Anti-toxoplasma activity and DNA-binding of copper(II) and zinc(II) coordination compounds with 5-nitroimidazole-based ligands.

Tetrahedral copper(II) and zinc(II) coordination compounds from 5-nitroimidazole derivatives, viz. 1-(2-chloroethyl)-2-methyl-5-nitroimidazole (cenz) and ornidazole 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (onz), were synthesized and spectroscopically characterized. Their molecular structures were determined by X-ray diffraction studies. The complexes [Cu(onz)2X2], [Zn(onz)2X2], [Cu(cenz)2X2] and [Zn(cenz)2X2] (X- = Cl, Br), are stable in solution and exhibit positive LogD7.4 values that are in the range for molecules capable of crossing the cell membrane via passive difussion. Their biological activity against Toxoplasma gondi was investigated, and IC50 and lethal dose (LD50) values were determined. The ornidazole copper(II) compounds showed very good antiparasitic activity in its tachyzoite morphology. The interaction of the coordination compounds with DNA was examined by circular dichroism, fluorescence (using intercalating ethidium bromide and minor groove binding Hoechst 33258) and UV-Vis spectroscopy. The copper(II) compounds interact with the minor groove of the biomolecule, whereas weaker electrostatic interactions take place with the zinc(II) compounds. The spectroscopic data achieved for the two series of complexes (namely with copper(II) and zinc(II) as metal center) agree with the respective DNA-damage features observed by gel electrophoresis.

Electrophilic Modulation of the Superoxide Anion Radical Scavenging Ability of Copper(II) Complexes with 4-Methyl Imidazole.

Three Cu(II) coordination compounds with 4-methyl imidazole were obtained, such as [Cu(C4H6N2)4(NO3)2], [Cu(C4H6N2)4Br2], and [Cu(C4H6N2)4Cl2]. Crystallographic studies confirmed their structural similarity with Cu(II) in the active site of endogenous copper-zinc superoxide dismutase (CuZn-SOD). The superoxide anion radical (O2•-) scavenging activity was evaluated by the non-enzymatic experimental assay and followed the trend [Cu(C4H6N2)4(NO3)2] > [Cu(C4H6N2)4Br2] > [Cu(C4H6N2)4Cl2]. The density functional theory and the hard and soft acids and bases principle showed the importance of the electron-deficient character of Cu(II) in the chemical reactivity of the coordination compounds; Cu(II) is the softest site in the molecule and it is preferred for the nucleophilic and radical attacks of the soft O2•-. A simple rule was obtained: "the electron-deficient character of Cu(II) is the key index for the O2•- scavenging activity and is modulated by the electron-releasing counteranion effect on the coordination compound".

Efficient copper-based DNA cleavers from carboxylate benzimidazole ligands.

Four copper(II) coordination compounds from 2-benzimidazole propionic acid (Hbzpr) and 4-(benzimidazol-2-yl)-3-thiobutanoic acid (Hbztb) were synthesized and fully characterized by elemental analyses, electronic spectroscopy, FT-IR and mass spectrometry. The molecular structure for the four complexes was confirmed by single-crystal X-ray crystallography. The DNA-interacting properties of the two trinuclear and two mononuclear compounds were investigated using different spectroscopic techniques including absorption titration experiments, fluorescence spectroscopy and circular dichroism spectroscopy. Trinuclear [Cu3(bzpr)4(H2O)2](NO3)2·3H2O·CH3OH (2) and [Cu3(bzpr)4Cl2]·3H2O (3) bind to DNA through non-intercalative interactions, while for mononuclear [Cu(bzpr)2(H2O)]·2H2O (1) and [Cu(bztb)2]·2H2O (4), at minor concentrations in relation to the DNA, a groove binding interaction is favored, while at higher concentrations an intercalative mode is preferred. The nuclease properties of all complexes were studied by gel electrophoresis, which showed that they were able to cleave supercoiled plasmid DNA (form I) to the nicked form (form II). Compound 4 is even capable of generating linear form III (resulting from double-strand cleavage). The proposed mechanism of action involves an oxidative pathway (Fenton-type reaction), which produces harmful reactive species, like hydroxyl radicals.

DNA recognition site of anticancer tinidazole copper(II) complexes.

This paper describes the recognition process of tetrahedral [CuII(tnz)2X2] (X = Cl, Br) complexes by a DNA chain, analyzing the specific interaction between the DNA bases and backbone with the metal and the tinidazole (tnz) ligand. We identified the coordination of the copper metal center with one or two phosphates as the first recognition site for the tinidazole copper(II) complexes, while the ligands present partial intercalation into the minor groove. Also, we discuss a novel trigonal copper(I) tnz bromide complex, obtained by reducing the previously reported [Cu(tnz)2Br2]. This complex sheds light on the mechanism of action of tnz metal complexes as one of the most stable DNA-complex adducts depicts a trigonal geometry around the copper ion.

Coordination compounds with heterocyclic ester derivatives. Structural characterization and anti-proliferative activity.

A series of new coordination compounds of cobalt(II), copper(II) and zinc(II) with heterocyclic ester derivatives (ethyl 4-methyl-5-imidazole-carboxylate (emizco), 1-(2-(phenylsulphonyl)ethyl)-4-imidazole carboxylate (semizco)) and methyl 5-(propylthio)-2-benzimidazolecarbamate (albendazole, abz) were synthesized. They were fully characterized by different techniques such as IR, UV-Vis-NIR, elemental analysis, molar conductivity and magnetic susceptibility. Additionally, X-ray crystal structures of semizco and its [Co(semizco)2Cl2]·2CH3CN 10, [Co(smmizco)2Br2]·2CH3CN 11 and [Cu(semizco)2Br2] 15 coordination compounds are analyzed. These compounds present lone pair SO⋯π interactions between the sulfone and the imidazolic ring. These ligands showed three coordination modes: monodentate, through an imidazolic nitrogen atom, or a bidentate chelating mode by a nitrogen and an oxygen atom from the ester group. The different coordination modes and the number of coordinated ligands gave rise to tetrahedral and octahedral compounds, or for [Cu(semizco)(µ-Br)Br]n·0.5H2O 7 a square base pyramidal geometry. A cytotoxic study was carried out with the free ligands and their copper(II) and zinc(II) halide coordination compounds on HeLa (cervix-uterine), MCF-7 (breast), HCT-15 (colon), PC3 (prostate) human carcinoma cell lines and L929 mouse fibroblast (healthy cells). A TUNEL assay (terminal deoxynucleotidyl transferase dUTP nick end labeling) was performed with the most active copper(II) compounds to determine if cell death was by apoptosis.

Synthesis, structure and biological activities of cobalt(II) and zinc(II) coordination compounds with 2-benzimidazole derivatives.

In this work we present the synthesis, structural and spectroscopic characterisation of a series of cobalt(II) and zinc(II) coordination compounds with benzimidazole (bz) and its 2-benzimidazole derivatives: 2-aminobenzimidazole (2ab), albendazole (abz) and tris(2-benzimidazolylmethyl)amine (ntb). The compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Micrococcus luteus, Salmonella typhi, Pseudomonas aeruginosa, Escherichia coli and Proteus vulgaris. Their cytotoxic activity was also evaluated using human cancer lines, HeLa, HCT-15 and SKLU-1. The halide tetrahedral compounds [Co(bz)2Br2] 3, [Zn(2ab)2Cl2].0.5H2O 11, [Co(abz)Cl2(H2O)].3H2O 14, [Co(abz)Br2(H2O)] 15, [Zn(abz)Cl2(H2O)].3H2O 17 and [Zn(abz)Br2(H2O)].H2O 18 displayed similar minimal inhibition concentration (MIC) values against Micrococcus luteus and Escherichia coli, comparable to those of amoxicillin and chloramphenicol. Additionally, 11 showed a wide range of activity towards Gram(+) and Gram(-) microorganisms. The tetradentate ntb and its trigonal bipyramidal cobalt(II) and zinc(II) compounds were active, regardless of the anion present in the complex. Compound [Co(abz)Cl2(H2O)].3H2O 14 showed promising activity in HeLa cells, while [Co(ntb)Br]Br.H2O 21 inhibited Hela and HCT-15 cell lines.

DNA interactions of non-chelating tinidazole-based coordination compounds and their structural, redox and cytotoxic properties.

Novel tinidazole (tnz) coordination compounds of different geometries were synthesised, whose respective solid-state packing appears to be driven by inter- and intramolecular lone pairπ interactions. The copper(ii) compounds exhibit interesting redox properties originating from both the tnz and the metal ions. These complexes interact with DNA through two distinct ways, namely via electrostatic interactions or/and groove binding, and they can mediate the generation of ROS that damage the biomolecule. Cytotoxic studies revealed an interesting activity of the dinuclear compound [Cu(tnz)2(µ-Cl)Cl]27, which is further more efficient towards cancer cells, compared with normal cells.

Novel antihelmintic activity of tinidazole coordination compounds. Relevance of the metal ion and structural properties.

The in vitro and in vivo antihelmintic activity of cobalt(II), copper(II) and zinc(II) coordination compounds of tinidazole (tnz) were investigated in cultivated spotted rose snapper, infested with dactylogyrid monogeneans. The tinidazole coordination compounds [Co(tnz)2Cl2], [Co(tnz)2Br2], [Cu(tnz)2Cl2], [Cu(tnz)2Br2], [Zn(tnz)2Cl2] and [Zn(tnz)2Br2] were synthesized and spectroscopically characterized. Their molecular structures were determined by their single crystal X-ray diffraction. The metal ions presented distorted tetrahedral geometries, with an intramolecular bifurcated lone pair SO⋯π, from the sulfone group with the imidazolic ring, which contributed to the stability of the compounds in solid state and in solution. Adults of dactylogyrids were exposed in vitro to tinidazole and its coordination compounds. The effective median concentrations of copper(II) coordination compounds were lower than those of cobalt(II) and zinc(II), tnz showed no activity. In vivo oral intubation tests were carried out with [Cu(tnz)2Br2], [Zn(tnz)2Br2] and tnz on snappers infected with dactylogyrids, where the copper(II) compound showed better activity. The absorption and distribution assessment for the [Cu(tnz)2Br2], showed that copper concentrations in liver were significantly higher than in blood and gills, indicating bioaccumulation in this organ. In vivo baths of [Cu(tnz)2Br2] at 25mg/L showed an effective (95% at 8h) antihelmintic effect, while [Zn(tnz)2Br2] had low antihelmintic efficacy. This study indicates that [Cu(tnz)2Br2] has an effective antihelmintic activity towards dactylogyrids monogeneans affecting cultivated spotted red snapper.

On the CH...Cu agostic interaction: chiral copper(II) compounds with ephedrine and pseudoephedrine derivatives.

The ephedrine derivative, (H2ceph), yields [Cu(Hceph)2], showing a CH...Cu(II) agostic interaction; while in the analogous compound [Cu(Hcpse)2], with pseudoephedrine (H2cpse), that interaction is absent, despite the fact that these two diasteromers differ only in the orientation of the methyl and phenyl groups: erythro in H2ceph and threo in H2cpse. The X-ray crystal structure of [Cu(Hceph)2], indicates a Cu...HC length of 2.454 A and the theoretical study reveals the formation of a Cu...HC bond since the associated electronic density shows both a bond critical point and a bond ring critical point.

Crystal structure, solid state and solution characterisation of copper(II) coordination compounds of ethyl 5-methyl-4-imidazolecarboxylate (emizco).

The synthesis and characterisation of the following compounds derived from the biological relevant compound ethyl 5-methyl-4-imidazolecarboxylate (emizco) (1): [Cu(emizco)Cl2] (2), [Cu(emizco)2Cl2] (3), [Cu(emizco)2Br2] (4), [Cu(emizco)2(H2O)2](NO3)2 (5) and [Cu(emizco)4](NO3)2 (6), is presented. These compounds were characterised by IR and UV spectroscopic techniques, in addition the crystal structures of compounds 1-5 were determined. For complexes 2-5, emizco is coordinated as a bidentate ligand, through the oxygen atom of the carboxylate moiety and the nitrogen atom of the imidazolic ring. Different geometries are stabilised: compound 2 includes a pentacoordinated square pyramidal metal centre, while 3-5 are derived from octahedral geometry. Halide compounds 3 and 4 show a cis-octahedral arrangement, which is not very common on [CuN2O2X2] systems, while 5 stabilises the trans-octahedral isomer. Compound 6 displays a square planar geometry. Finally, hydrolysis of emizco to its corresponding carboxylic acid (mizco), allowed the preparation of another square planar complex 7, identified as [Cu(mizco)2] 0.5H2O. Solution studies of these compounds indicate that emizco is not substituted from the coordination sphere, remaining as a bidentate ligand. Halides are substituted by water molecules, changing from cis octahedral to the trans-[Cu(emizco)2(H2O)2]2+ isomer.

2,6-Bis(2,6-diethylphenyliminomethyl)pyridine coordination compounds with cobalt(II), nickel(II), copper(II), and zinc(II): synthesis, spectroscopic characterization, X-ray study and in vitro cytotoxicity.

Coordination compounds with cobalt(II), nickel(II), copper(II) and zinc(II) and the ligand 2,6-bis(2,6-diethylphenyliminomethyl)pyridine (L) were synthesized and fully characterized by IR and UV-Vis-NIR spectroscopy, elemental analysis, magnetic susceptibility and X-ray diffraction for two representative cases. These novel compounds were designed to study their activity as anti-proliferative drugs against different human cancer cell lines. The tridentate ligand forms heptacoordinated compounds from nitrate metallic salts, where the nitrate acts in a chelating form to complete the seven coordination positions. In vitro cell growth inhibition was measured for Co(II), Cu(II) and Zn(II) complexes, as well as for the free ligand. Upon coordination, the IC50 value of the transition-metal compounds is improved compared to the free ligand. The copper(II) and zinc(II) compounds are the most promising candidates for further in vitro and in vivo studies. The activity against colon and prostate cell lines merits further research, in views of the limited therapeutic options for such cancer types.

Redox-active and DNA-binding coordination complexes of clotrimazole.

DNA interactions of anticancer mononuclear Cu(2+), Co(2+), Zn(2+), and Ni(2+) complexes with the biologically active ligand clotrimazole (clotri) are reported. To fully characterize DNA binding modes for these complexes of the formulae [M(clotri)2Cl2]·nH2O (1-4), [M(clotri)2Br2]·nH2O (5,6), [M(clotri)3NO3]NO3·nH2O (9), and [M(clotri)3(NO3)2] (10), circular dichroism (CD) and linear dichroism (LD) spectroscopy, UV melting experiments, atomic force microscopy (AFM) and ethidium bromide (EtBr) displacement methods were used. Results indicate mixed electrostatic interactions, possibly through groove binding, that result in accretion and coiling of DNA. Electrochemical studies indicate that the Cu(2+) complex 9 readily reduces to the reactive-oxygen-species-generating Cu(+), which oxidatively damages DNA. There is a subtle correlation between log P values, calculated electrostatic potentials, and cytotoxicity of the complexes. The extent of cell-nucleus DNA-metal adduct formation in the HeLa cervix-uterine carcinoma cell line does not necessarily correlate with cytotoxicity, indicating that the nature of DNA lesions may be crucial to activity.

Supramolecular structures of metronidazole and its copper(II), cobalt(II) and zinc(II) coordination compounds.

In this work we present the synthesis and structural and spectroscopic characterization of Cu(II), Co(II) and Zn(II) coordination compounds with the antibiotic metronidazole ([double bond]emni). Coordination to metal ions is through its imidazolic nitrogen, while the hydroxyethyl and nitro groups act as supramolecular synthons. [Co(emni)(2)Br(2)], and [Zn(emni)(2)X(2)] (X(-)=Cl, Br) stabilize zig-zag chains, and a 2D supramolecular structure is formed by inter-chain contacts through inter-molecular hydrogen-bonding. Pleated sheet or layers are formed by [Co(emni)(2)Cl(2)] and [Cu(emni)(2)Cl(H(2)O)](2)Cl(2), respectively. The dinuclear Cu(II) compound [Cu(emni)mu(O(2)CMe)(2)](2) gives a one-dimensional zig-zag arrangement. The contribution of metal ions in metronidazole coordination compounds is shown in the stabilization of the different aggregate structures.

Cytotoxic copper(II), cobalt(II), zinc(II), and nickel(II) coordination compounds of clotrimazole.

Sixteen novel mononuclear Cu(II), Co(II), Zn(II), and Ni(II) complexes of the biologically active ligand clotrimazole (clotri) of the forms [M(clotri)(2)Cl(2)]·nH(2)O (1-4), [M(clotri)(2)Br(2)]·nH(2)O (5-7), [M(clotri)(3)Br(2)] (8), [M(clotri)(3)NO(3)]NO(3)·nH(2)O (9, 11), [M(clotri)(3)(NO(3))(2)]·nH(2)O (10), and [M(clotri)(3)(OH(2))(2)NO(3)]NO(3)·nH(2)O (12) were synthesized and fully characterized. Dinuclear [Cu(2)(clotri)(4)µ(2)-Cl(4)]·2H(2)O (1a) and [Cu(2)(clotri)(4)µ(2)-Br(2)]·2H(2)O (5b) as well as tetranuclear [Cu(4)(clotri)(4)µ(4)-Br(6)µ(4)-O] (5a) complexes were also isolated. Complexes 1-7, 9, and 11 present a tetrahedral geometry; complex 8 exhibits a pentacoordinated structure; complexes 1a, 10 and 12 an octahedral geometry. X-ray crystal structures of [Cu(clotri)(2)Cl(2)](1), [Cu(clotri)(2)(EtOH)Cl(2)](1·EtOH), [Zn(clotri)(2)Cl(2)] (3), [Zn(clotri)(2)Br(2)] (7), and [Cu(4)(clotri)(4)µ(4)-Br(6)µ(4)-O] (5a) were obtained. Complexes 1-12 were tested for cytotoxic activity against the human carcinoma cell lines HeLa (cervix-uterine), PC3 (prostate), and HCT-15 (colon) displaying IC(50) values <30 µM. Confocal microscopy and nuclear dying (DAPI) for complex 1 showed condensation of cromatin and nuclear membrane fragmentation. Immunocytochemical detection/expression of biomarkers suggests that complexes 1 and 9 induce cell death via apoptosis. TUNEL assay detected DNA fragmentation in HeLa cells, resulting from apoptotic signaling cascades induced by Cu(II) complexes 1 and 9. (1)H NMR studies of the Zn(II) complexes showed that they can bind to nucleotides.

Chemical reactivity of the imidazole: a semblance of pyridine and pyrrole?

It has been suggested that pyridine and pyrrole could be patterns for imidazole reactivity studies due to the amine (-NH-) and aza (-N═) nitrogen atoms. The analyses of the local and global electronic indexes prove and quantify that imidazole has an intermediate analogy between pyrrole and pyridine.

Coordination chemistry of a bis(benzimidazole) disulfide: eleven membered chelate ring in cobalt(II), zinc(II) and cadmium(II) halide compounds; oxidative disulfide cleavage when coordinated to nickel(II).

Herein we report the synthesis, structural and spectroscopic characterization of coordination compounds with bis[2-(1H-benzimidazol-2-yl)phenyl]disulfide [bis-(2phSbz)] (1) and cobalt(II), zinc(II) and cadmium(II) halides (2-7). Their X-ray diffraction analyses showed that the metal ions present similar distorted tetrahedral structures, with the disulfide ligand coordinated through the imidazolic nitrogen atoms, forming a twisted eleven membered chelate ring. Structures of nickel(II) compounds 8 and 9, showed that the disulfide bond in the ligand was cleaved forming six membered chelates. In 8, the two ligands are sulfides, however in 9 one of them was oxidized to a sulfone. In both compounds the nickel(II) has a distorted square planar geometry and the sulfur atoms are in cis positions. The oxidation reaction of bis-(2phSbz) was performed in KMnO4/NaOH, giving the 2-(1H,3H-benzimidazolium-2-yl)-benzene sulfonate (10). The solid state structure of compounds 2-5 and 7-10 was determined by X-ray diffraction analyses.

Cytotoxic activity, X-ray crystal structures and spectroscopic characterization of cobalt(II), copper(II) and zinc(II) coordination compounds with 2-substituted benzimidazoles.

Herein we present the synthesis, structural and spectroscopic characterization of coordination compounds of cobalt(II), copper(II) and zinc(II) with 2-methylbenzimidazole (2mbz), 2-phenylbenzimidazole (2phbz), 2-chlorobenzimidazole (2cbz), 2-benzimidazolecarbamate (2cmbz) and 2-guanidinobenzimidazole (2gbz). Their cytotoxic activity was evaluated using human cancer cell lines, PC3 (prostate), MCF-7 (breast), HCT-15 (colon), HeLa (cervic-uterine), SKLU-1 (lung) and U373 (glioblastoma), showing that the zinc(II) and copper(II) compounds [Zn(2mbz)(2)Cl(2)].0.5H(2)O, [Zn(2cmbz)(2)Cl(2)].EtOH, [Cu(2cmbz)Br(2)].0.7H(2)O and [Cu(2gbz)Br(2)] had significant cytotoxic activity. The isostructural cobalt(II) complexes showed not significant activity. The cytotoxic activity is related to the presence of halides in the coordination sphere of the metal ion. Recuperation experiments with HeLa cells, showed that the cells recuperated after removing the copper(II) compounds and, on the contrary, the cells treated with the zinc(II) compounds did not. These results indicate that the mode of action of the coordination compounds is different.

Cobalt(II) coordination compounds of ethyl 4-methyl-5-imidazolecarboxylate: chemical and biochemical characterization on photosynthesis and seed germination.

In this work we present the synthesis, structural and spectroscopic characterization of Co(2+) coordination compounds with ethyl 4-methyl-5-imidazolecarboxylate (emizco). The effects of emizco, the metal salts CoCl(2).6H(2)O, CoBr(2), Co(NO(3))(2).6H(2)O and their metal coordination compounds [Co(emizco)(2)Cl(2)], [Co(emizco)(2) Br(2)].H(2)O, [Co(emizco)(2) (H(2)O)(2)(NO(2))(2).2H(2)O were evaluated on photosynthesis in spinach chloroplasts. Seed germination and seedling growth of the monocotyledonous species Lolium multiflorum and Triticum aestivum and the dicotyledonous species Trifolium alexandrinum and Physalis ixocarpa were also assayed under the effect of the compounds and salts. The results showed that cobalt(II) salts and their emizco coordination compounds inhibit photosynthetic electron flow and ATP-synthesis, behaving as Hill reaction inhibitors. Coordination compounds are more potent inhibitors than the salts. It was found that the salts target is at the b(6)f level while the complexes targets are at Q(B)(D1)-protein and b(6)f level. The Q(B) inhibition site was confirmed by variable chlorophyll a fluorescence yield. On the other hand, emizco inhibits seed germination, root and shoot development, in both weed and crop species. Cobalt(II) coordination compounds are the most effective photosynthesis inhibitors, but they are less potent than emizco in germination and seedling growth, while the metal salts are the least active of all.

Estreptomicina: propiedades fisicoquímicas y toxicidad vestibular / Streptomycin, physical and chemical characteristics and vestibular toxicity

Propósito: Los antibióticos aminoglucósidos estreptomicina (STP) y kanamicina (KAN) son tóxicos para las células sensoriales del vestíbulo y de la cóclea, respectivamente. Químicamente están constituidos por estreptidina (STD) un derivado del inositol y dos azúcares, la esteptosa (Stosa) y la N-metilglucosamida (nm-GLUN); sin embargo, en la STP, la STD tiene dos sustituyentes guanidino, los que están ausentes en la KAN. Por lo tanto, se propone estudiar si la vestíbulo-toxicidad específica de la STP se debe a los grupos guanidino. Material y Métodos: Se incubaron en vitro, membranas celulares aisladas de los órganos vestibulares, con 3H-espermidina (3H-Spdina), un análogo estructural de la STP. Se midió la capacidad de los siguientes compuestos: STP, STD, KAN, guanidina (GUA) y n-acetilglucosamina (na-GLUN) para desplazarlos específicamente. Resultados: Se encontró que el orden de desplazamiento de la 3HSPdina para esas sustancia era STP=STD KanGUAn-a-GLUN. Conclusiones: Los resultados sugieren fuertemente que la STP debe su especificidad vestibulotóxica, a la presencia de los grupos guanidino en la porción de STD de su molécula, los que interactuarían por sus cargas positivas con estructuras membranales vestibulares relacionadas con la transducción, muy probablemente los cilios sensorios de las células ciliadas vestibulares