and 3 exhibited the greatest antifungal activity with a broad spectrum of action at low concentrations and high selectivity. Some morphological changes induced by these metal complexes in S. brasiliensis cells included yeast-hyphae conversion, an increase in cell size and cell wall damage. The strategy of coordination of clinic drugs (KTZ and CTZ) to zinc and copper was successful, since the corresponding metal complexes were more effective than the parent drug. Particularly, the promising antifungal activities displayed by Zn-KTZ complexes make them potential candidates for the development of an alternative drug to treat mycoses. A series of new Zn(II)/Cu(II)- azole drug complexes were synthesized, characterized and evaluated against three fungal species of medical relevance: Candida albicans , Cryptococcus neoformans, and Sporothrix brasiliensis. Zn(II)-KTZ (KTZ: Ketoconazole) complexes exhibited the greatest antifungal activity with a broad spectrum of action at low concentrations and high selectivity. [Display omitted] • Ten novel Zn(II)/Cu(II)-azole drug complexes were synthesized. • X-ray structure of two Zn(II)/Cu(II)-CTZ (CTZ: Clotrimazole) complexes were elucidated. • They were evaluated against three fungal species of medical relevance. • Zn(II)-KTZ (KTZ: Ketozonazole) complexes were the most effective antifungal agents. • They displayed high selectivity towards fungi over mammalian cells. [ABSTRACT FROM AUTHOR]