Gold(I) and Silver(I) Complexes Containing Hybrid Sulfonamide/Thiourea Ligands as Potential Leishmanicidal Agents.

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from MI metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HLR) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with AgI and AuI, leading to the formation of complexes of composition [M(HLR)2]X (M = Ag or Au; X = NO3- or Cl-). All compounds were characterized by FTIR, 1H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets.

Effect of essential oil of Alpinia zerumbet on cardiovascular and autonomic function in rats with isoproterenol induced acute myocardial infarction.

Alpinia zerumbet is a plant popularly used to treat hypertension and anxiety. Studies with Alpinia zerumbet demonstrate antihypertensive and vasodilator effects, among others. The objective of this study was to analyze the effect of essential oil of Alpinia zerumbet (EOAz) on cardiovascular and autonomic function in rats with isoproterenol-induced myocardial infarction. Male Wistar rats (n=32) were equally allocated into four groups: Control, ISO (150mg/kg, subcutaneous), EOAz (100mg/kg by gavage), ISO+EOAz. The rats were evaluated for cardiovascular and, autonomic parameters, electrocardiogram, and infarct size. EOAz was not able to reduce the electrocardiographic variations induced by ISO. Heart rate variability showed a decrease in sympathetic modulation on the heart in the groups treated with EOAz. The cardiopulmonary reflex induced by serotonin invoked a superior blood pressure variation at the 2 µg/kg dose in the EOAz treated groups, while the heart rate variation was significantly higher at the 16 µg/kg dose, when compared to other doses, in all groups, except EOAz+ISO. The sympathetic vagal index was higher in ISO group than in control. EOAz did not reduce the infarct size. We conclude that pretreatment with EOAz does not reverse the hemodynamic and electrocardiographic damage caused by isoproterenol but does reduce sympathetic modulation.

New ruthenium(II) complexes with cyclic thio- and semicarbazone: evaluation of cytotoxicity and effects on cell migration and apoptosis of lung cancer cells.

We describe the synthesis, physicochemical characterization, and in vitro antitumor assays of four novel analogous ruthenium(II) complexes with general formula cis-[RuII(N-L)(P-P)2]PF6, where P-P = bis(diphenylphosphine)methane (dppm, in complexes 1 and 2) or bis(diphenylphosphine)ethane (dppe, in complexes 3 and 4) and N-L = 5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (Btsc, in complexes 1 and 3) or 5,6-diphenyltriazine-3-one (Bsc, in complexes 2 and 4). The data were consistent with cis arrangement of the biphosphine ligands. For the Btsc and Bsc ligands, the data pointed to monoanionic bidentate coordination to ruthenium(II) through N,S and N,O, respectively. Single-crystal X-ray diffraction showed that complex 1 crystallized in the monoclinic system, space group P21/c. Determination of the cytotoxicity profiles of complexes 1-4 gave SI values ranging from 1.19 to 3.50 against the human lung adenocarcinoma cell line A549 and the non-tumor lung cell line MRC-5. Although the molecular docking studies suggested that the interaction between DNA and complex 4 was energetically favorable, the experimental results showed that they interacted weakly. Overall, our results demonstrated that these novel ruthenium(II) complexes have interesting in vitro antitumor potential and this study may contribute to further studies in medicinal inorganic chemistry.

Electrocatalytic properties of a novel ruthenium(II) terpyridine-based complex towards CO2 reduction.

The electrocatalytic properties of Ru complexes are of great technological interest given their potential application in reactions such water splitting and CO2 reduction. In this work, a novel terpyridine-based Ru(II) complex, [RuCl(trpy)(acpy)], trpy = 2,2':6',2''-terpyridine, acpy- = 2-pyridylacetate was synthesized and its spectroscopic, electrochemical and catalytic properties were explored in detail. In dry acetonitrile, the complex exhibits two reduction peaks at -1.95 V and -2.20 V vs. Fc/Fc+, attributed to consecutive 1 e- reduction. Under CO2 atmosphere, a catalytic wave is observed (Eonset = 2.1 V vs. Fc/Fc+), with CO as the main reduction product. Bulk electrolysis reveals a turnover number (TON) of 12 (kobs = 1.5 s-1). In the presence of 1% water, an improvement in the catalytic activity is observed (TONCO = 21 and kobs = 2.0 s-1) and, additionally, formate was also detected (TONHCOO = 7). Spectroelectrochemical experiments allowed the identification of a metallocarboxylate (Ru-COO-) intermediate under anhydrous conditions, while in water, the partial labilization of the acpy- ligand was observed in the course of the catalytic cycle. The experimental data was combined with DFT calculations, allowing the proposal of a catalytic cycle. The results establish important relationships between selectivity, ligand structure and reaction conditions.

Gallium and indium complexes with isoniazid-derived ligands: Interaction with biomolecules and biological activity against cancer cells and Mycobacterium tuberculosis.

Gallium and indium octahedral complexes with isoniazid derivative ligands were successfully prepared. The ligands, isonicotinoyl benzoylacetone (H2L1) and 4-chlorobenzoylacetone isonicotinoyl hydrazone (H2L2), and their respective coordination compounds with gallium and indium [GaL1(HL1)] (GaL1), [GaL2(HL2)] (GaL2), [InL1(HL1)] (InL1) and [InL2(HL2)] (InL2) were investigated by NMR, ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction and elemental analysis. In vitro interaction studies with human serum albumin (HSA) evidenced a moderate affinity of all complexes with HSA through spontaneous hydrophobic interactions. The greatest suppression of HSA fluorescence was caused by GaL2 and InL2, which was associated to the higher lipophilicity of H2L2. In vitro interaction studies with CT-DNA indicated weak interactions of the biomolecule with all complexes. Cytotoxicity assays with MCF-7 (breast carcinoma), PC-3 (prostate carcinoma) and RWPE-1 (healthy human prostate epithelial) cell lines showed that complexes with H2L2 are more active and selective against MCF-7, with the greatest cytotoxicity observed for InL2 (IC50 = 10.34 ± 1.69 µM). H2L1 and H2L2 were labelled with gallium-67, and it was verified that 67GaL2 has a greater lipophilicity than 67GaL1, as well as higher stability in human serum or in the presence of apo-transferrin. Cellular uptake assays with 67GaL1 and 67GaL2 evidenced that the H2L2-containing radiocomplex has a higher accumulation in MCF-7 and PC-3 cells than the non-halogenated congener 67GaL1. The anti-Mycobacterium tuberculosis assays revealed that both ligands and metal complexes are potent growth inhibitors, with MIC90 (µg mL-1) values observed from 0.419 ± 0.05 to 1.378 ± 0.21.

Are there synergies in the decarbonization of aviation and shipping? An integrated perspective for the case of Brazil.

Aviation and shipping account for 22% of total transport-related CO2 emissions. Low-carbon fuels (such as biofuels and e-fuels) are the most promising alternatives to deeply decarbonize air and maritime transport. A number of technological routes focused on the production of renewable jet fuel can coproduce marine fuels, emulating the economies of scope of crude oil refineries. This work aims to investigate possible synergies in the decarbonization of aviation and shipping in Brazil, selected as an interesting case study. An Integrated Assessment Model (IAM) of national scope is used to explore different combinations of sectoral and national climate targets. This IAM represents not only the energy supply and transport systems but also the agricultural and land-use systems. In the absence of a deep mitigation policy for Brazil, results indicate synergies related to oilseed- and lignocellulosic-based biofuels production routes. Imposing a strict carbon budget to the Brazilian economy compatible with a world well below 2°C, the portfolio of aviation and shipping fuels changes significantly with the need for carbon dioxide removal strategies based on bioenergy. In such a scenario, synergies between the two sectors still exist, but most renewable marine energy supply is a by-product of synthetic diesel produced for road transport, revealing a synergy different from the one originally investigated by this work.

Latent Tuberculosis: A Promising New Compound to Treat Non-Replicating and Intramacrophagic Mycobacteria.

As a biologic reservoir of Mycobacterium tuberculosis (M. tb), one-quarter of the world population is infected with the well-known latent tuberculosis (LTBI). About 5-10% of LTBI patients will progress to active disease in the first years after primary infection and, despite using the recommended treatment, 20% can still reactivate the infection. A new LTBI treatment could minimize adverse effects and antibiotic resistance that can occur when the same drug is used to treat the latent and active disease. New hydrazones were evaluated, and they showed great inhibitory activity against intramacrophagic and non-replicating M. tb, commonly found at this stage of infection, in addition to bactericidal and narrow-spectrum activity. When tested against eukaryotic cells, the hydrazones showed great safety at different exposure times. In vitro, these compounds performed better than isoniazid and could be considered new candidates for LTBI treatment, which may promote greater engagement in its prescription and adherence.

Zinc(II) complexes bearing N,N,S ligands: Synthesis, crystal structure, spectroscopic analysis, molecular docking and biological investigations about its antifungal activity.

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.

Mechanistic investigation of the aerobic oxidation of 2-pyridylacetate coordinated to a Ru(II) polypyridyl complex.

A new ruthenium polypyridyl complex, [Ru(bpy)2(acpy)]+ (acpy = 2-pyridylacetate, bpy = 2,2'-bipyridine), was synthesized and fully characterized. Distinct from the previously reported analog, [Ru(bpy)2(pic)]+ (pic = 2-pyridylcarboxylate), the new complex is unstable under aerobic conditions and undergoes oxidation to yield the corresponding α-keto-2-pyridyl-acetate (acpyoxi) coordinated to the RuII center. The reaction is one of the few examples of C-H activation at mild conditions using O2 as the primary oxidant and can provide mechanistic insights with important implications for catalysis. Theoretical and experimental investigations of this aerobic oxidative transformation indicate that it takes place in two steps, first producing the α-hydroxo-2-pyridyl-acetate analog and then the final product. The observed rate constant for the first oxidation was in the order of 10-2 h-1. The reaction is hindered in the presence of coordinating solvents indicating the role of the metal center in the process. Theoretical calculations at the M06-L level of theory were performed for multiple reaction pathways in order to gain insights into the most probable mechanism. Our results indicate that O2 binding to [Ru(bpy)2(acpy)]+ is favored by the relative instability of the six-ring chelate formed by the acpy ligand and the resulting RuIII-OO˙- superoxo is stabilized by the carboxylate group in the coordination sphere. C-H activation by this species involves high activation free energies (ΔG‡ = 41.1 kcal mol-1), thus the formation of a diruthenium µ-peroxo intermediate, [(RuIII(bpy)2(O-acpy))2O2]2+via interaction of a second [Ru(bpy)2(acpy)]+ was examined as an alternative pathway. The dimer yields two RuIVO centers with a low ΔG‡ of 2.3 kcal mol-1. The resulting RuIVO species can activate C-H bonds in acpy (ΔG‡ = 23.1 kcal mol-1) to produce the coordinated α-hydroxo-2-pyridylacetate. Further oxidation of this intermediate leads to the α-keto-2-pyridyl-acetate product. The findings provide new insights into the mechanism of C-H activation catalyzed by transition-metal complexes using O2 as the sole oxygen source.

Copper(II) complexes based on thiosemicarbazone ligand: Preparation, crystal structure, Hirshfeld surface, energy framework, antiMycobacterium activity, in silico and molecular docking studies.

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.

Gold(III) complexes with thiosemicarbazonate ligands as potential anticancer agents: Cytotoxicity and interactions with biomolecular targets.

Gold(III) complexes have been studied for the past years due to their anticancer properties and great affinity to biotargets, such as enzymes and proteins, which support their pharmacological applications. Within this scope, in this work the antiproliferative activities of two Au(III)-thiosemicarbazonate complexes, [AuClL1] (1, L1: (E,Z)-N-ethyl-N'-(3-nitroso-kN)butan-2-ylidene)carbamohydrazonothioato-k2N2,S) and [Au(Hdamp)L2]Cl (2, L2: N-(N'',N''-diethylaminothiocarbonyl)-N'(N''', N'''-dimethylcarbothioamide)benzamidineto-kN,k2S and Hdamp: 2-(N,N-dimethylaminomethyl)-phenyl-C1), and their affinities to possible biological targets were investigated. Three different tumor cell lines were used to perform the cytotoxicity assays, including one cisplatin-resistant model, and the results showed lower EC50 for 1 over 2 in every case: B16F10 (4.1 µM and 15.6 µM), A431 (4.0 µM and >50 µM) and OVCAR3 (4.2 µM and 24.5 µM). However, a lower toxicity to fibroblast 3T3 cell line was observed for 2 (30.58 µM) when compared to 1 (7.17 µM), resulting in comparable therapeutic indexes. Both complexes presented strong affinity to HSA: they distorted the secondary structure of the protein, as verified by circular dichroism, but 1 additionally presented the apparent fluorescence quenching constant (Kapp) ten times greater than 2, which was probably due to the fact of 1 being able to denature HSA. The ethidium bromide displacement assay showed that neither 1 nor 2 are strong DNA intercalators, which is in agreement with what was observed through the UV-vis titration. In both cases, the 260 nm band presented hyperchromism, which can indicate ionic interactions or DNA damage. In fact, 1 was able to damage the pGEM plasmid, similarly to cisplatin, as verified by agarose gel electrophoresis and Atomic Force Microscopy. Biophysical studies in cancer cells model membranes were also performed in order to investigate the interaction of the gold complexes to lipid bilayers and revealed that the compounds interact with the membranes by exhibiting partition coefficients of 103 order of magnitude. Overall, both complexes were found to be promising candidates for the development of a future anticancer drug against low sensitive or cisplatin resistant tumors.

Intramolecular C(sp2)-C (sp2) bond formation between phenanthroline and ß-diketone thiosemicarbazones in PtII complexes: crystal structures and computational studies.

[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.

Spectroscopic characterization of a new Re(I) tricarbonyl complex with a thiosemicarbazone derivative: towards sensing and electrocatalytic applications.

This work describes the preparation of a new thiosemicarbazone derivative, (Z)-N-ethyl-2-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)hydrazinecarbothioamide (phet) and its respective Re(i) tricarbonyl chloro complex, fac-[ReCl(CO)3(phet)]. The spectroscopic, photophysical and electrochemical properties of the new complex were fully investigated through steady state and time-resolved techniques along with computational calculations. In fac-[ReCl(CO)3(phet)], the new ligand is coordinated to the metal center through the pyridyl rings of the phenanthroline moiety. The unbound electron pairs in the S atom of the bending thiosemicarbazone group induce new low energy lying electronic transitions. Consequently, enhanced visible light absorption up to 550 nm is observed in acetonitrile due to the overlap between MLCTRe→phet and ILphet(n→π*) transitions. The absorption bands and emission quantum yields of fac-[ReCl(CO)3(phet)] are sensitive to proton concentration due to an acid-basic equilibrium in the N atoms of the thiosemicarbazone. Proton dissociation constants of 10.0 ± 0.1 and 11.4 ± 0.2 were determined respectively for the ground and excited states of the new complex. Spectral changes could also be observed in the presence of Zn2+ cations which can be further explored for sensing applications. The electrochemical behavior of the new complex was studied in detail, revealing up to four one electron reduction processes in the range from 0 to -2.4 V vs. Fc+/Fc. With support of DFT calculations, the first three processes are ascribed to the reduction of the coordinated phet ligand followed by the ReI/0 reduction and consequent Cl- release. The new complex was able to act as an electrocatalyst for CO2 reduction into CO (Eonset = -1.92 V vs. Fc+/Fc), with a turnover frequency of 2.81 s-1 and turnover number of 24 ± 1 in anhydrous acetonitrile, being the first Re(i) tricarbonyl complex with a thiosemicarbazone derivative described for this goal. The detailed characterization carried out here can drive the development of new Re(i)-thiosemicarbazone derivatives for different applications.

Palladium(ii) complexes with thiosemicarbazones derived from pyrene as topoisomerase IB inhibitors.

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.

Forecasting dengue fever in Brazil: An assessment of climate conditions.

Local climate conditions play a major role in the biology of the Aedes aegypti mosquito, the main vector responsible for transmitting dengue, zika, chikungunya and yellow fever in urban centers. For this reason, a detailed assessment of periods in which changes in climate conditions affect the number of human cases may improve the timing of vector-control efforts. In this work, we develop new machine-learning algorithms to analyze climate time series and their connection to the occurrence of dengue epidemic years for seven Brazilian state capitals. Our method explores the impact of two key variables-frequency of precipitation and average temperature-during a wide range of time windows in the annual cycle. Our results indicate that each Brazilian state capital considered has its own climate signatures that correlate with the overall number of human dengue-cases. However, for most of the studied cities, the winter preceding an epidemic year shows a strong predictive power. Understanding such climate contributions to the vector's biology could lead to more accurate prediction models and early warning systems.

Organometallic Gold(III) Complex [Au(Hdamp)(L14)]+ (L1 = SNS-Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease.

Chagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs against Trypanosoma cruzi, we evaluated both the in vitro and in vivo activity of the organometallic gold(III) complex [Au(III)(Hdamp)(L14)]Cl (L1 = SNS-donating thiosemicarbazone), henceforth denoted 4-Cl. Our results demonstrated that 4-Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In in vivo assays, 4-Cl in PBS solution loses the protonation and becomes the 4-neutral. 4-Neutral reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage at 2.8 mg/kg/day. All these changes resulted in the survival of 100% of the mice treated with the gold complex during the acute phase. Analyzing the surviving animals of the acute infection, the parasite load after 150 days of infection was equivalent to those treated with the standard dose of Bz without demonstrating the hepatotoxicity of the latter. In addition, we identified a modulation of interferon gamma (IFN-γ) levels that may be targeting the disease's positive outcome. To the best of our knowledge, this is the first gold organometallic study that shows promise in an in vivo experimental model against Chagas disease.

Heterobimetallic nickel(II) and palladium(II) complexes derived from S-benzyl-N- (ferrocenyl)methylenedithiocarbazate: Trypanocidal activity and interaction with Trypanosoma cruzi Old Yellow Enzyme (TcOYE).

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.

PtII, PdII and AuIII complexes with a thiosemicarbazone derived from diacethylmonooxime: Structural analysis, trypanocidal activity, cytotoxicity and first insight into the antiparasitic mechanism of action.

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.

Anti-Leishmania activity of new ruthenium(II) complexes: Effect on parasite-host interaction.

Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania. The many complications presented by the current treatment - including high toxicity, high cost and parasite resistance - make the development of new therapeutic agents indispensable. The present study aims to evaluate the anti-Leishmania potential of new ruthenium(II) complexes, cis­[RuII(η2-O2CR)(dppm)2]PF6, with dppm=bis(diphenylphosphino)methane and R=4-butylbenzoate (bbato) 1, 4-(methylthio)benzoate (mtbato) 2 and 3-hydroxy-4-methoxybenzoate (hmxbato) 3, in promastigote cytotoxicity and their effect on parasite-host interaction. The cytotoxicity of complexes was analyzed by MTT assay against Leishmania (Leishmania) amazonensis, Leishmania (Viannia) braziliensis, Leishmania (Leishmania) infantum promastigotes and the murine macrophage (RAW 264.7). The effect of complexes on parasite-host interaction was evaluated by in vitro infectivity assay performed in the presence of two different concentrations of each complex: the promastigote IC50 value and the concentration nontoxic to 90% of RAW 264.7 macrophages. Complexes 1-3 exhibited potent cytotoxic activity against all Leishmania species assayed. The IC50 values ranged from 7.52-12.59µM (complex 1); 0.70-3.28µM (complex 2) and 0.52-1.75µM (complex 3). All complexes significantly inhibited the infectivity index at both tested concentrations. The infectivity inhibitions ranged from 37 to 85%. Interestingly, the infectivity inhibitions due to complex action did not differ significantly at either of the tested concentrations, except for the complex 1 against Leishmania (Leishmania) infantum. The infectivity inhibitions resulted from reductions in both percentage of infected macrophages and number of parasites per macrophage. Taken together the results suggest remarkable leishmanicidal activity in vitro by these new ruthenium(II) complexes.