Victor M. Deflon

Dithiocarbazate complexes with the [M(PPh3)]2+ (M=Pd or Pt) moiety Synthesis, characterization and anti-Tripanosoma cruzi activity

New neutral Pd(II) and Pt(II) complexes of the type [M(L)(PPh(3))] (M = Pd or Pt) were prepared in crystalline form in high-yield synthesis with the S-benzyldithiocarbazates and S-4-nitrobenzyldithiocarbazates derivatives from 2-hydroxyacetophenone, H(2)L(1a) and H(2)L(1b), and benzoylacetone, H(2)L(2a) and H(2)L(2b). The new complexes [Pt(L(1a))(PPh(3))] (1), [Pd(L(1a))(PPh(3))] (2), [Pt(L(1b))(PPh(3))] (3), [Pd(L(1b))(PPh(3))] (4), [Pt(L(2a))(PPh(3))] (5), [Pd(L(2a))(PPh(3))] (6), [Pt(L(2b))(PPh(3))] (7) and [Pd(L(2b))(PPh(3))] (8) were characterized on the basis of elemental analysis, conductivity measurements, UV-visible, IR, electrospray ionization mass spectrometry (ESI-MS), NMR ((1)H and (31)P) and by X-ray diffraction studies. The studies showed that differently from what was observed for the H(2)L(1a) and H(2)L(1b) ligands, H(2)L(2a) and H(2)L(2b) assume cyclic forms as 5-hydroxypyrazolinic. Upon coordination, H(2)L(2a) and H(2)L(2b) suffer ring-opening reaction, coordinating in the same manner as H(2)L(1a) and H(2)L(1b), deprotonated and in O,N,S-tridentate mode to the (MPPh(3))(2+) moiety. All complexes show a quite similar planar fourfold environment around the M(II) center. Furthermore, these complexes exhibited biological activity on extra and intracellular forms of Trypanosoma cruzi in a time- and concentration-dependent manner with IC(50) values ranging from 7.8 to 18.7 μM, while the ligand H(2)L(2a) presented a trypanocidal activity on trypomastigote form better than the standard drug benznidazole.

Palladium(II) complexes with thiosemicarbazones: syntheses, characterization and cytotoxicity against breast cancer cells and Anti-Mycobacterium tuberculosis activity

Three PdII complexes were prepared from N(4)-substituted thiosemicarbazones: [Pd(aptsc)(PPh3)](NO3)•H2O, 1, [Pd(apmtsc)(PPh3)](NO3), 2, and [Pd(apptsc)(PPh3)](NO3)•H2O, 3, where PPh3 = triphenylphosphine; Haptsc = 2-acetylpyridine-thiosemicarbazone; Hapmtsc = 2-acetylpyridine-N(4)-methyl-thiosemicarbazone and Happtsc = 2-acetylpyridine-N(4)-phenyl-thiosemicarbazone. All complexes were characterized by elemental analysis, IR, UV-Vis, 1H and 31P{1H} NMR spectroscopies, and had their crystalline structures determined by X-ray diffractometry from single crystals. The monoanionic thiosemicarbazonate ligands act in a tridentate mode, binding to the metal through the pyridine nitrogen, the azomethine nitrogen and the sulfur atoms. The cytotoxic activity against the breast cancer cell line MDA-MB231 and the anti-Mycobacterium tuberculosis H37Rv ATCC 27294 activity were evaluated for the compounds. All PdII complexes were highly active against the studied cell line, presenting similar values of IC50, around 5 µmol L-1, while the clinically applied antitumor agent cisplatin was inactive. The compounds show remarkable anti-M. tuberculosis activities, presenting MIC values comparable or better than some commercial anti-M tuberculosis drugs.

Gold(III) complexes in medicinal chemistry

A number of gold(III) compounds has been designed with the objective of overcoming the disadvantages associated with the platinum-based drugs for cancer treatment. Compounds of a remarkable structural manifold show significant antiproliferative effects in vitro against a number of cancer cells, including cisplatin resistant ones. The target of most of them is, unlike that of cisplatin, not the DNA. Although the mechanisms of action displayed by the gold compounds in biological media are still under investigation, many studies show evidence that the cellular targets are mitochondria-based. Recent advances in gold(III) medicinal chemistry also recommend such compounds for other pharmacological applications such as the treatment of viral or parasitic diseases. The radioactive isotopes (198)Au and (199)Au present potential in radiotherapy.

Copper(I) pseudohalide complexes with 4,6-dimethylpyrimidine-2(1H)-thione and triphenylphosphane as ligands. The X-ray crystal structures of [Cu(N3)(dmpymtH)(PPh3)2] and [Cu(NCS)(dmpymtH)(PPh3)2]

Abstract The preparation of mixed-ligand copper(I) coordination compounds containing pseudohalides (azide and thiocyanate), 4,6-dimethylpyrimidine-2(1H)-thione (dmpymtH), and triphenylphosphane is described. The crystalline and molecular structure of [Cu(N3)(dmpymtH)(PPh3)2] (2) and [Cu(NCS)(dmpymtH)(PPh3)2] (3) have been determined by X-ray diffraction methods. The copper atom has a tetra-coordinate CuNP2S chromophore with distorted tetrahedral coordination in both complexes. Vibrational and 1H, 13C, 31P NMR spectra of the complexes are discussed and related to the structures.

Manganese(II) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents

Through a systematic variation on the structure of a series of manganese complexes derived from 2-acetylpyridine-N(4)-R-thiosemicarbazones (Hatc-R), structural features have been investigated with the aim of obtaining complexes with potent anti-Mycobacterium tuberculosis activity. The analytical methods used for characterization included FTIR, EPR, UV-visible, elemental analysis, cyclic voltammetry, magnetic susceptibility measurement and single crystal X-ray diffractometry. Density functional theory (DFT) calculations were performed in order to evaluate the contribution of the thiosemicarbazonate ligands on the charge distribution of the complexes by changing the peripheral groups as well as to verify the Mn-donor atoms bond dissociation predisposition. The results obtained are consistent with the monoanionic N,N,S-tridentate coordination of the thiosemicarbazone ligands, resulting in octahedral complexes of the type [Mn(atc-R)2], paramagnetic in the extension of 5 unpaired electrons, whose EPR spectra are consistent for manganese(II). The electrochemical analyses show two nearly reversible processes, which are influenced by the peripheral substituent groups at the N4 position of the atc-R(1-) ligands. The minimal inhibitory concentration (MIC) of these compounds against M. tuberculosis as well as their in vitro cytotoxicity on VERO and J774A.1 cells (IC50) was determined in order to find their selectivity index (SI) (SI=IC50/MIC). The results evidenced that the compounds described here can be considered as promising anti-M. tuberculosis agents, with SI values comparable or better than some commercial drugs available for the tuberculosis treatment.

Dependence on the reaction time of the coordination mode of 2,6-diacetylpyridine bis(2-furanoylhydrazone), H2dapf, towards ZnCl2. Crystal and molecular structures of [ZnCl(H2dapf)(H2O)]Cl · 4H2O and [Zn(dapf)]2

ZnCl2 reacts with the multidentate ligand 2,6-diacetylpyridine bis(2-furanoylhydrazone), H2dapf, to produce two complexes, [ZnCl(H2dapf)(H2O)]Cl · 4H2O and [Zn(dapf)]2, the predominant coordination mode of H2dapf being influenced by the reaction time. The mononuclear and binuclear complexes were prepared by refluxing DMF/H2O solutions of the reactants (1:1 molar ratio) for 3 and 6 h, respectively. The mononuclear complex possesses a distorted pentagonal bipyramidal (PBP) configuration, with the five ONNNO-donor atoms of the protonated H2dapf ligand in the pentagonal plane, with the water molecule and the chloride ion positioned in the axial position. The binuclear complex has two equivalent pseudo-octahedral ZnII centers, with the pyridyl nitrogen atoms of the two fully deprotonated ligands acting as bridges between the two metal atoms.

Synthesis and characterization of heptacoordinated tin(IV) complexes. X-ray crystal structure of [nBu2Sn(dappt)]·(Me 2CO)0.5 [H2dappt = 2,6-diacetylpyridine bis(4-phenylthiosemicarbazone)]

The reactions of the 2,6-diacetylpyridine bis(4-phenylthiosemicarbazone) ligand, H2dappt, with R4-mSnXm (m = 2, 3; R = Me, nBu, Ph and X = Cl) led to the formation of four new heptacoordinated organotin(IV) complexes, which were characterized by microanalyses and by IR and Mossbauer spectroscopies. The n-butyl derivative [nBu2Sn(dappt)]·(Me 2CO)0.5 was also analyzed by a single crystal X-ray diffraction study. It crystallized in the monoclinic system with a space group C2/c, with a = 36.164(14), b = 9.7050(15), c = 26.194(11) A, b = 132.00(2)o, Z = 8. The structure determination revealed a neutral complex of Sn(IV) in a distorted pentagonal bipyramidal (PBP) geometry, with the equatorial plane defined by the SNNNS donor system of the ligand and with the two n-butyl groups in the axial positions. Also, a correlation between Mossbauer and X-ray data based on the point-charge model is discussed.

In vitro and in vivo trypanocidal activity of H2bdtc-loaded solid lipid nanoparticles.

The parasite Trypanosoma cruzi causes Chagas disease, which remains a serious public health concern and continues to victimize thousands of people, primarily in the poorest regions of Latin America. In the search for new therapeutic drugs against T. cruzi, here we have evaluated both the in vitro and the in vivo activity of 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyl dithiocarbazate) (H2bdtc) as a free compound or encapsulated into solid lipid nanoparticles (SLN); we compared the results with those achieved by using the currently employed drug, benznidazole. H2bdtc encapsulated into solid lipid nanoparticles (a) effectively reduced parasitemia in mice at concentrations 100 times lower than that normally employed for benznidazole (clinically applied at a concentration of 400 µmol kg−1 day−1); (b) diminished inflammation and lesions of the liver and heart; and (c) resulted in 100% survival of mice infected with T. cruzi. Therefore, H2bdtc is a potent trypanocidal agent.

Darstellung und Kristallstrukturen von Dicyanamido(triphenylphosphan)gold(I) und Nitrosodicyanmethanido(triphenylphosphan)gold(I)

Die Koordinationsverbindungen [(Ph3P)Au{N(CN)2}] (1) und [(Ph3P)Au{ONC(CN)2}] (2) werden durch Umsetzung von [Au(PPh3)]NO3 mit Na[N(CN)2] bzw. K[ONC(CN)2] in CH2Cl2 erhalten. Die Verbindungen werden IR-spektroskopisch und durch Kristallstrukturanalysen charakterisiert. 1 kristallisiert triklin in der Raumgruppe P 1 mit a = 930,16(4), b = 1011,89(13), c = 1118,35(16) pm, α = 115,327(10), β = 90,899(8), γ = 103,394(8)°, Z = 2. 2 kristallisiert monoklin in der Raumgruppe P21/n mit a = 832,59(10), b = 1139,30(16), c = 2078,9(4) pm, α = 99,84(2)°, Z = 4. Die Kristallstrukturen beider Verbindungen sind aus paarweise antiparallel angeordneten Molekulen mit linear koordinierten Goldatomen und schwachen zwischenmolekularen Au–N-Wechselwirkungen aufgebaut. Preparation and Crystal Structures of Dicyanamido(triphenylphosphane)gold(I) and Nitrosodicyanomethanido(triphenylphosphane)gold(I) The coordination compounds [(Ph3P)Au{N(CN)2}] (1) and [(Ph3P)Au{ONC(CN)2}] (2) are obtained by the reaction of [Au(PPh3)]NO3 with Na[N(CN)2] or K[ONC(CN)2] in CH2Cl2. The compounds are characterized by IR spectroscopy and by crystal structure determination. 1 crystallizes triclinic in the space group P 1 with a = 930.16(4), b = 1011.89(13), c = 1118.35(16) pm, α = 115.327(10), β = 90.899(8), γ = 103.394(8)°, Z = 2. 2 crystallizes monoclinic in the space group P21/n with a = 832.59(10), b = 1139.30(16), c = 2078.9(4) pm, β = 99.84(2)°, Z = 4. The crystal structures of both compounds are built up by pairs of antiparallel oriented molecules with linear coordinated gold atoms and weak intermolecular Au–N-interactions.

Novel zwitterionic oxorhenium(V) complexes: synthesis, characterization and crystal structure of [ReOX2(Hdhp)(PPh3)] (X = Cl, Br; H2dhp = 2,3-dihydroxypyridine)

Dois novos complexos zwitterionicos de oxorrenio(V), [ReOCl2(Hdhp)(PPh3)] (1) e [ReOBr2(Hdhp)(PPh3)] (2) (H2dhp = 2,3-dihidroxipiridina), foram sintetizados e caracterizados por espectroscopia de absorcao no infravermelho, ressonância magnetica nuclear de 1H e 31P, analise elementar e determinacao da estrutura cristalina e molecular por difracao de raios X em monocristais. Os complexos apresentam geometria de coordenacao octaedrica bastante distorcida, com os dois ligantes haletos arranjados em posicoes cis equatoriais, o ligante trifenilfosfina em posicao trans a um dos haletos e o ligante Hdhp- coordenado de forma bidentada atraves de seus atomos de oxigenio, sendo um em posicao trans ao ligante oxo e o outro em posicao trans com relacao ao outro haleto. Este ligante tem seu atomo de nitrogenio protonado. Os compostos 1 e 2 apresentam empacotamento cristalino bastante diferente, influenciado em ambos os casos por ligacoes de hidrogenio intermoleculares dos tipos N-H...X (X = Cl, Br) e N-H...O.