5-Nitroimidazole-derived Schiff bases and their copper(II) complexes exhibit potent antimicrobial activity against pathogenic anaerobic bacteria.

In the present work a family of novel secnidazole-derived Schiff base compounds and their copper(II) complexes were synthesized. The antimicrobial activities of the compounds were evaluated against clinically important anaerobic bacterial strains. The compounds exhibited in vitro antibacterial activity against Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides ovatus, Parabacteroides distasonis and Fusubacterium nucleatum pathogenic anaerobic bacteria. Upon coordination to copper(II) the antibacterial activity significantly increased in several cases. Some derivatives were even more active than the antimicrobial drugs secnidazole and metronidazole. Therefore, the compounds under study are suitable for in vivo evaluation and the microorganisms should be classified as susceptible to them. Electrochemical studies on the reduction of the nitro group revealed that the compounds show comparable reduction potentials, which are in the same range of the bio-reducible drugs secnidazole and benznidazole. The nitro group reduction potential is more favorable for the copper(II) complexes than for the starting ligands. Hence, the antimicrobial activities of the compounds under study might in part be related to intracellular bio-reduction activation. Considering the increasing resistance rates of anaerobic bacteria against a wide range of antimicrobial drugs, the present work constitutes an important contribution to the development of new antibacterial drug candidates.

Synthesis, crystal structure and magnetic properties of a novel heterobimetallic rhenium(IV)-dysprosium(III) chain.

The use of the mononuclear rhenium(IV) precursor [ReBr5 (H2 pydc)](-) (H2 pydc=3,5-pyridinedicarboxylic acid) as a metalloligand towards dysprosium(III) afforded the first heterobimetallic Re(IV) -Dy(III) complex. Crystal structures and static and dynamic magnetic properties of both rhenium-containing species are reported herein. The 5d-4f compound shows an extended 1D structure and the AC magnetic measurements reveal frequency dependence at low temperature suggesting slow relaxation of the magnetization.

Synthesis, crystal structures and magnetic behaviour of four coordination compounds constructed with a phosphinic amide-TEMPO radical and [M(hfac)2] (M = Cu(II), Co(II) and Mn(II)).

In the present work we describe the synthesis, crystal structures and magnetic properties of four coordination compounds obtained by assembling a new phosphinic amide containing the TEMPO moiety, 1-piperidinyloxy-4-[(diphenylphosphinyl)amino]-2,2,6,6-tetramethyl radical (dppnTEMPO), with [M(hfac)2] building blocks (M = Cu(II), Co(II), Mn(II)). The crystal structures of the coordination compounds revealed the usefulness of the functionalized radical to provide discrete or extended architectures. In the copper compound () the ligand is coordinated through the oxygen atom of the NP[double bond, length as m-dash]O linkage to the metal, which exists in a square pyramidal or octahedral geometry. For the cobalt and manganese complexes (), both the phosphinic amide and the nitroxide oxygen atoms are involved in the coordination to the metal leading to one dimensional systems. In the cobalt complex () an interesting spin topology in the zig-zag chain was obtained due to the oxygen atom of the phosphinic amide group being µ2 coordinated to two cobalt(ii) ions. The magnetic behaviour of the coordination compounds shows overall antiferromagnetic interactions involving the metal ion and the organic radical. DFT calculations were performed in order to assign the main path for the magnetic interactions.

New families of hetero-tri-spin 2p-3d-4f complexes: synthesis, crystal structures, and magnetic properties.

In this work we report the synthesis, crystal structures, and magnetic behavior of 2p-3d-4f heterospin systems containing the nitroxide radical 4-azido-2,2,6,6-tetramethylpiperidine-1-oxyl radical (N3tempo). These compounds were synthesized through a one-pot reaction by using [Cu(hfac)2], [Ln(hfac)3] (hfac = hexafluoroacetylacetonate, Ln = Dy(III), Tb(III) or Gd(III)), and the N3tempo radical. Depending on the stoichiometric ratio used, the synthesis leads to penta- or trimetallic compounds, with molecular formulas [Cu3Ln2(hfac)8(OH)4(N3tempo)] (Ln = Gd, Tb, Dy) and [CuLn2(hfac)8(N3tempo)2(H2O)2] (Ln = Gd, Dy). The magnetic properties of all compounds were investigated by direct current (dc) and alternating current (ac) measurements. The ac magnetic susceptibility measurements of Tb(III)- and Dy(III)-containing compounds of both families revealed slow relaxation of the magnetization, with magnetic quantum tunneling in zero field.

Synthesis, crystal structure and luminescence properties of the Ln(III)-picrate complexes with 1-ethyl-3-methylimidazolium as countercations.

New anionic complexes of lanthanide picrates containing 1-ethyl-3-methylimidazolium (EMIm) as countercation have been prepared. The Ln(III) complexes were characterized by complexometric titration, elemental analyses, infrared spectroscopy and molar conductivity. The molecular structures of the (EMIm)2[Ln(Pic)4(H2O)2]Pic complexes, Ln(III)=Sm, Eu, Gd and Tb, and Pic=picrate, were determined by X-ray crystallography. In these structures the picrate anion appears in three forms: as uncoordinated counteranion, as monodentated and bidentate ligand. The coordination polyhedron around the Ln(III) atom can be described as tricapped trigonal prismatic molecular geometry. The theoretical molecular structures of the complexes were also calculated using the Sparkle/PM3 model for Ln(III) complexes, allowing analysis of intramolecular energy transfer processes of the Eu(III) compound. The spectroscopic properties of the 4f(6) intraconfigurational transitions of the Eu(III) complex were then studied experimentally and theoretically. The low value of emission quantum efficiency of (5)D0 emitting level (η) of Eu(III) ion (ca. 10%) is due to the vibrational modes of the water molecule that act as luminescence quenching. In addition, the luminescence decay curves, the experimental intensity parameters (Ωλ), lifetimes (τ), radiative (Arad) and non-radiative (Anrad) decay rates, theoretical quantum yield (q) were also determined and discussed.

New synthetic route toward heterometallic 3d-3d' and 3d-4f single-molecule magnets. The first Co(II)-Mn(III) heterometallic complex.

Four tetranuclear heterometallic complexes, [Co(II)2Mn2(III)(dpm)4(MeO)6] (1) and [Ln(III)2Mn(III)2(dpm)6(MeO)6(MeOH)n], where Ln = Gd (2, n = 2), Tb (3, n = 2), and Dy (4, n = 0), have been obtained following the same general synthetic route, namely, the one-pot reaction between 2,2,6,6-tetrametil-3,5-heptanodione (Hdpm), MnCl2 and CoCl2 or Ln(NO3)3 in the presence of sodium methoxide. Within the four compounds, the metal ions bridged by methoxide ligands display a defect-diheterocubane core. Compounds 1, 3, and 4 show slow relaxation of the magnetization below 4 K.

Synthesis, cytotoxicity and antiplasmodial activity of novel ent-kaurane derivatives.

This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of (1)H, (13)C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs.

Improved antileishmanial activity of Dppz through complexation with antimony(III) and bismuth(III): investigation of the role of the metal.

Two novel trivalent antimony(III) and bismuth(III) complexes with the nitrogen-donor heterocyclic ligand dipyrido[3,2-a:2',3'-c]phenazine (dppz) were synthesized and characterized as [Sb(dppz)Cl3]∙H2O∙CH3OH and [Bi(dppz)Cl3]. The crystal structure of Sb(III) complex was determined by X-ray crystallography. These complexes were evaluated for their activity against the promastigote form of Sb(III)-sensitive and -resistant Leishmania infantum chagasi and Leishmania amazonensis strains. Both complexes were more effective than dppz alone in inhibiting the growth of Leishmania promastigotes and were at least 77 and 2,400 times more active than potassium antimonyl tartrate in Sb(III)-sensitive and -resistant Leishmania, respectively. The cytotoxicity of dppz and its complexes against mouse peritoneal macrophages occurred at dppz concentrations at least 6-fold greater than those found to be active against Leishmania promastigotes.To investigate the role of the metal in the improved antileishmanial activity of dppz, the activity of the Sb(III) complex was compared between the Sb-resistant mutants and their respective parental sensitive strains. The lack of cross-resistance to the Sb(III)-dppz complex together with the much lower activity of antimonyl tartrate, SbCl3 and BiCl3 strongly support the model that the metal is not active by itself but improves the activity of dppz through complexation.

Gold(I) complexes with thiosemicarbazones: cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity.

Complexes [Au(H2Ac4DH)Cl]∙MeOH (1) [Au(H(2)2Ac4Me)Cl]Cl (2) [Au(H(2)2Ac4Ph)Cl]Cl∙2H(2)O (3) and [Au(H(2)2Bz4Ph)Cl]Cl (4) were obtained with 2-acetylpyridine thiosemicarbazone (H2Ac4DH), its N(4)-methyl (H2Ac4Me) and N(4)-phenyl (H2Ac4Ph) derivatives, as well as with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone (H2Bz4Ph). The compounds were cytotoxic to Jurkat (immortalized line of T lymphocyte), HL-60 (acute myeloid leukemia), MCF-7 (human breast adenocarcinoma) and HCT-116 (colorectal carcinoma) tumor cell lines. Jurkat and HL-60 cells were more sensitive than MCF-7 and HCT-116 cells. Upon coordinating to the gold(I) metal centers in complexes (2) and (4), the cytotoxic activity of the H2Ac4Me and H2Bz4Ph ligands increased against the HL-60 and Jurkat tumor cell lines. 2 was more active than auranofin against both leukemia cells. Most of the studied compounds were less toxic than auranofin to peripheral blood mononuclear cells (PBMC). All compounds induced DNA fragmentation in HL-60 and Jurkat cells indicating their pro-apoptotic potential. Complex (2) strongly inhibited the activity of thioredoxin reductase (TrxR), which suggests inhibition of TrxR to be part of its mechanism of action.

Pyridine-derived thiosemicarbazones and their tin(IV) complexes with antifungal activity against Candida spp.

[(n-Bu)Sn(2Ac4oClPh)Cl2] (1), [(n-Bu)Sn(2Ac4oFPh)Cl2] (2), [(n-Bu)Sn(2Ac4oNO2Ph)Cl2] (3), [(n-Bu)Sn(2Bz4oClPh)Cl2] (4), [(n-Bu)Sn(2Bz4oFPh)Cl2] (5) and [(n-Bu)Sn(2Bz4oNO2Ph)Cl2] (6) were obtained by reacting [(n-Bu)SnCl3] with 2-acetylpyridine-N4-orthochlorophenyl thiosemicarbazone (H2Ac4oClPh), 2-acetylpyridine-N4-orthofluorphenyl thiosemicarbazone (H2Ac4oFPh), 2-acetylpyridine-N4-orthonitrophenyl thiosemicarbazone (H2Ac4oNO2Ph), and with the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2ABz4oFPh and H2Bz4oNO2Ph). The antifungal activity of the studied compounds was evaluated against several Candida species. Upon coordination of H2Bz4oNO2Ph to tin in complex (6) the antifungal activity increased three times against Candida albicans and Candida krusei and six times against Candida glabrata and Candida parapsilosis. The minimum inhibitory concentration (MIC) values of H2Ac4oNO2Ph and its complex (3) against C. albicans, C. parapsilosis and C. glabrata are similar to that of fluconazole. All studied compounds were more active than fluconazole against C. krusei.

2-Acetylpyridine thiosemicarbazones: cytotoxic activity in nanomolar doses against malignant gliomas.

2-acetylpyridine N(4)-phenyl thiosemicarbazone (H2Ac4Ph), and its N(4)-ortho-tolyl (H2Ac4oT), N(4)-meta-tolyl (H2Ac4mT), N(4)-para-tolyl (H2Ac4pT), N(4)-ortho-chlorophenyl (H2Ac4oClPh), N(4)-meta-chlorophenyl (H2Ac4mClPh) and N(4)-para-chlorophenyl (H2Ac4pClPh) derivatives were assayed for their cytotoxicity against RT2 (expressing p53 protein) and against T98 (expressing mutant p53 protein) glioma cells. The compounds were highly cytotoxic against RT2 (IC50=24-1.4 nM) and T98 cells (IC50=50-1.0 nM). IC50 for cisplatin=5 (RT2) and 17 µM (T98). The thiosemicarbazones presented haemolytic activity with IC50>10(-3)M, indicating a very good therapeutic index. SAR studies suggested that stereo properties are critical to define the potential activity of the studied compounds against the RT2 cell line, while electronic properties seem to be important for interaction with the biological target in T98 cells.

Role of the substituent effect over the squarate oxocarbonic ring: spectroscopy, crystal structure, and density functional theory calculations of 1,2-dianilinosquairane.

This work presents the crystal structure and the investigation under a supramolecular perspective of a squaric acid derivative obtained from the replacement of the hydroxyl groups by anilines. The squaraine obtained (1,2-dianilinesquaraine) crystallizes in the Pbcn space group, in a unit cell with a = 26.5911(8) Å, b = 6.1445(10) Å, and c = 7.5515(5) Å. The bond lengths in the oxocarbon ring, squarate-N and C−O bonds present the character of double bonds. Also the difference between the longer and shorter C-C bond in the four-membered ring (ΔCC) is 0.0667 Å, showing a good degree of equalization of these bond lengths. The phenyl rings are slightly distorted in relation to the squarate ring, and the angle measured between the best plane fitted in each ring is 37.2(9)°. Each molecule is connected to the other through a hydrogen bond involving the N-H···O moieties, where the donor···acceptor distance is 2.826(1) Å, forming ribbons in a unidimensional arrangement C(5)R22(10) along the b axis. These structures are mutually connected by π-stacking interactions extending the supramolecular structure in a two-dimensional fashion. Besides, an interesting crossed structure can be easily identified in the formed sheets that are built through the C-H/π interactions. DFT calculations at the B3LYP/6-311++G(d,p) level of theory show an approximately planar molecular structure for the isolated molecule. However, when a dimer model built from hydrogen bonds is considered, the optimized structure presents considerable torsion between the phenyl and squarate rings, as observed in the experimental data. The electronic spectrum shows a strong absorption band at 341 nm that is red-shifted compared to the squarate maximum absorption (290 nm), indicating a more effective electronic delocalization. The most characteristic vibrational modes of the oxocarbon species were used as spectroscopic probe to understand how the substituent groups affect the oxocarbon moiety and, consequently, the vibrational spectra. The analysis shows that the modes associated with the C-Cox bonds are the most affected. Also the character of the double bond of squarate-N and the single bond for the phenyl-N are easily identified. In a general form, the calculated vibrational modes of the dimer model were in better accordance with the experimental data, mainly when the mode has a contribution from the acceptor molecule in the intermolecular interaction.

Preparation and characterization of solid dispersion of simvastatin.

CONTEXT: Simvastatin (SIM), a widely used drug for the treatment of hypercholesterolemia, is a crystalline substance and practically insoluble in water. Its low dissolution rate leads to a poor absorption, distribution, and target organ delivery because the bioavailability of drugs with low aqueous solubility is limited by their dissolution rates. OBJECTIVE: The aim of this study was to prepare solid dispersions (SD) of SIM with inert carriers in an attempt to improve the release profile. METHODS: In this work, SIM SD with polyethylene glycol (PEG 6000) or polyvinylpyrrolidone (PVP K15) in 1:1, 1:2, 1: 3, 1:4, and 1:5 ratios were prepared and their stability and dissolution properties were investigated. SD were characterized by differential scanning calorimetry and X-ray powder diffraction. Tablets containing SD SIM : PEG 6000 were developed and their dissolution profile evaluated. RESULTS: Drug release from all SD was significantly improved when compared to their corresponding physical mixture or SIM alone. SD SIM:PVP showed drug degradation. The tablets gradually released SIM with a final quantity greater than 80% in 60 minutes. CONCLUSIONS: The preparation of SIM SD with PEG or PVP is a promising strategy to improve the bioavailability of the drug. SIM SD with PEG are more advantageous over the dispersions prepared with PVP because they do not show drug degradation during preparation.

Synthesis, characterization and biocidal activity of new organotin complexes of 2-(3-oxocyclohex-1-enyl)benzoic acid.

The reaction of 1,3-cyclohexadione with 2-aminobenzoic acid has produced the 2-(3-oxocyclohex-1-enyl)benzoic acid (HOBz). Subsequent reactions of the ligand with organotin chlorides led to [Me(2)Sn(OBz)O](2) (1), [Bu(2)Sn(OBz)O](2) (2), [Ph(2)Sn(OBz)O](2) (3), [Me(3)Sn(OBz)] (4), [Bu(3)Sn(OBz)] (5) and [Ph(3)Sn(OBz)] (6). All complexes have been fully characterized. In addition the structure of complexes (2) and (4) have been authenticated by X-ray crystallography. The biological activity of all derivatives has been screened against Cryptococcus neoformans and Candida albicans. In addition we have performed toxicological testes employing human kidney cell. The complexes (3), (5) and (6) displayed the best values of inhibition of the fungus growing, superior to ketoconazole. Compound (5) presented promising results in view of the antifungal and cytotoxicity assays.

2-Benzoylpyridine-N(4)-tolyl thiosemicarbazones and their palladium(II) complexes: cytotoxicity against leukemia cells.

The palladium(II) complexes [Pd(2Bz4oT)Cl], [Pd(2Bz4mT)Cl], and [Pd(2Bz4pT)Cl] were prepared with N(4)-ortho- (H2Bz4oT) N(4)-meta- (H2Bz4mT) and N(4)-para- (H2Bz4pT) tolyl-thiosemicarbazones derived from 2-benzoylpyridine. The free thiosemicarbazones proved to be highly cytotoxic against Jurkat, HL60 and the resistant HL60.Bcl-X(L) leukemia cell lines at nanomolar concentrations, but were much less cytotoxic to HepG2human hepatoma cells. Upon coordination to palladium(II) the cytotoxic activity against all studied cell lines decreases. However, the high cytotoxicity of the free thiosemicarbazones against leukemia, together with their hepatotoxic profile similar to that of cisplatin suggest that N(4)-tolyl thiosemicarbazones have potential as chemotherapeutic drug candidates.

Redetermination of tetra-kis(N,N-diethyl-dithio-carbamato)tin(IV).

The crystal structure of the title compound, [Sn(C(5)H(10)NS(2))(4)], was originally determined by Harreld & Schlemper [Acta Cryst. (1971), B27, 1964-1969] using intensity data estimated from Weissenberg films. In comparison with the previous refinement, the current redetermination reveals anisotropic displacement parameters for all non-H atoms, localization of the H atoms, and higher precision of lattice parameters and inter-atomic distances. The complex features a distorted S(6) octa-hedral coordination geometry for tin and a cis disposition of the monodentate dithio-carbamate ligands.

4-nitroacetophenone-derived thiosemicarbazones and their copper(II) complexes with significant in vitro anti-trypanosomal activity.

N(4)-methyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4M, 1), N(4),N(4)-dimethyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4DM, 2) and N(4)-piperidyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4Pip, 3) and their copper(II) complexes [Cu(4NO(2)Ac4M)(2)] (4), [Cu(4NO(2)Ac4DM)(2)] (5) and [Cu(4NO(2)Ac4Pip)(2)] (6) were tested for their in vitro ability to inhibit the growth of Trypanosoma cruzi epimastigote forms. H4NO(2)Ac4DM (2), [Cu(4NO(2)Ac4M)(2)] (4) and [Cu(4NO(2)Ac4DM)(2)] (5) proved to be as active as the clinical reference drugs nifurtimox and benznidazol. Taking into consideration the serious side effects and the poor efficacy of the reference drugs, as well as the appearance of resistance during treatment, the studied compounds could constitute a new class of anti-trypanosomal drug candidates.