RESUMEN

The Golgi apparatus is a critical organelle in protein sorting and lipid metabolism. Characterized by its stacked, flattened cisternal structure, the Golgi exhibits distinct polarity with its cis- and trans-faces orchestrating various protein maturation and transport processes. At the heart of its structural integrity and organisation are the Golgi Matrix Proteins (GMPs), predominantly comprising Golgins and GRASPs. These proteins contribute to this organelle's unique stacked and polarized structure and ensure the precise localization of Golgi-resident enzymes, which is crucial for accurate protein processing. Despite over a century of research since its discovery, the Golgi architecture's intricate mechanisms still need to be fully understood. Here, we discuss that GMPs across different Eukaryotic lineages present a significant tendency to form biomolecular condensates. Moreover, we validated experimentally that members of the GRASP family also exhibit a strong tendency. Our findings offer a new perspective on the possible roles of protein disorder and condensation of GMPs in the Golgi organisation.

Asunto(s)

Aparato de Golgi , Proteínas de la Matriz de Golgi , Proteínas de la Matriz de Golgi/metabolismo , Aparato de Golgi/metabolismo , Humanos , Animales , Transporte de Proteínas , Separación de Fases

RESUMEN

In the present work, the synthesis, characterization, antifungal activity, molecular docking study and in silico approach of five thiosemicarbazone derivatives and their corresponding zinc(II) complexes are described. The compounds were characterized by elemental analysis, IR, UV-Vis and NMR spectroscopic measurements, molar conductivity measurements, emission spectra, high-resolution mass spectrometry and X ray study. The antifungal activity of the free ligands and synthesized compounds was preliminarily evaluated against Candida albicans (ATCC 90028), Candida tropicalis (ATCC 13803) and Candida glabrata (ATCC 2001), by the minimum inhibitory concentration (MIC) assay. Two complexes, 4 (MIC = 3.18 to 6.37 µM) and 5 (MIC = 25.95 µM for all) showed promising results, being highly active against all strains evaluated. The X-ray analyses shown that the complex 2 crystallizes in the centrosymmetric space group P21/c of the monoclinic system and the coordination sphere around zinc(II) atom is better described as slightly distorted octahedral. The Hirshfeld surface (HS) analysis showed that non-classical H···H and C···H/H···C contacts contribute with 65.9% while the S···H and N···H (21%) and Cl···H and O···H interactions (12%) complete the HS area. The molecular docking results, performed against CYP51 enzyme (sterol 14α-demethylase) of C. albicans and C. glabrata shows that the complexes 4 (ΔG = -10.75 and - 12.90 kcal/ mol) and 5 (ΔG = -11.12 and - 14.53 kcal/ mol) showed the highest binding free energies of all compounds. The ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) in silico parameters evaluated showed promising results for all compounds.

Asunto(s)

Complejos de Coordinación , Tiosemicarbazonas , Simulación del Acoplamiento Molecular , Antifúngicos/química , Zinc/química , Ligandos , Tiosemicarbazonas/química , Pruebas de Sensibilidad Microbiana , Candida albicans , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Estructura Molecular

RESUMEN

Considering the promising previous results on the remarkable activity exhibited by cobalt(III) and manganese(II) thiosemicarbazone compounds as antibacterial agents, the present study aimed to prepare and then evaluate the antibacterial activity of two different types of Cu(II) complexes based on a 2-acetylpyridine-N(4)-methyl-thiosemicarbazone ligand (Hatc-Me), a monomer complex [CuCl(atc-Me)] and a novel dinuclear complex [{Cu(µ-atc-Me)}2µ-SO4]. The compounds were characterized by infrared spectra, ultraviolet visible and CHN elemental analysis. In addition, the crystalline structures of the complexes were determined by single-crystal X-ray diffraction. In both cases, the Schiff base ligand coordinated in a tridentate mode via the pyridine nitrogen, imine nitrogen and sulfur atoms. The two Cu(II) atoms in the dimer are five coordinate, consisting of three NNS-donor atoms from the thiosemicarbazone ligand connected by a sulfate bridge. The Hirshfeld surface and energy framework of the complexes were additionally analyzed to verify the intermolecular interactions. The biological activity of the Cu(II) salts, the free ligand and its Cu(II) complexes was evaluated against six strains of mycobacteria including Mycobacterium tuberculosis. The complexes showed promising results as antibacterial agents for M. avium and M. tuberculosis, which ranged from 6.12 to 12.73 µM. Furthermore, molecular docking analysis was performed and the binding energy of the docked compound [{Cu(µ-atc-Me)}2µ-SO4] with M. tuberculosis and M. avium strains were extremely favorable (-11.11 and - 14.03 kcal/mol, respectively). The in silico results show that the complexes are potential candidates for the development of new antimycobacterial drugs.

Asunto(s)

Antituberculosos/farmacología , Complejos de Coordinación/farmacología , Tiosemicarbazonas/farmacología , Antituberculosos/síntesis química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Proteínas Bacterianas/metabolismo , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacocinética , Cobre/química , Ligandos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Unión Proteica , Relación Estructura-Actividad , Termodinámica , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/metabolismo , Tiosemicarbazonas/farmacocinética

RESUMEN

INTRODUCTION: Interleukin 17 (IL-17) is produced by Th17 and other cells. It is debatable whether IL-17 is atherogenic or atheroprotective. The role of this interleukin in the development and progression of coronary artery disease is unknown. Our aim was to evaluate if there were differences in serum IL-17A levels according to to clinical presentation of coronary artery disease. METHODS: This cross-sectional study enrolled 101 patients with acute coronary syndrome (ACS), 100 patients with chronic coronary syndrome (CCS), and 70 healthy volunteers. Blood samples were collected from patients and controls (within 48 h) to analyze IL-17A levels. Clinical characteristics were recorded using questionnaires. This study was approved by the Ethics Committee. RESULTS: Comparisons of the clinical characteristics between patients with ACS and CCS revealed the following: mean age (62 ± 12.4 years vs. 63.3 ± 9.8 years, P = 0.4), male (63.4% vs. 58%, P = 0.4), hypertension (85.1% vs. 79%, P = 0.1), dyslipidemia (48% vs. 31%, P = 0.01), diabetes mellitus (47.5% vs. 41%, P = 0.3), previous myocardial infarction (57.4% vs. 40%, P = 0.01), and smoking (29.7% vs. 38%, P = 1). The peripheral concentrations of IL-17A in ACS, CCS and controls were 5.36 ± 8.83, 6.69 ± 17.92, and 6.26 ± 11.13, respectively, with P = 0.6. In addition, the comparison between ACS and CCS showed: 5.36 ± 8.83 vs. 6.69 ± 17.92%, P = 0.3. CONCLUSION: The main finding of this study was that circulating IL-17 levels were similar in patients with ACS, CCS, and healthy volunteers. In addition, there was no difference between patients with ACS and those with CCS. Therefore, in patients with ACS and CCS, circulating IL-17A concentrations are low and there were no differences between patients with coronary artery disease and healthy individuals.

RESUMEN

Considering our previous findings on the remarkable activity exhibited by cobalt(III) with 2-acetylpyridine-N(4)-R-thiosemicarbazone (Hatc-R) compounds against Mycobacterium tuberculosis, the present study aimed to explored new structure features of the complexes of the type [Co(atc--R)2]Cl, where R = methyl (Me, 1) or phenyl (Ph, 2) (13C NMR, high-resolution mass spectrometry, LC-MS/MS, fragmentation study) together with its antibacterial and antiviral biological activities. The minimal inhibitory and minimal bactericidal concentrations (MIC and MBC) were determined, as well as the antiviral potential of the complexes on chikungunya virus (CHIKV) infection in vitro and cell viability. [Co(atc-Ph)2]Cl revealed promising MIC and MBC values which ranged from 0.39 to 0.78 µg/mL in two strains tested and presented high potential against CHIKV by reducing viral replication by up to 80%. The results showed that the biological activity is strongly influenced by the peripheral substituent groups at the N(4) position of the atc-R1- ligands. In addition, molecular docking analysis was performed. The relative binding energy of the docked compound with five bacteria strains was found in the range of -3.45 and -9.55 kcal/mol. Thus, this work highlights the good potential of cobalt(III) complexes and provide support for future studies on this molecule aiming at its antibacterial and antiviral therapeutic application.

Asunto(s)

Cobalto/farmacología , Tiosemicarbazonas/química , Antibacterianos/farmacología , Antivirales/farmacología , Bacterias/efectos de los fármacos , Fiebre Chikungunya/tratamiento farmacológico , Virus Chikungunya/efectos de los fármacos , Cromatografía Liquida/métodos , Cobalto/química , Complejos de Coordinación/farmacología , Ligandos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem/métodos , Tiosemicarbazonas/farmacología

RESUMEN

Cyclometallated palladium(ii) and platinum(ii) pyrenyl-derived thiosemicarbazone (H2PrR) complexes of the type [M4(µ-S-PrR-κ3-C,N,S)4] (M = PdII, PtII; R = ethyl, cyclohexyl) have been synthesised in good yields and fully characterised. X-ray crystallography showed that the tetranuclear complex [Pt4(µ-S-PrCh-κ3-C,N,S)4](CH3)2COCHCl3 contains an eight-membered ring of alternating M-S atoms. The ethyl derivatives [M4(µ-S-PrEt-κ3-C,N,S)4] exhibit potent antiproliferative activity towards A2780 human ovarian cancer cells, with IC50 values of 1.27 µM (for M = PdII) and 0.37 µM (for M = PtII), the latter being an order of magnitude more potent than the anticancer drug cisplatin (IC50 1.20 µM). These promising complexes had low toxicity towards non-cancerous human MRC5 cells, which points towards an early indication of differential toxicity between cancer and normal cells. Experiments that investigated the effects of these tetranuclear complexes on the cell cycle, integrity of the cell membrane, and induction of apoptosis, suggested that their mechanism of action of does not involve DNA targeting, unlike cisplatin, and therefore could be promising for combatting cisplatin resistance.

Asunto(s)

Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Paladio/farmacología , Platino (Metal)/farmacología , Pirenos/farmacología , Tiosemicarbazonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Paladio/química , Platino (Metal)/química , Pirenos/química , Tiosemicarbazonas/química

RESUMEN

[PtCl2(phen)] reacts with thiosemicarbazones derived from ß-diketones (H2LR) leading to an intramolecular C-C coupling between phen and the ketone upon formation of tetradentate N,N,N,S chelates [PtII(LRphen)]. The reactions proceed via bidentate coordination of the doubly deprotonated (LR)2- followed by an intra-nucleophilic attack and consecutive C-C bond formation.

RESUMEN

New palladium complexes with thiosemicarbazonate ligands derived from pyrene exhibit potent antiproliferative activity against A2780 and cisplatin-resistant A2780Cis human ovarian cancer cells, which is dependent on substituent groups of the thiosemicarbazone ligands. Cellular accumulation and distribution studies confirmed that palladium enters the cell nucleus. DNA and topoisomerase IB studies show that one complex is a potent TopIB inhibitor, with selectivity for cancer versus normal cells.

Asunto(s)

Antineoplásicos/química , Complejos de Coordinación/química , Paladio/química , Pirenos/química , Tiosemicarbazonas/química , Inhibidores de Topoisomerasa/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Complejos de Coordinación/farmacología , Resistencia a Antineoplásicos , Humanos , Cinética , Inhibidores de Topoisomerasa/farmacología

RESUMEN

The incidence of coronary artery aneurysms ranges from 0.2% to 10.5%. Aneurysms have been described after percutaneous coronary interventions (PCIs) and hypersensitivity to polymers, nickel, cobalt, inflammatory reaction rich in eosinophils, drug released by the stent, fracture and malapposition of the stent, stent endothelialization delay, high pressures used in the procedures, oversizing of balloons and stents, unhealed dissections, atheroablative techniques, and trauma of the arterial wall are related to appearance of coronary artery aneurysms. In this case report, we described a patient with human immunodeficiency virus and thrombophilia who underwent primary PCI and at the end of the procedure had thrombi in the coronary artery. It was decided by triple therapy and new angiographic study 2 days later. This new angiography revealed thrombi resolution but the appearance of an aneurysm in the middle portion of the drug-eluting stent. The anticoagulant was stopped and we performed watchful waiting strategy with new serial angiograms that revealed progressive reduction and disappearance of the aneurysm. Subsequently triple therapy with warfarin, aspirin and clopidogrel was restarted and the patient progressed asymptomatic and performed his daily activities normally. At 6 months of clinical follow-up, we advised the patient to suspend aspirin and to continue secondary prevention of cardiovascular events.

RESUMEN

The tricuspid valve (TV) has been known as the forgotten valve. However, considering recent information from scientific studies, this nomenclature may need to be adjusted for the valve, which also needs to be better studied and understood. For decades, tricuspid regurgitation (TR) was not fully appreciated and was never the priority. However, studies have revealed that such pathology is related to a possible negative impact on prognosis of patients. Severe TR is a predictor of higher mortality. For the treatment of TR, repair or valve replacement can be performed. Repair techniques can be performed on the annulus (suture annuloplasty or ring implant), on the leaflets (e.g. triangular resection), on the cords (transfers or new cords) and on the papillary muscles (e.g. sliding technique). The anatomical characteristics of the TV determine the repair technique to be used. In some cases, valve repair is not possible and/or not indicated and valve replacement is selected based on the strategy. Nowadays transcatheter therapies have been used and studied. The main transcatheter strategies for the treatment of TR are based on reduction of the annulus (Cardioband, Trialign, TriCinch, Millipede and TRAIPTA), improvement of the leaflet coaptation (Mitraclip, FORMA device, PASCAL system, and TV occluder), reduction of the reflux for the vena cava system (Tric valve and Sapien valve implant), and valve implants (Navigate, Trisol, Sapien, Melody). In this context, there are still other devices (such as Tricentro, Pasta, etc.) being developed and tested throughout several phases of research. In the future, improved knowledge of the TV and the evolution of transcatheter treatments will alter the history of the TV. The transcatheter revolution is coming!

RESUMEN

Reactions of Ni(II) and Pd(II) precursors with S-benzyl-N-(ferrocenyl)methylenedithiocarbazate (HFedtc) led to the formation of heterobimetallic complexes of the type [MII(Fedtc)2] (M = Ni and Pd). The characterization of the compounds involved the determination of melting point, FTIR, UV-Vis, 1H NMR, elemental analysis and electrochemical experiments. Furthermore, the crystalline structures of HFedtc and [NiII(Fedtc)2] were determined by single crystal X-ray diffraction. The compounds were evaluated against the intracellular form of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity assays were assessed using LLC-MK2 cells. The results showed that the coordination of HFedtc to Ni(II) or Pd(II) decreases the in vitro trypanocidal activity while the cytotoxicity against LLC-MK2 cells does not change significantly. [PdII(Fedtc)2] showed the greater potential between the two complexes studied, showing an SI value of 8.9. However, this value is not better than that of the free ligand with an SI of 40, a similar value to that of the standard drug benznidazole (SI = 48). Additionally, molecular docking simulations were performed with Trypanosoma cruzi Old Yellow Enzyme (TcOYE), which predicted that HFedtc binds to the protein, almost parallel to the flavin mononucleotide (FMN) prosthetic group, while the [NiII(Fedtc)2] complex was docked into the enzyme binding site in a significantly different manner. In order to confirm the hypothetical interaction, in vitro experiments of fluorescence quenching and enzymatic activity were performed which indicated that, although HFedtc was not processed by the enzyme, it was able to act as a competitive inhibitor, blocking the hydride transfer from the FMN prosthetic group of the enzyme to the menadione substrate.

Asunto(s)

Compuestos de Bencilo/farmacología , Complejos de Coordinación/farmacología , Inhibidores Enzimáticos/farmacología , Hidrazinas/farmacología , Metalocenos/farmacología , NADPH Deshidrogenasa/antagonistas & inhibidores , Níquel/farmacología , Paladio/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Hidrazinas/química , Macaca mulatta , Metalocenos/química , Simulación del Acoplamiento Molecular , Estructura Molecular , NADPH Deshidrogenasa/química , NADPH Deshidrogenasa/metabolismo , Níquel/química , Níquel/metabolismo , Paladio/química , Paladio/metabolismo , Relación Estructura-Actividad , Tripanocidas/química , Tripanocidas/metabolismo , Trypanosoma cruzi/metabolismo

RESUMEN

The Golgi complex is part of the endomembrane system and is responsible for receiving transport cargos from the endoplasmic reticulum and for sorting and targeting them to their final destination. To perform its function in higher eukaryotic cells, the Golgi needs to be correctly assembled as a flattened membrane sandwich kept together by a protein matrix. The precise mechanism controlling the Golgi cisternae assembly is not yet known, but it is widely accepted that the Golgi Reassembly and Stacking Protein (GRASP) is a main component of the Golgi protein matrix. Unlike mammalian cells, which have two GRASP genes, lower eukaryotes present only one gene and distinct Golgi cisternae assembly. In this study, we performed a set of biophysical studies to get insights on the structural properties of the GRASP domains (DGRASPs) from both human GRASP55 and GRASP65 and compare them with GRASP domains from lower eukaryotes (Saccharomyces cerevisiae and Cryptococcus neoformans). Our data suggest that both human DGRASPs are essentially different from each other and that DGRASP65 is more similar to the subgroup of DGRASPs from lower eukaryotes in terms of its biophysical properties. GRASP55 is present mainly in the Golgi medial and trans faces, which are absent in both fungi, while GRASP65 is located in the cis-Golgi. We suggest that the GRASP65 gene is more ancient and that its paralogue GRASP55 might have appeared later in evolution, together with the medial and trans Golgi faces in mammalians.

Asunto(s)

Proteínas Fúngicas/química , Proteínas de la Matriz de Golgi/química , Homología Estructural de Proteína , Cryptococcus neoformans , Evolución Molecular , Proteínas Fúngicas/genética , Proteínas de la Matriz de Golgi/genética , Proteínas de la Matriz de Golgi/metabolismo , Saccharomyces cerevisiae

RESUMEN

New complexes of composition [MX(HL1)] (M = PtII, PdII, X = Cl- or I-) and [MX(L1)] (M = AuIII, X = Cl-; M = PtII, PdII, X = PPh3) have been synthesized using a potentially tridentate thiosemicarbazone (H2L1) containing an additional oxime binding site. Among other analytical methods, all the seven complexes have been structurally characterized by single crystal X-ray diffractometry. Interesting structural features such as the influence of the halide ligands on hydrogen bonds and the formation of supramolecular structures for the phosphine derivatives are discussed. The in vitro trypanocidal activity of the free ligand H2L1 and its derivatives against both extracellular trypomastigote and intracellular amastigote (IC50try/ama) forms of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity was assessed on LLC-MK2 cell line. The results showed that complexation of the thiosemicarbazone ligand H2L1 to PtII, PdII and AuIII metal centers enhances the in vitro trypanocidal activity and that the cytotoxicity is dependent on both the metal center and coligands. Within the studied series, the AuIII complex showed the greatest potential, being not the most active but the most selective compound with a similar selectivity index to that of the standard drug benznidazole. In order to get a preliminary insight into the mechanism of action of these compounds, in vitro experiments of fluorescence quenching and enzymatic activity were performed using the AuIII complex and Trypanosoma cruzi Old Yellow Enzyme (TcOYE) which indicated that the gold derivative was capable of abstracting the hydride from the prosthetic FMN group of the enzyme. Additionally, molecular docking studies followed by semiempirical simulations showed that the [AuCl(L1)] binds to the binary complex TcOYE/FMN, almost parallel to the FMN prosthetic group, in a close distance that an electron/proton transfer might occur among them.

Asunto(s)

Compuestos Organometálicos/farmacología , Oximas/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Oro/química , Oro/farmacología , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Oximas/química , Paladio/química , Paladio/farmacología , Pruebas de Sensibilidad Parasitaria , Platino (Metal)/química , Platino (Metal)/farmacología , Relación Estructura-Actividad , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química

RESUMEN

Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn(II)) thiosemicarbazone complexes [Zn(atc-Et)2] (1) and [Zn(atc-Ph)2] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research.

Asunto(s)

Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacocinética , Zinc/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Artemia , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HeLa , Células Hep G2 , Humanos , Técnicas In Vitro , Ratones , Estructura Molecular , Tiosemicarbazonas/administración & dosificación , Tiosemicarbazonas/química , Pruebas de Toxicidad Aguda

RESUMEN

Tridentate thiosemicarbazone ligands with an ONS donor set, H2L(R) (R = Me and Et) were prepared by reactions of 1-phenyl-1,3-butanedione with 4-R-3-thiosemicarbazides. H2L(R) reacts with Na[AuCl4]·2H2O in MeOH in a 1:1 M ratio under formation of green gold(III) complexes of composition [AuCl(L(R))]. These compounds represent the first examples of gold(III) complexes with ONS chelate-bonded thiosemicarbazones. The in vitro anti-Trypanosoma cruzi activity against both trypomastigote and amastigote forms (IC50try/ama) of CL Brener strains as well as the cytotoxicity against LLC-MK2 cells of the free ligands and complexes was evaluated. The complex [AuCl(L(Me))] was found to be more active and more selective than its precursor ligand and the standard drug benznidazole with a SItry/ama value higher than 200, being considered as a lead candidate for Chagas disease treatment. Moreover the in vitro activity against the replicative amastigote form (IC50ama) of T. cruzi was additionally investigated revealing that [AuCl(L(Me))] was also more potent than benznidazole still with a similar selectivity index. Finally, docking studies showed that free ligands and complexes interact with the same residues of the parasite protease cruzain but with different intensities, suggesting that this protease could be a possible target for the trypanocidal action of the obtained compounds.

Asunto(s)

Complejos de Coordinación/farmacología , Oro/química , Tiosemicarbazonas/farmacología , Tripanocidas/química , Animales , Enfermedad de Chagas/tratamiento farmacológico , Complejos de Coordinación/química , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tiosemicarbazonas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos

RESUMEN

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.

Asunto(s)

Antibacterianos/química , Antibacterianos/farmacología , Manganeso/química , Mycobacterium tuberculosis/efectos de los fármacos , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Animales , Chlorocebus aethiops , Cristalografía por Rayos X , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Células Vero

RESUMEN

The thermo-solvatochromism of 2,6-dibromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr(2), has been studied in mixtures of water, W, with ionic liquids, ILs, in the temperature range of 10 to 60 degrees C, where feasible. The objectives of the study were to test the applicability of a recently introduced solvation model, and to assess the relative importance of solute-solvent solvophobic interactions. The ILs were 1-allyl-3-alkylimidazolium chlorides, where the alkyl groups are methyl, 1-butyl, and 1-hexyl, respectively. The equilibrium constants for the interaction of W and the ILs were calculated from density data; they were found to be linearly dependent on N(C), the number of carbon atoms of the alkyl group; van't Hoff equation (log K versus 1/T) applied satisfactorily. Plots of the empirical solvent polarities, E(T) (MePMBr(2)) in kcal mol(-1), versus the mole fraction of water in the binary mixture, chi(w), showed non-linear, i.e., non-ideal behavior. The dependence of E(T) (MePMBr(2)) on chi(w), has been conveniently quantified in terms of solvation by W, IL, and the "complex" solvent IL-W. The non-ideal behavior is due to preferential solvation by the IL and, more efficiently, by IL-W. The deviation from linearity increases as a function of increasing N(C) of the IL, and is stronger than that observed for solvation of MePMBr(2) by aqueous 1-propanol, a solvent whose lipophilicity is 12.8 to 52.1 times larger than those of the ILs investigated. The dependence on N(C) is attributed to solute-solvent solvophobic interactions, whose relative contribution to solvation are presumably greater than that in mixtures of water and 1-propanol.