Synthesis, characterization and biological activity of a gold(I) triazenide complex against chronic myeloid leukemia cells and biofilm producing microorganisms

ABSTRACT The enhancement of anti-leukemia therapy and the treatment of infections caused by multidrug-resistant pathogens are major challenges in healthcare. Although a large arsenal of drugs is available, many of these become ineffective, and as a result, the discovery of new active substances occurs. Notably, triazenes (TZCs) have been consolidated as a promising class of compounds, characterized by significant biological activity, especially antiproliferative and antimicrobial properties. The aim of this study is the synthesis and characterization of a new triazenide complex of gold (I), as well as the in vitro assessment of its antiproliferative activity against the K562 cell line (Chronic Myeloid Leukemia), and antibacterial activity against bacterial isolates of biofilm-producing coagulase-negative staphylococci. The combination of TZC with gold metal tends to have a synergistic effect against all biofilm-producing isolates, with Minimum Inhibitory Concentration values (MIC) between 32 and 64 µg mL-1. It has also shown activity against K562 cell line, getting an IC50=4.96 µM. Imatinib mesylate (Glivec) was used as reference, with IC50=3.86 µM. To the best of our knowledge, this study represents the first report of the activity of a TZC complexed with gold ion in the oxidation state (I) against microorganisms that produce biofilm and K562 cells.

Atividade antibacteriana de um composto triazenido com ouro frente a cepas bacterianas e isolados clínicos / Actividad antibacteriana de un triazenido compuesto de oro frente a las cepas bacterianas y los aislados clínicos / Antibacterial activity of gold complexed triazenid against bacterial strains and clinical isolates

Introdução: de uma forma alarmante, estudos demonstraram que nos últimos anos ocorreu um grande aumento na resistência bacteriana frente aos antibióticos. Consequentemente, há uma grande necessidade de descoberta de novas substâncias ativas, e entre essas, os compostos triazenos vêm demonstrado-se como uma classe promissora de metalofármacos, com significativa atividade antimicrobiana. Além do mais, a associação do radical farmacofórico triazenos com metais, como o ouro, favorece a produção de moléculas com maior atividade biológica. Objetivo: avaliar a atividade antibacteriana in vitro do composto triazenos inédito complexado com ouro no estado de oxidação I {(1-(2-bromofenil)-3-(2-nitrofenil)triazenido(trifenilfosfina)ouro(I)}, frente a cepas bacterianas padrões de referência American Type Culture Collection e isolados clínicos com resistência múltipla as drogas (MDR). Métodos: a atividade antibacteriana do composto triazenos foi determinada através do método de Concentração Inibitória Mínima, baseado no Clinical and Laboratory Standards Institute de 2012. A CIM foi caracterizada visualmente, como a menor concentração que inibiu completamente o crescimento dos microrganismos nos poços de diluição. Resultados: o composto em estudo apresentou pronunciada atividade antibacteriana, sendo ativo em 43,4 por cento (10/23) das bactérias testadas, mostrando-se seletivo frente a cepas Gram positivas. Conclusão: o complexo triazenos apresentou estreito espectro de ação, sendo ativo somente frente aos microrganismos classificados como Gram positivos, demonstrando assim uma alternativa para a concepção de uma nova classe de metalofármacos com atividade antibacteriana(AU)

Introducción: de una manera alarmante, los estudios han demostrado que en los últimos años hubo un gran aumento de la resistencia bacteriana a los antibióticos. Por consiguiente, hay una gran necesidad para el descubrimiento de nuevas sustancias activas, y entre estas, los compuestos triazenos se muestran como una clase prometedora de metalofármacos con actividad antimicrobiana significativa. Por otra parte, la asociación de triazeno farmacóforo radical con metales como el oro favorece la producción de moléculas con actividad biológica superior. Objetivo: evaluar la actividad antibacteriana in vitro del compuesto sin precedentes triazeno complejado con oro en el estado de oxidación I {(1-(2-bromofenil)-3-(2-nitrofenil)triazenido(trifenilfosfina)ouro(I)}, frente a las cepas de las normas bacterianas, cepas de referencia American Type Culture Collection y los aislados clínicos con resistencia múltiple a los medicamentos. Métodos: la actividad antibacteriana del triazeno compuesto se determinó por el método de la concentración inhibitoria mínima, sobre la base de estándares clínicos y de laboratorio de 2012. Este método se caracteriza visualmente como la menor concentración que inhibió completamente el crecimiento de microorganismos en los pocillos de dilución. Resultados: el compuesto de ensayo mostró actividad antibacteriana pronunciada, el cual fue activo en 43,4 por ciento (10/23) de las bacterias ensayadas, uy mostró ser selectivo contra las cepas grampositivas. Conclusión: el complejo triazeno mostró estrecho espectro de acción, el cual es activo solo frente a los microorganismos clasificados como grampositivos, lo que demuestra una alternativa para la concepción de una nueva clase de metalofármacos con actividad antibacteriana(AU)

Introduction: several studies have revealed that the increase of bacterial resistance to antibiotic is really alarming in the last few years. Consequently, the discovery of new active substances is a must and the triazene compounds appear as a promising class of metal drugs with significant antimicrobial action. On the other hand, the association of radical pharmacophorous triazene with metals such as gold facilitates the production of greater biological action molecules. Objective: to evaluate the in vitro antibacterial activity of this unprecedented compound called gold complexed with triazene at oxidation state I {(1-(2-bromophenyl)-3-(2-nitrophenyl)triazenide (triphenylphosphane) gold(I)} against the bacterial standard strains, American Type Culture Collection reference strains and the multiple drug resistance clinical isolates. Methods: the antibacterial activity of the compound triazene was estimated by the minimal inhibitory concentration method on the basis of the clinical and laboratory standards 2012. This method is visually characterized as the lowest concentration that fully inhibited the bacterial growth in the dilution wells. Results: the tested compound showed significant antibacterial activity, being active in 43.4 percent (10/23) of tested bacteria and selective for Gram-positive strains. Conclusions: triazene complex showed narrow action spectrum since it is only active against Gram-positive microorganisms, which is in turn an alternative for conception of a new class of metal drugs with antibacterial action(AU)

1-(2,4,6-Trioxo-1,3-diazinan-5-yl-idene)thio-semicarbazide.

The title mol-ecule, C(5)H(5)N(5)O(3)S, is approximately planar, with a maximum deviation from the mean plane through the non-H atoms of 0.182 (3) Šfor the amine N atom. In the crystal, mol-ecules are connected via N-H⋯O and N-H⋯S inter-actions, building a three-dimensional hydrogen-bonded network. Additionally, a weak intra-molecular N-H⋯O hydrogen bond is observed.

Bis{4-phenyl-1-[1-(pyridin-2-yl-κN)ethyl-idene]thio-semicarbazidato-κ(2)N(1),S}cadmium.

The reaction of cadmium acetate dihydrate with 2-acetyl-pyridine (4-phenyl-thio-semicarbazone) yielded the title compound, [Cd(C(14)H(13)N(4)S)(2)]. The Cd(II) atom is six-coordin-ated in a distorted octa-hedral environment by two deproton-ated thio-semicarbazone ligands acting in a tridentate chelating mode through two N and one S atoms, forming metalla-rings. In the crystal, mol-ecules are connected through inversion centers via pairs of N-H⋯S inter-actions, building a one-dimensional hydrogen-bonded polymer along [0-1-1].

N'-[3-(Hy-droxy-imino)-butan-2-yl-idene]-4-methyl-benzene-1-sulfono-hydrazide.

In the title compound, C(11)H(15)N(3)O(3)S, the C-S-N(H)-N linkage is nonplanar, the torsion angle being 75.70 (12)°. The compound has two almost planar fragments linked to the S atom: the hydrazone-derivative fragment [(HONC(4)H(6))N-N(H)-] and the tolyl fragment (C(7)H(7)-) have maximum deviations from the mean plane through the non-H atoms of 0.0260 (10) and 0.0148 (14) Å, respectively. The two planar fragments make an inter-planar angle of 79.47 (5)°. In the crystal, mol-ecules are connected through inversion centers via pairs of N-H⋯O and O-H⋯N hydrogen bonds.

4-Methyl-N'-(2-oxoindolin-3-yl-idene)benzene-1-sulfono-hydrazide.

In the title compound, C(15)H(13)N(3)O(3)S, the C-S-N(H)-N linkage is non-planar, the torsion angle being -65.12 (13)° and the S atom showing a tetra-hedral environment. The compound has two almost planar fragments linked to the S atom: the isatin-derivative fragment [(C(8)H(5)NO)N-N(H)-] and the tolyl fragment [C(7)H(7)-] have maximum deviations from the mean plane through the non-H atoms of 0.0813 (13) and 0.0094 (16) Å, respectively, and make an inter-planar angle of 80.48 (3)°. In the crystal, mol-ecules are connected into inversion dimers via pairs of N-H⋯O hydrogen bonds. Additionally, the mol-ecular structure is stabilized by an intra-molecular N-H⋯O hydrogen bond.

1-(5-Bromo-2-oxoindolin-3-yl-idene)thio-semicarbazide acetonitrile monosolvate.

In the crystal structure of the title compound, C(9)H(7)BrN(4)OS·C(2)H(3)N, the mol-ecules are connected via N-H⋯O and N-H⋯S inter-actions into zigzag chains perpendicular to [001]. The mol-ecules in these chains are additionally linked to acetonitrile solvent mol-ecules through N-H⋯N hydrogen bonding. The mol-ecules are arranged in layers and are stacked in the direction of the c axis indicative of π-π inter-actions, with distance = 3.381 (7) Šfor the C⋯C interaction parallel to [001]. An intra-molecular N-H⋯O hydrogen bond is also observed in the main mol-ecule.

Preparation, crystallography and spectroscopic properties of the polymeric {(1-(E)-2-pyridinylmethylidene)semicarbazone)(aqua)copper(II)} sulphate dihydrate complex: evidence of dynamic Jahn-Teller effect.

Pyridine-2-carbaldehyde semicarbazone ligand (HL) reacts with copper(II) sulphate in water solution to yield the coordination polymer [{Cu(II)(HL)(H(2)O)(SO(4))}(n)] (1). The crystals are triclinic with space group P(-1) and the metal ion is occupying a distorted octahedral geometry. EPR results show that a dynamic Jahn-Teller (J-T) effect is operative in water solutions and also support the stability of the polymeric chains as they continue to show a characteristic half-field Δm(S)=±2 transitions. UV-visible spectrum analysis allowed access to the J-T stabilization energy of 5995 cm(-1) in water. Thermogravimetric/differential thermal analysis curves showed a step-by-step decomposition of complex 1 with loss of water, release of SO(3) and oxidation of the semicarbazone ligand in the 30-422°C range.