Isabel García-Santos

Synthesis, crystal structures and spectroscopy of meclofenamic acid and its metal complexes with manganese(II), copper(II), zinc(II) and cadmium(II). Antiproliferative and superoxide dismutase activity.

Some new complexes of meclofenamic acid (N-(2,6-dichloro-m-tolyl)anthranilic acid), Hmeclo (1), with potentially interesting biological activities are described. Complexes [Mn(meclo)(2)] (2), [Cu(meclo)(2)(H(2)O)(2)] (3), [Zn(meclo)(2)(H(2)O)(2)] (4) and [Cd(meclo)(2)(H(2)O)(2)] (5) were prepared and structurally characterized by means of vibrational, electronic and (1)H and (13)C NMR spectroscopies. The crystal structure of complexes [Cu(4)(meclo)(6)(OH)(2)(DMSO)(2)]2DMSO (3a) and [Cd(meclo)(2)(DMSO)(3)] (5a) have been determined by X-ray crystallography. Complex (3a) is a centrosymmetric tetramer built up around the planar cyclic Cu(2)(OH)(2) unit. Complex 5a is mononuclear seven-coordinated complex with the meclofenamato ligand behaving as a bidentate deprotonated chelating ligand. Intra and intermolecular hydrogen bonds stabilize these two structures, while the crystal packing is determined by π-π and C-H--π interactions. Meclofenamic acid and its metal complexes have been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines, MCF-7 (breast cancer cell line), T24 (bladder cancer cell line), and A-549 (non-small cell lung carcinoma), and a mouse fibroblast L-929 cell line. Complex 5 exhibits the highest selectivity against MCF-7 and 4 shows the highest selectivity against T-24. Complexes 2-5 were found to be more potent cytotoxic agents against T-24 and complex 5 against MCF-7 cancer cell lines than the prevalent benchmark metallodrug, cis-platin. The superoxide dismutase activity was measured by the Fridovich test which showed that complex [Cu(meclo)(2)(H(2)O)(2)] is a good superoxide scavenger.

Zinc(II) complexes of 2-acetyl pyridine 1-(4-fluorophenyl)-piperazinyl thiosemicarbazone: Synthesis, spectroscopic study and crystal structures – Potential anticancer drugs

2-Acetyl pyridine thiosemicarbazone containing an 1-(4-fluorophenyl)-piperazinyl ring incorporated at N(4)-position, HAcPipPheF (1) and the zinc(II) complexes [Zn(AcPipPheF)(2)] (2) and [Zn(OAc)(AcPipPheF)](2) (3) have been prepared and structurally characterized by means of vibrational and NMR ((1)H and (13)C) spectroscopy. The crystal structures of the compounds 1-3 have been determined by X-ray crystallography. The metal coordination geometry of [Zn(AcPipPheF)(2)] is described as distorted octahedral configuration in a trans-N-cis-N-cis-S configuration. In [Zn(OAc)(AcPipPheF)](2) one of the acetato group exhibits monoatomic bridge and the other bridges in a bidentate manner. The zinc(1) metal ion is coordinated in a distorted octahedral configuration while the metal coordination of Zn(2) is described as distorted square pyramidal. Biomedical studies revealed that, compounds 1-3 displayed potent anticancer activity. The antiproliferative activity of 1-3 was found to be considerably stronger than that of cis-platin. The IC(50) values range from 26 to 90nM, against all cell lines tested, while for cis-platin the IC(50) values range from 2 to 17microM and for the zinc salt, ZnCl(2), the IC(50) values range from 81 to 93microM. The complex 3 shows the highest activity against all four cancer cell lines and the highest selectivity against K562 and MDA-MB-453 cancer cell lines. The compounds inhibited tumor cell proliferation by arresting the cell cycle progression at the S phase.

Quasi-aromatic Möbius Metal Chelates

We report the design as well as structural and spectroscopic characterizations of two new coordination compounds obtained from Cd(NO3)2·4H2O and polydentate ligands, benzilbis(pyridin-2-yl)methylidenehydrazone (LI) and benzilbis(acetylpyridin-2-yl)methylidenehydrazone (LII), in a mixture with two equivalents of NH4NCS in MeOH, namely [Cd(SCN)(NCS)(LI)(MeOH)] (1) and [Cd(NCS)2(LII)(MeOH)] (2). Both LI and LII are bound via two pyridyl-imine units yielding a tetradentate coordination mode giving rise to the 12 π electron chelate ring. It has been determined for the first time (qualitatively and quantitatively), using the EDDB electron population-based method, the HOMA index, and the ETS-NOCV charge and energy decomposition scheme, that the chelate ring containing CdII can be classified as a quasi-aromatic Möbius motif. Notably, using the methyl-containing ligand LII controls the exclusive presence of the NCS- connected with the CdII atom (structure 2), while applying LI allows us to simultaneously coordinate NCS- and SCN- ligands (structure 1). Both systems are stabilized mostly by hydrogen bonding, C-H···π interactions, aromatic π···π stacking, and dihydrogen C-H···H-C bonds. The optical properties have been investigated by diffused reflectance spectroscopy as well as molecular and periodic DFT/TD-DFT calculations. The DFT-based ETS-NOCV analysis as well as periodic calculations led us to conclude that the monomers which constitute the obtained chelates are extremely strongly bonded to each other, and the calculated interaction energies are found to be in the regime of strong covalent connections. Intramolecular van der Waals dispersion forces, due to the large size of LI and LII, appeared to significantly stabilize these systems as well as amplify the aromaticity phenomenon.

In situ generation of functionalized 1,2,4-triazole-5-thiones containing pyridine or pyrazine moieties and their coordination to HgII

The reaction of 2-cyanopyridine or 2-cyanopyrazine with N-methylthiosemicarbazide afforded (Z)-2-(amino(pyridin-2-yl)methylene)-N-methylhydrazinecarbothioamide (HPyAm4M) and (Z)-2-(amino(pyrazin-2-yl)methylene)-N-methylhydrazinecarbothioamide (HPzAm4M), respectively. Prolonged heating under reflux in methanol in the synthesis of these thiosemicarbazones led to the formation of 4-methyl-5-pyridin-2-yl-2,4-dihydro-[1,2,4]triazole-5-thione (HMPytat, 1) and 4-methyl-5-pyrazin-2-yl-2,4-dihydro-[1,2,4]triazole-5-thione (HMPztat, 2) by oxidative cyclization of the starting thiosemicarbazones. Reactions of thiosemicarbazones with mercury(II) salts gave new complexes of general formulae [Hg(tat)X] (3, 4) and [Hg(Htat)2X2] (5, 7, 9–11), along with [Hg3(HEPytat)2(EPytat)2Cl4]·3H2O (6) and [Hg(EPytat)(HEPytat)I]·H2O (8) (Htat = general 1,2,4,-triazole-5-thione). The complexes were isolated as solids and were characterized by elemental analysis, mass spectrometry and IR, 1H NMR and 13C NMR spectroscopy. Recrystallization of the complexes from DMSO gave the compounds [Hg(MPytat)2]n (3a), [Hg(HMPytat)2Br2]·H2O (4a), [{Hg(HEPytat)(μ2-NS-EPytat)Cl2}2Hg] (6a), [Hg(EPytat)2]n (6b), [Hg(MPztat)2]n (10a) and [Hg(EPztat)2]n (11a) (HEPytat = 4-ethyl-5-pyridin-2-yl-2,4-dihydro-[1,2,4]triazole-5-thione and HEPztat = 4-ethyl-5-pyrazin-2-yl-2,4-dihydro-[1,2,4]triazole-5-thione). These complexes were studied by single-crystal X-ray diffraction. The structural analysis revealed the versatility of heterocyclic functionalized 1,2,4-triazole-5-thiones to coordinate to mercury(II) in the thione and thiolate forms through the use of various donor atoms to give different and interesting crystalline packings. The supramolecular assemblies observed in the solid state were analysed. These elegant assemblies are formed by a combination of several noncovalent interactions, including intermolecular hydrogen-bonding supramolecular synthons and aromatic–aromatic interactions. The short Hg⋯Hg distance of 3.660 A indicates the presence of a probable mercurophilic interaction in 6a.

Solid State Structures of Cadmium Complexes with Relevance for Biological Systems

This chapter provides a review of the literature on structural information from crystal structures determined by X-ray diffractometry of cadmium(II) complexes containing ligands of potential biological interest. These ligands fall into three broad classes, (i) those containing N-donors such as purine or pyrimidine bases and derivatives of adenine, guanine or cytosine, (ii) those containing carboxylate groups such as α-amino acids, in particular the twenty essential ones, the water soluble vitamins (B-complex) or the polycarboxylates of EDTA type ligands, and (iii) S-donors such as thiols/thiolates or dithiocarbamates. A crystal and molecular structural analysis has been carried out for some representative complexes of these ligands, specifically addressing the coordination mode of ligands, the coordination environment of cadmium and, in some significant cases, the intermolecular interactions.

Synthesis, structures and antimicrobial activity of copper derivatives of N-substituted imidazolidine-2-thiones: unusual bio-activity against Staphylococcus epidermidis and Enterococcus faecalis

The main objective of this study was to explore the antimicrobial activity of several copper(I) complexes with N,S-donor thio-ligands against Gram positive bacteria, namely Staphylococcus aureus (MTCC 740), Staphylococcus epidermidis (MTCC 435), and Enterococcus faecalis (MTCC 439), Gram negative bacteria, Shigella flexneri (MTCC 1457) and Escherichia coli (MTCC 119), and yeast, Candida tropicalis (MTCC 230). New copper complexes were prepared from copper(I) halides and imidazolidine-2-thiones (L-NR, R = Et; Prn; Bun; Ph) with triphenylphosphine as a co-ligand. The complexes are mononuclear, [CuX(L-NR)(PPh3)2] (X, R: Cl, Prn, 1; Br, Prn, 2; Cl, Bun, 3; I, Bun, 4; I, Ph, 6) and [CuBr(L-NPh)2(PPh3)] 5, and halogen-bridged dinuclear, [Cu2(μ-X)2(L-NR)2(PPh3)2] (Br, Et, 7; Cl, Prn, 8; Br, Prn, 9; I, Prn, 10; Br, Ph, 11; I, Ph, 12). These complexes were characterized using analytical data, IR, 1H/13C-NMR spectroscopy, single crystal X-ray crystallography, electron spray ionization mass spectrometry (ESI-MS) and techniques for antimicrobial study (agar diffusion, agar dilution, MTT assay). All of the complexes are found to be bactericidal against Staphylococcus aureus. The most significant outcome of this investigation is that several complexes have shown significant activity against Staphylococcus epidermidis and Enterococcus faecalis, which is higher than that of the standard drug Gentamicin. Finally, these complexes were nearly inactive against Shigella flexneri, Escherichia coli and yeast Candida tropicalis.

Synthesis, structures, antimicrobial activity and biosafety evaluation of pyridine-2-formaldehyde-N-susbtituted-thiosemicarbazonates of copper(II)

Pyridine-2-formaldehyde-N1-substituted-thiosemicarbazones {(C5H4N4)HC2N3–N2(H)–C1(S)N1HR} (abbrev. HL1-R: R = Me, Et, Ph) with copper(I) halides in an acetonitrile–dichloromethane mixture (1 : 1, v/v) have yielded a novel series of CuII complexes with a central coordination core: [CuIIX(N,N,S-L1-R)] (R = Me, Et, Ph: X = I, 1–3; Br, 4–6, Cl, 7–9), which have been characterized with the help of analytical data, IR, UV-visible and ESR spectroscopy, ESI-mass spectrometry and single crystal X-ray crystallography. The thio-ligands coordinate to CuII as anions (L1-R)− through pyridyl nitrogen-N4, azomethine nitrogen-N3 and thiolato sulfur and CuII is further bonded to iodide, bromide or chloride. In order to explore their bio-activity, complexes (1–9) as well as the previously reported CuII complexes of 2-benzoylpyridine-N-substituted thiosemicarbazones {(C5H4N4)(C6H5)–C2N3–N2(H)–C1(S)–N1HR; HL2-R}, namely, [CuIIX(N,N,S-L2-R)] (R = Me, Et, Ph: X = I, 10–12; Br, 13–15; Cl, 16–18), have been evaluated for their antimicrobial potential against different microbial strains. The microbial strains investigated are Staphylococcus aureus (MTCC740), Klebsiella pneumoniae (MTCC530), Shigella flexneri (MTCC1457), Salmonella typhimurium 1 (MTCC98), Salmonella typhimurium 2 (MTCC1251), Escherichia coli (MTCC119), Staphylococcus epidermidis (MTCC435), methicillin resistant Staphylococcus aureus (MRSA) and a yeast culture Candida albicans (MTCC227). Several complexes tested have shown high antimicrobial activity; specifically, against methicillin resistant Staphylococcus aureus, Staphylococcus epidermidis and Salmonella typhimurium 2; the activity is found to be high at low minimum inhibitory concentration (MIC) values as compared to that of the standard Gentamicin. Using MTT cytotoxicity assay {MTT = 3-[(4,5-dimethylthiazol-2-yl)-2,5-diphenyl]tetrazolium bromide}, complexes tested were found to be biosafe with high cell viability (90–98%).