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The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role, however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.

The synthesis, photoactivation and biological activity of a new piano-stool Ru(II) complex is herein reported. The peculiarity of this complex is that its monodentate ligand which undergoes the photodissociation is an asymmetric bis-thiocarbohydrazone ligand that possesses a pyridine moiety binding to Ru(II) and the other moiety contains a quinoline that endows the ligand with the capacity of chelating other metal ions. In this way, upon dissociation, the ligand can be released in the form of a metal complex. In this article, the double ability of this new Ru(II) complex to photorelease the ligand and to chelate copper and nickel is explored and confirmed. The biological activity of this compound is studied in cell line A549 revealing that, after irradiation, proliferation inhibition is reached at very low half maximal inhibitory concentration (IC50) values. Further, biological assays reveal that the dinuclear complex containing Ni is internalized in cells.

Great are the expectations for a new generation of antimicrobials, and strenuous are the research efforts towards the exploration of diverse molecular scaffolds—possibly of natural origin – aimed at the synthesis of new compounds against the spread of hazardous fungi. Also high but winding are the paths leading to the definition of biological targets specifically fitting the drug’s structural characteristics. The present study is addressed to inspect differential biological behaviours of cinnamaldehyde and benzaldehyde thiosemicarbazone scaffolds, exploiting the secondary metabolism of the mycotoxigenic phytopathogen Aspergillus flavus. Interestingly, owing to modifications on the parent chemical scaffold, some thiosemicarbazones displayed an increased specificity against one or more developmental processes (conidia germination, aflatoxin biosynthesis, sclerotia production) of A. flavus biology. Through the comparative analysis of results, the ligand-based screening strategy here described has allowed us to delineate which modifications are more promising for distinct purposes: from the control of mycotoxins contamination in food and feed commodities, to the environmental management of microbial pathogens, to the investigation of specific structure–activity features for new generation drug discovery.

Background: In recent decades, there has been an increase in male infertility, and in many cases, the etiology remains unclear. Several studies relate male hypo-fertility to xenobiotic exposure, even if no data exist about multiple exposure at the environmental level. Methods: The study involved 86 males with diagnosis of idiopathic male infertility (IMI), and 46 controls with no alteration in sperm characteristics. Seminal plasma (SP) and urine samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to quantify biomarkers of exposure (the main metabolites of benzene, toluene, 1,3-butadiene, 3-monochloropropanediol, styrene, and naphthol) and effect (oxidized products of nucleic acids).Results: Biomarker concentrations were similar in subjects with IMI and controls even if a stronger correlation between biomarkers of exposure and effects were observed in SP. Data show that, both in SP and urine, most metabolites were inter-correlated, indicating a simultaneous co-exposure to the selected substances at the environmental level. Principal component analysis showed in SP the clustering of mercapturic acids indicating a preferential metabolic pathway with Glutathione (GSH) depletion and, consequently, an increase of oxidative stress. This result was also confirmed by multivariable analysis through the development of explanatory models for oxidized products of nucleic acids. Conclusions: This study highlights how oxidative stress on the male reproductive tract can be associated with a different representation of metabolic pathways making the reproductive tract itself a target organ for different environmental pollutants. Our results demonstrate that SP is a suitable matrix to assess the exposure and evaluate the effects of reproductive toxicants in environmental/occupational medicine. The statistical approach proposed in this work represents a model appropriate to study the relationship between multiple exposure and effect, applicable even to a wider variety of chemicals.

The possibility to influence the physiological concentration of copper ions through the careful choice of ligands is emerging as a novel intriguing strategy in the treatment of pathologies such as cancer and Alzheimer. Thiosemicarbazones play an important role in this field, because they offer a wide variety of potential functionalizations and different kinds of coordination modes. Here we report the synthesis of some 8-hydroxyquinoline thiosemicarbazone ligands containing an ONN'S donor set and their Zn(II) and Cu(II) complexes. The metal complexes were characterized in solution and in the solid state and the X-ray structure of one of the copper(II) complex is reported. The Cu(II) complexes were characterized also by means of quantum mechanical calculations. The Cu(II) complexes displayed cytostatic activity in different cancer cell models. In particular, the most active Cu(II) complex significantly inhibited cell proliferation with an IC50 value lower than 1 μM; this effect was associated with a block of the cell cycle in the G2/M phase. This Cu(II) complex induced neither the production of reactive oxygen species (ROS) nor the accumulation of p53 protein, suggesting the lack of DNA damage.

Nanoparticles are widely studied for applications in medical science. In recent years, they have been developed for agronomical purposes to target microbial pest such as bacteria, fungi, and viruses. Nanoparticles are also proposed to limit the use of pesticides, whose abuse is causing environmental impact and human health concerns. In this study, nanoparticles were obtained by using poly-(e-caprolactone), a polyester chosen for its biocompatibility and biodegradability properties. Poly-(e-caprolactone) nanoparticles were formulated by using poly(vinyl alcohol) or Pluronic® F127 as non-ionic surfactants, and then loaded with benzophenone or valerophenone thiosemicarbazone, two compounds that inhibit aflatoxin production by Aspergillus flavus. The different types of nanoparticles were compared in terms of size, polydispersity index, morphology, and drug loading capacity. Finally, their effects were investigated on growth, development, and aflatoxin production in the aflatoxigenic species Aspergillus flavus, a ubiquitous contaminant of maize, cereal crops, and derived commodities. Aflatoxin production was inhibited to various extents, but the best inhibitory effect was obtained with respect to sclerotia production that was most effectively suppressed by both benzophenone and valerophenone thiosemicarbazone-loaded nanoparticles. These data support the idea that it is possible to use such nanoparticles as an alternate to pesticides for the control of mycotoxigenic sclerotia-forming fungi.

Metal complexes still represent promising pharmacological tools in the development of new anticancer drugs. Bis(citronellalthiosemicarbazonate)nickel(ii) is a metal compound extremely effective against leukemic and NCS cancer cell lines. Preliminary experiments performed with this compound and with its Cu(ii) and Pt(ii) analogues evidenced alterations, detectable by comet assay, in the DNA of treated U937 cells. In addition, [Cu(tcitr)2] and [Pt(tcitr)2] were also able to induce gene mutations and produce frameshift events. To gain further insights into the mechanism of action of these metal compounds, we carried out a multidisciplinary study to investigate whether their biological activity can be ascribed to the direct interaction with DNA or with chromatin. The DNA interaction was investigated by means of CD and UV-Vis spectroscopic techniques and by AFM, whereas the chromatin interaction was studied by analyzing the effects of the compounds on the structure of a peptide that mimicks the potential metal binding site in the “C-tail” region of histone H2A by means of NMR, CD, UV-Vis and MS. The intensities of the effects induced by the metal compounds on the peptide follow the order [Ni(tcitr)2] > [Pt(tcitr)2] ≫ [Cu(tcitr)2]. From the AFM data, a remarkable DNA compaction was observed in the presence of [Pt(tcitr)2], while [Ni(tcitr)2] causes the formation of large interlaced DNA aggregates.

The development of microbial antibiotic resistance has become one of the biggest threats to global health and the search for new molecules active against resistant pathogenic strains is a challenge that must be tackled. In many cases nosocomial infections are caused by bacteria characterized by multi-drug resistance patterns and by their ability to produce biofilms. These properties lead to the persistence of pathogens in the hospital environment. This paper reports the synthesis and characterization of three thiosemicarbazone derivatives based on a compound containing the cinnamaldehyde natural scaffold but possessing different logPow values. These molecules are then used as ligands to prepare complexes of the Cu(II) and Zn(II) ions. All these compounds, ligands and complexes, were screened in vitro on stains of Escherichia coli and Klebsiella pneumoniae for their antibacterial activity. Despite their molecular similarity they revealed variegated behaviors. Only two of them present interesting antimicrobial properties and have also been studied to verify their stability in solution. The compound with the lowest partition coefficient is the most promising. The minimal bactericidal concentration on K. pneumoniae and E. coli of these substances are very interesting and demonstrate that the use of metalloantibiotics is a promising device to fight antibiotic resistance.

A comparative study between two bisthiosemicarbazones, 2,3-butanedione bis(4,4-dimethyl-3-thiosemicarbazone) and 2,3-butanedione bis(2-methyl-3-thiosemicarbazone), and their copper(ii) complexes is reported. The four compounds have been tested on a leukemia cell line U937 (p53-null) and on an adenocarcinoma cell line A549. The study includes cell viability, cell cycle, morphological changes, assessment of apoptosis, analysis of autophagy, measurement of reactive oxygen species (ROS) and of lipid peroxidation, protein determination, assessment of the expression of p53 and cellular uptake of metal complexes. Tests about the copper uptake under normoxic and hypoxic conditions were also carried out on a solid tumour cell line A549. The four compounds under study elicit different effects on the two lines adopted as representatives of p53 and p53-null cells. The role of the metal is relevant and it is likely that the metal-mediated oxidative stress plays an essential role in the whole process. The mechanisms induced by these molecules differ not only as a function of the cell line but also of dose. The responses include two distinct self-destructive processes, autophagy and apoptosis.

As key players in biotic stress response of plants, jasmonic acid (JA) and its derivatives cover a specific and prominent role in pathogens-mediated signaling and hence are promising candidates for a sustainable management of phytopathogenic fungi. Recently, JA directed antimicrobial effects on plant pathogens has been suggested, supporting the theory of oxylipins as double gamers in plant-pathogen interaction. Based on these premises, six derivatives (dihydrojasmone and cis-jasmone, two thiosemicarbazonic derivatives and their corresponding complexes with copper) have been evaluated against 13 fungal species affecting various economically important herbaceous and woody crops, such as cereals, grapes and horticultural crops: Phaeoacremonium minimum, Neofusicoccum parvum, Phaeomoniella chlamydospora, Fomitiporia mediterranea, Fusarium poae, F. culmorum, F. graminearum, F. oxysporum f. sp. lactucae,F. sporotrichioides, Aspergillus flavus, Rhizoctonia solani,Sclerotinia spp. and Verticillium dahliae. The biological activity of these compounds was assessed in terms of growth inhibition and, for the two mycotoxigenic species A. flavus and F. sporotrichioides, also in terms of toxin containment. As expected, the inhibitory effect of molecules greatly varied amongst both genera and species, cis-jasmone thiosemicarbazone in particular has shown the wider range of effectiveness. However, our results show that thiosemicarbazones derivatives are more effective than the parent ketones in limiting fungal growth and mycotoxins production, supporting possible applications for the control of pathogenic fungi.

The asymmetric synthesis of a set of hydroxyphenyl γ-valerolactones was achieved starting from 2-silyloxyfuran and alkoxy-substituted benzaldehydes as common precursors. Key synthesis steps included an enantioselective vinylogous Mukaiyama aldol reaction and a Barton–McCombie deoxygenation. Five enantioenriched γ-valerolactone targets were obtained in 5–6 steps, 18–63% overall yields and 82–98 % ee, paving the way for the straightforward entry to this class of biologically effective and poorly available flavan-3-ol metabolites. In parallel, an unprecedented one-pot reductive ring expansion process was fortuitously discovered, yielding racemic δ-lactone analogues from phenolic butanolide precursors.

In this paper, we report the syntheses, characterization and studies on the inhibition efficiency in mild steel acidic corrosion of 4-fluorobenzaldehyde thiosemicarbazone, Hfbt, 4-fluorobenzaldehyde 2-methylthiosemicarbazone, Me-fbt, and their Zn(II) complexes [Zn(fbt)2] and [Zn(Me-fbt)2]Cl2. The ligands present a good degree of activity that can be assigned to their molecular planar shape and to the presence of electron lone pairs that can interact with metal orbitals. The two zinc complexes present diametrically opposite properties: [Zn(fbt)2] is by far less active than the ligands, while [Zn(Me-fbt)2]Cl2 is the most efficient. Quantum chemical studies were carried out in an attempt to rationalize this behaviour.

Two small series of Pt(IV) complexes of the general formula cis,cis,trans-[PtA2Cl2L2] (A = 2 × NH3, series 1, or cyclohexane-1R,2R-diamine, dach, series 2, L = aromatic carboxylate of different chain length, i.e. –OCO(CH2)nC6H5, n = 0 (a), 1 (b), and 2 (c)) were synthesized and fully characterized, including X-ray structure analysis of one of them. The antiproliferative activity of the complexes was evaluated against a panel of eight human cancer cell lines, proving to be at the nanomolar level for the platinum-sensitive A2780 and at the sub-micromolar level for the chemoresistant mesothelioma cell lines. In contrast with Pt(IV) complexes bearing aliphatic carboxylates, whose antiproliferative potency increases with the number of carbon atoms, a clear structure–activity relationship cannot be drawn in the bis(benzoato) series. The inclusion reaction with cyclodextrins (CDs), a widely accepted approach for drug formulation, was performed in order to obtain adducts able to bypass the limitations imposed by the low water solubility of bis(benzoato) complexes. Phase-solubility tests demonstrated that β-CD was able to efficiently solubilize only the very active prototype [Pt(NH3)2Cl2(C6H5COO)2] 1a. Two methods were used to prepare the host–guest inclusion systems (i.e., simple solubilization at room temperature of 1a in solution containing excess of β-CD or thermal reaction with subsequent isolation of a solid adduct) and the resulting adducts were tested for cytotoxicity against the cancer cell lines. The presence of β-CD in solution did not decrease the remarkable antitumor activity of 1a, whereas the solid-state inclusion system underwent extensive aggregation, proving to be detrimental for Pt accumulation in the cells and, therefore, overall cytotoxicity.

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable π-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated.

With a steadily increasing world population, a more efficient system of food production is of paramount importance. One of the major causes of food spoilage is the presence of fungal pathogens and the production and accumulation of mycotoxins. In the present work we report a study on the activity of a series of functionalized thiosemicarbazones (namely cuminaldehyde, trans -cinnamaldehyde, quinoline-2-carboxyaldehyde, 5-fluoroisatin thiosemicarbazone and 5-fluoroisatin N 4 -methylthiosemicarbazone), as antifungal and anti-mycotoxin agents, against the two major genera of cereal mycotoxigenic fungi, i.e. Fusarium and Aspergillus . These thiosemicarbazones display different patterns of efficacy on fungal growth and on mycotoxin accumulation depending on the fungal species. Some of the molecules display a greater effect on mycotoxin synthesis than on fungal growth.

In this paper, citronellal, vanillin and pyridoxal thiosemicarbazones were modified with polar substituents, namely ethylmorpholine and glucose, to increase their polarity and compare the effects of these moieties on their biological activity. Altogether, nine ligands were synthesized and for each of them also their copper(II) and nickel(II) complexes were prepared and used for the biological tests. Eventually, assays on proliferation inhibition were conducted using leukemic cell line U937, already used as a model for previous citronellal thiosemicarbazone tests. Biological tests were also performed on solid tumor cell line HT29. From the first screenings, two of the metal complexes showed remarkable interesting properties, and, therefore, were also tested for histosensitivity.

The issue of food contamination by aflatoxins presently constitutes a social emergency, since they represent a severe risk for human and animal health. On the other hand, the use of pesticides has to be contained, since this generates long term residues in food and in the environment. Here we present the synthesis of a series of chelating ligands based on the thiosemicarbazone scaffold, to be evaluated for their antifungal and antiaflatoxigenic effects. Starting from molecules of natural origin of known antifungal properties, we introduced the thio- group and then the corresponding copper complexes were synthesised. Some molecules highlighted aflatoxin inhibition in the range 67–92% at 100 μM. The most active compounds were evaluated for their cytotoxic effects on human cells. While all the copper complexes showed high cytotoxicity in the micromolar range, one of the ligand has no effect on cell proliferation. This hit was chosen for further analysis of mutagenicity and genotoxicity on bacteria, plants and human cells. Analysis of the data underlined the importance of the safety profile evaluation for hit compounds to be developed as crop-protective agents and at the same time that the thiosemicarbazone scaffold represents a good starting point for the development of aflatoxigenic inhibitors.

Aspergillus flavus is an opportunistic mold that represents a serious threat for human and animal health due to its ability to synthesize and release, on food and feed commodities, different toxic secondary metabolites. Among them, aflatoxin B1 is one of the most dangerous since it is provided with a strong cancerogenic and mutagenic activity. Controlling fungal contamination on the different crops that may host A. flavus is considered a priority by sanitary authorities of an increasing number of countries due also to the fact that, owing to global temperature increase, the geographic areas that are expected to be prone to experience sudden A. flavus outbreaks are widening. Among the different pre- and post-harvest strategies that may be put forward in order to prevent fungal and/or mycotoxin contamination, fungicides are still considered a prominent weapon. We have here analyzed different structural modifications of a natural-derived compound (cuminaldehyde thiosemicarbazone) for their fungistatic and anti-aflatoxigenic activity. In particular, we have focused our attention on one of the compound that presented a prominent anti-aflatoxin specificity, and performed a set of physiological and molecular analyses, taking also advantage of yeast (Saccharomyces cerevisiae) cell as an experimental model.

Polycyclic indole architectures, including carbazole and hydrocarbazole skeletons, represent privileged structural motifs found in a number of natural alkaloids, many of which displaying interesting activities against a diverse set of biological targets.[1] Accordingly, the search for efficient methods for the assembly of these structures has drawn a great deal of attention in the synthetic organic chemistry community.[2,3] An unprecedented technique for the in situ generation of indolyl ortho-quinodimethanes from 2-methylindole-based methylenemalononitriles 1 by amine-mediated remote C(sp3)-H deprotonation was developed. These intermediates were efficiently trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-carbazole-3-carboxyaldehyde structures 3 through a formal asymmetric [4+2] eliminative cycloaddition governed by a ?,?-diphenylprolinol trimethylsilyl ether catalyst.[4] A stepwise reaction mechanism of the formal catalytic asymmetric [4+2] cycloaddition of methylenemalononitrile 1a with enal 2a catalyzed by (S)-C1 is proposed. Parole chiave: asymmetric synthesis, cycloaddition heterocycles, organocatalysis, vinylogy Riferimenti: 1) A. G?uszynska, Eur. J. Med. Chem. 2015, 94, 405. 2) N. H. Krishna, A. P. Saraswati, M. Sathish, N. Shankaraiah, A. Kamal, Chem. Commun. 2016, 52, 4581. 3) Y. Li, F. Tur, R. P. Nielsen, H. Jiang, F. Jensen, K. A. Jørgensen, Angew. Chem. Int. Ed. 2016, 55, 1020; Angew. Chem. 2016, 128, 1032. 4) G. Rassu, C. Curti, V. Zambrano, L. Pinna, N. Brindani, G. Pelosi, and F. Zanardi, Chem. Eur. J. 2016, 22, 12637 - 12640 Ringraziamenti: Financial support provided by the Università degli Studi di Parma.

The gold standard for the treatment of metastatic colorectal cancer consists of combination chemotherapy. Over time, however, the development of chemoresistant tumor clones leads to relapse. It may be possible to overcome oxaliplatin chemoresistance in colorectal cancer cells by exploiting a complex obtained from the insertion of the cyclohexane-1R,2R-diamine carrier ligand (the same diamine present in oxaliplatin) into an octahedral Pt(IV) scaffold with high lipophilicity conferred by two benzoate axial ligands. Herein we report the synthesis, characterization (including X-ray structure), biological activity, and cellular accumulation of trans,cis,cis-bis(benzoato)dichlorido(cyclohexane-1R,2R-diamine)platinum(IV) complex in a panel of several human cancer cell lines, including a colon carcinoma cell line resistant to oxaliplatin. The compound under investigation shows the best performance in terms of in vitro anti-proliferative activity and ability to overcome chemoresistance, with respect to oxaliplatin and some other Pt(II) reference complexes. This result is likely related to the high lipophilicity shown by the title compound that favors its cellular accumulation by passive diffusion.

The first Lewis acid catalyzed vinylogous Mukaiyama-type Mannich addition of 3-alkenyl-2-silyloxyindoles to in situ generated N-Boc imines has been established, which affords chiral α-alkylidene-δ-amino-2-oxindole products with good efficiency and complete γ-site- and Z-selectivity. The reaction is wide in scope, as it can be applied with equal convenience to different silyloxyindole donors and aromatic or aliphatic aminal-derived aldimine acceptors. The utility of these scaffolds is demonstrated by their easy transformation into either spirocyclopropane oxindole or homotryptamine-like products, featuring nontraditional indole-based skeleton connections.

Aflatoxins represent a serious problem for a food economy based on cereal cultivations used to fodder animal and for human nutrition. The aims of our work are two-fold: first, to perform an evaluation of the activity of newly synthesized thiosemicarbazone compounds as antifungal and anti-mycotoxin agents and, second, to conduct studies on the toxic and genotoxic hazard potentials with a battery of tests with different endpoints. In this paper we report an initial study on two molecules: S-4-isopropenylcyclohexen-1-carbaldehydethiosemicarbazone and its metal complex, bis(S-4-isopropenylcyclohexen-1-carbaldehydethiosemicarbazonato)nickel (II). The outcome of the assays on fungi growth and aflatoxin production inhibition show that both molecules possess good antifungal activities, without inducing mutagenic effects on bacteria. From the assays to ascertain that the compounds have no adverse effects on human cells, we have found that they are cytotoxic and, in the case of the nickel compound, they also present genotoxic effects.

The asymmetric synthesis of a set of hydroxyphenyl γ-valerolactones was achieved starting from 2-silyloxyfuran and alkoxy-substituted benzaldehydes as common precursors. Key synthesis steps included an enantioselective vinylogous Mukaiyama aldol reaction and a Barton–McCombie deoxygenation. Five enantioenriched γ-valerolactone targets were obtained in 5–6 steps, 18–63% overall yields and 82–98 % ee, paving the way for the straightforward entry to this class of biologically effective and poorly available flavan-3-ol metabolites. In parallel, an unprecedented one-pot reductive ring expansion process was fortuitously discovered, yielding racemic δ-lactone analogues from phenolic butanolide precursors.

3-Alkylidene oxindoles (methyleneindolinones), be they natural or man-made substances, occupy a preeminent position among the various classes of chemically and medicinally relevant small-molecule scaffolds. Their plural functional architecture featuring a lactam carbonyl flanked by a highly substituted exocyclic double bond renders them enabling intermediates to be elaborated into a myriad of useful nitrogen heterocycles of varied complexity. For example, 3-alkylidene oxindoles can be viewed as electrophilic Michael acceptors, which react with carbon-centered anions to give bsubstituted oxindoles of type A (Scheme 1a). In addition, they can act as electron-poor components in synchronous (Scheme 1b) or stepwise (Scheme 1c) cycloadditive functionalizations, thus opening the way to a wide range of highly valuable 3,3-spirocyclic structures of type B or C. Whereas these protocols have been largely pursued and formed the basis of many synthetic achievements, an “umpolung” option could also be envisaged (Scheme 1d), and capitalizes on the vinylogous pro-nucleophilic character of the alkyl group attached at the b-position of the ylidene. By reacting with the proper acceptors, these nucleophiles furnish olefinic oxindoles of type D, which are functionalized at the most distant point of the molecule (Cγ).

A catalyst-free, environmentally benign three-component vinylogous Mukaiyama-Mannich reaction of pyrrole-based silyl dienolates is presented, which works effectively in both aqueous and solvent-free environments. Both lipophilic and hydrophilic aldehyde candidates are suitable substrates, allowing access to a rich repertoire of unsaturated vicinal aminolactam structures with virtually complete g-site selectivity and moderate to good anti-diastereoselectivity. The utility of this technology is highlighted by protecting group-free synthesis of densely hydroxylated, sugar-related lactam frameworks. The role of water as an indispensable H-bonding reaction propeller is demonstrated.

Pyrrole-based silyl dienolates undergo asymmetric vinylogous Mukaiyama Mannich reactions with a series of N-aryl aldimines in the presence of the Hoveyda-Snapper amino acid-derived silver(I) catalysts. The Mannich products-α,β-unsaturated δ-amino-γ-butyrolactams-are typically obtained in high yields, excellent γ-site selectivities and anti-diastereoselectivities, and up to 80% enantioselectivity.

The syntheses of four compounds, obtained by the reaction of methylpyruvate thiosemicarbazone (Hmpt) and its methyl (Me-Hmpt) and allyl (Allyl-Hmpt) derivatives with bis(triphenylphosphine)copper(I) acetate, are reported. The compounds [Cu(PPh3)2(ptc)(Hptc)]·H2O (1), [Cu(PPh3)2(Me-ptc)] (2), [Cu2(PPh3)2μ-S(Me-pt)μ-S(Me-ptc)]·H2O (3) and [Cu(PPh3)2(Allyl-ptc)] (4) [H2pt = pyruvic acid thiosemicarbazone and Hptc = cyclized pyruvic acid thiosemicarbazone, Me = methyl and Allyl are radical substituents on the amino nitrogen] were characterized by elemental analysis, IR, 1H NMR, and by X-ray crystallography. Compound 3 was also studied by EPR because of the presence in the compound of two copper atoms in two different oxidation states. During the complexation reaction, the thiosemicarbazone ligands tend to undergo a cyclization reaction that leads to the formation of a six-member heterocyclic ring. All four compounds present the [Cu(PPh3)2]+ fragment and constant but different coordination situations. Compound 1 contains two cyclic ligand molecules, one protonated and the other deprotonated, bound as monodentate through the sulfur. Compounds 2 and 4 present a single deprotonated cyclic SN bidentate ligand molecule, while compound 3 contains copper(I) and copper(II), and two ligand molecules, one of which is linear and behaves as SNO tridentate and the other is cyclic and behaves as bridging μSN.

This paper reports the synthesis of a series of methylpyruvate thiosemicarbazone derivatives containing, on the terminal nitrogen, substituents of different nature and size and namely, ethyl, phenyl and methylphenyl. These ligands were reacted with bis(triphenylphosphine)copper(I) nitrate and acetate to produce the respective complexes: [Cu(PPh3)2(Et-Hmpt)]2(NO3)2 (1), [Cu(PPh3)2(Ph-Hmpt)]NO3 (2), [Cu(PPh3)2(MePh-Hmpt)]NO3 (3), [Cu2(O2CCH3)(Et-pt)(PPh3)2] · H2O (4), [Cu(Ph-mpt)(PPh3)] (5) and [Cu2(MePh-mpt)2(PPh3)2] (6). All of them were characterized by elemental analysis, IR, 1H NMR, EPR spectroscopy and, for compounds 1, 2, 4, and 6, by X-ray crystallography. The characterization revealed that the coordinating behaviour of the ligands is influenced by a series of factors, predominant among which is the hard soft nature of the atoms involved in the interactions with the metal centre. The complexes obtained from the nitrate copper(I) salt are formed by cationic molecules with a nitrate as a counterion, while those derived from the acetate salt present deprotonated ligands and a few unexpected features. In particular, one of the compounds (4) is a mixed valence dinuclear complex with an acetate oxygen and the thiosemicarbazone sulfur acting as bridging between the two Cu(I) and Cu(II) ions. Another one (6) presents instead a Cu(I)–Cu(I) sulfur bridged binuclear cluster.

Two racemic 2-azabicyclo[2.2.1]heptane structures, 15 and 21 , and two chiral non-racemic 6-azabicyclo[3.2.1]octane representatives, 28 and 36 , have been synthesized starting from 1-( tert -butoxycarbonyl)-2-( tert -butyldimethylsilyloxy)pyrrole (TBSOP, 5 ) and suitable ketones, 9 , 16 , 22 and 29 . 2-Azabicycle 15 was then elaborated to racemic cyclopentane amino acid 38 , while 6-azabicycle 36 served to access the enantiomerically pure normorphan-type structure 40 . For all substrates, a uniform synthetic scheme was implemented based on the combination of two diastereoselective aldol-type carbon-carbon bond-forming reactions, the efficiencies of which were secured by appropriate aldol-stabilizing steps. A mechanistic rationale accounting for the markedly diastereoselective character of the key Mukaiyama aldol reactions between TBSOP and the ketone acceptors has been postulated that involves hetero-Diels-Alder transition-state structures in which the preference for endo versus exo addition is governed by the electronic nature of the substituents in the ketone substrates.

By reacting thiosemicarbazides substituted on the aminic nitrogen with 5-formyluracil, several new 5-formyluracil thiosemicarbazones (H 3 ut) derivatives were synthesised and characterized. These ligands, treated with copper chloride and nitrate, afforded two different kinds of compounds. In the complexes derived from copper chloride the metal atom is pentacoordinated, being surrounded by the neutral ligand binding through SNO donor atoms and by two chlorines, while the nitrate derivatives consist of monocations and nitrate anions. The copper coordination (4 + 2) involves the SNO ligand atoms, two water oxygens and an oxygen atom of a monodentate nitrate group. On varying the substituents on the thiosemicarbazidic moiety, remarkable modifications of the coordination geometry are not observed for the complexes with the same counterion. For all the compounds, interactions with DNA (calf thymus) were studied using UV–Vis spectroscopy; the nuclease activity was verified on plasmid DNA pBR 322 by electrophoresis.

In the course of a research on metal-based compounds active on white blood cell cancers (leukemia, lymphoma and myeloma) nine aliphatic thiosemicarbazones and their nickel complexes have been synthesized with the aim to test their effect on histiocytic lymphoma U937 cell proliferation. All compounds were characterized by elemental, IR and NMR spectra analyses and for five of the complexes also by X-ray crystallography diffraction analysis. Heptanal thiosemicarbazone and the corresponding nickel complex were chosen after a solubility/stability test to carry out preliminary experiments in vitro on human leukemia cell line U937. The complex possesses a remarkable biological activity in inhibiting cell growth and in inducing apoptosis.

Reaction of aqueous solutions of Ni(NO3)2 and pyridoxal semicarbazone (PLSC) in the presence of NaN3 afforded two complexes, viz. green, paramagnetic binuclear octahedral [Ni2(PLSC)2(l1,1-N3)2(N3)2] AE 2H2 O( 1) and, as admixture, red, octahedral [Ni(PLSC– H)2] AE 2H2 O( 2) complex. Under the same reaction conditions, pyridoxal thiosemicarbazone (PLTSC) gave only one diamagnetic square-planar, red complex [Ni(PLTSC–H)N3] AE H2 O( 3). In the absence of NaN3, the reaction of PLTSC and Ni(NO3)2 yielded brown paramagnetic octahedral complex [Ni(PLTSC)2](NO3)2 AE H2 O( 4). The complexes were characterized by elemental analysis, conductometric and magnetochemical measurements, IR and UV–Vis spectra, and the octahedral complexes 1, 2 and 4 also by X-ray monocrystal diffraction method. � 2007 Elsevier Ltd. All rights reserved.

This paper reports the synthesis and characterization of six compounds of copper(I), stabilized in its reduced state by two triphenylphosphines, in which 4-fluorobenzaldehyde thiosemicarbazone and N-methylthiosemicarbazone act as chelating through their sulfur and imino nitrogen. The three oxoanions that have been chosen, NO3−, SO42− and CH3COO−, play an important role: their oxygens are bad competitors with the imino nitrogen of the thiosemicarbazone moiety and moreover they form strong charge assisted hydrogen bondings that stabilize the neutral form of the ligand. The overall packing is determined by intermolecular phenyl–phenyl van der Waals interactions.

Reaction of phenylisothiocyanate with different aromatic amines allowed the synthesis of compounds containing the thiourea moiety. By reacting silver bis(triphenylphosphine)nitrate with suitable ligands belonging to this family of sulphurated compounds, three new complexes have been afforded. Ligands and complexes were characterized also by X-ray diffraction. The structures reveal remarkable differences in the silver coordination geometry in function of the nature and size of the ligand. The emission properties of all compounds were characterized at 10 and at 298 K.

The 2:1 reaction of [Ru(H2O)2(NH3)5]2+ with 1,2,4,5-tetrazine (tz) gives rise to the formation of the dinuclear complex ion [{Ru(NH3)5}2(μ-tz-N1:N4)]4+. Its tetraphenylborate and hexafluoro-phosphate salts have been fully characterized; the X-ray structure of the former has also been determined.

9-cis-Retinal thiosemicarbazone and its Co(III), Ni(II) and Cu(II) complexes are synthesized and characterized. Central Co(III) atom is in an octahedral environment while Ni(II) and Cu(II) atoms are in a square planar environment. DNA binding constants and spectroscopic data show an intercalative behavior for the nickel complex; an external binding mode is envisaged for the ligand and its copper complex. No DNA interaction can be hypothesized for the cobalt complex. The free ligand and its Ni(II) and Cu(II) complexes have a good lipophilic degree for an efficient uptake by the cells. The metal complexes exhibit a proliferation inhibition action against cell line U937 at micromolar concentration. Cu(II) complex also induces apoptosis, while Ni(II) complex has a strong interaction with CT-DNA.

Human American trypanosomiasis is resurgent in Latin Americans, and new drugs are urgently required as current medications suffer from a number of drawbacks. Some nitroheterocycles have been demonstrated to exert a potent activity against trypanosomes. However, host toxicity issues halted their development as trypanocides. As part of the efforts to develop new compounds in order to treat parasitic infections, it is important to define their structure-activity relationship. In this study, 5-nitromegazol and two of its analogues, 4-nitromegazol, and 1-methyl-5-nitro-2-imidazolecarboxaldehyde 5-nitroimidazole-thiosemicarbazone, were tested and compared for in vitro induction of DNA damage in human leukocytes by the comet assay, performed at different pHs to better identify the types of damage. Specific oxidatively generated damage to DNA was also measured by using the comet assay with endonucleases. DNA damage was found in 5-nitromegazol-treated cells: oxidative stress appeared as the main source of DNA damage. 4-Nitromegazol did not produce any significant effect, thus confirming that 4-nitroimidazoles isomers have no important biological activity. The 5-nitroimidazole-thiosemicarbazone induced DNA damage with a higher efficiency than 5-nitromegazol. The central role in the reduction process played by the acidic hydrazine proton present in the thiosemicarbazone group but not in the cyclic (thiadiazole) form can contribute to rationalise our results. Given its versatility, thiosemicarbazone moiety could be involved in different reactions with nitrogenous bases (nucleophilic and/or electrophilic attacks).

A series of quinoline-2-carboxaldehyde thiosemicarbazones and their copper(II) and nickel(II) complexes were synthesized and characterized. In all complexes the ligands are in the E configuration with respect to the imino bond and behave as terdentate. The copper(II) complexes form square planar derivatives with one molecule of terdentate ligand and chloride ion. A further non-coordinated chloride ion compensates the overall charge. Nickel(II) ions form instead octahedral complexes with two ligands for each metal ion, independently from the stoichiometric metal:ligand ratio used in the synthesis. Ligands and complexes were tested for their antiproliferative properties on histiocytic lymphoma cell line U937. Copper(II) derivatives are systematically more active than the ligands and the nickel complexes. All copper derivatives result in inhibiting topoisomerase IIa in vitro. Computational methods were used to propose a model to explain the different extent of inhibition presented by these compounds. The positive charge of the dissociated form of the copper complexes may play a key role in their action.

Two crystal structures are described in this article: (a) the structure of a monomeric Mn I I complex with the tridentate N-centered N 3 ligand tris[(1-methyl-2-imidazolyl)methyl]amine (TMIMA) ([Mn I I (TMIMA) 2 ] 2 + ); and(b) the structure of a monomeric Mn I I I complex with the tridentate N-centered N 2 O ligand 2-{[(1-methyl-2-imidazolyl)methyl]amino}phenolate (PI - ) [ 2 ] ([Mn I I I (PI) 2 ] + ) (5). The latter was isolated both in the Mn I I and in the Mn I I I state, although only Mn I I I crystals were successfully grown. They are part of a series of Mn complexes prepared as SOD mimics, namely [Mn(BMPG)(H 2 O)] + (2) {BMPG = N,N-bis[(6-methyl-.2-pyridyl)methyl]glycinate}, [Mn(IPG)(MeOH)] + (3) {IPG = N-[(1-methyl-2-imidazolyl) methyl]-N-(2-pyridylmethyl)glycinate), [Mn(BIG)(H 2 O) 2 ] + (4) {BIG = N,N-bis[(1-methyl-2-imidazolyl)methyl]glycinate}. The reactivity of Mn I I complexes 1 and 2 in an anhydrous medium is described and compared to that of complexes 3 and 4, the data for which was previously published. The cyclic voltammograms of the whole complex series were recorded in an aqueous medium (collidine buffer). Their SOD-like activities were estimated by the McCord-Fridovich test (IC50 with 22 μM cytc Fe I I I : 1.6′0.1 μMolL - 1 for 1, 1.2′0.5 μmolL - 1 for 2, 3.0′0.2 μmolL - 1 for 3, 3.7′0.6 μmolL - 1 for 4, 0.8′0.1 μmolL - 1 for 5). IC50 values were converted into the corresponding kinetic constant k M c C F values. A linear correlation between E a and log(k M c C F ) was obtained, indicating that in this series the conversion to Mn I I I is probably the rate-limiting step. This is of substantial importance for further Mn-SOD mimic design in this series.

Novel N-N-N-O-type of tetradentate ligands H(3)obap (H(3)obap = oxamido-N-aminopropyl-N'-benzoic acid) and H(3)maeb (H(3)maeb = malamido-N-aminoethyl-N'-benzoic acid) and the corresponding square-planar copper(H) complexes have been prepared and characterized. The obap(3)- and maeb(3)- ligands coordinate to the copper(II) ion via four ligating atoms (three deprotonated atoms: one carboxylate oxygen and two deprotonated amide nitrogens; one amine nitrogen) with in-plane square chelation. A four coordinate, square-planar geometry has been established crystallographically for the binuclear Na-2[Cu(obap)](2)center dot 2H(2)O complex. Structural data correlating the square-planar geometry of the [Cu(obap)](-) unit and an extensive strain analysis are discussed in relation to the information obtained for similar complexes. The infrared and electronic absorption spectra of the complexes are discussed in comparison to the related complexes of known geometries. Antibacterial activity of ligands and copper(H) complexes towards common Gram-negative and Gram-positive bacteria are reported as well. (c) 2005 Elsevier B.V. All rights reserved.

Nickel, copper, and zinc complexes of isatin (H(2)L(1)) and N-methylisatin 3-picolinoyl hydrazone (HL(2)), were synthesized and characterized by means of spectroscopic techniques. H(2)L(1) and a nickel complex [Ni(L(2))(2)].2C(6)H(14) were also characterized by X-ray diffractometry. Biological studies, carried out in vitro on human leukemic cell lines TOM 1 and NB4, have shown that both ligands and some copper and nickel complexes are active in inhibiting cell proliferation. Compounds H(2)L(1), Cu(HL(1))(2).2H(2)O, Zn(HL(1))(2).2H(2)O inhibit DNA synthesis and act constantly with time between 0 and 72 h. The cell cycle analysis has highlighted a reduction in the number of cells in phase S of about 40%. The same compounds present only a precocious action on cell line NB4 and therefore their activity is cell target specific.

Two new 5-formyluracil thiosemicarbazone (H(3)ut) derivatives, Me-H(3)ut (1) and Me(2)-H(3)ut (2), were synthesized by reacting thiosemicarbazides, mono- and dimethylated on the aminic nitrogen, with 5-formyluracil and were subsequently characterized. These ligands, treated with copper chloride and nitrate, afforded three complexes: [Cu(Me-H(3)ut)Cl(2)].H(2)O (3), [Cu(Me(2)-H(3)ut)Cl(2)].H(2)O (4), and [Cu(Me-H(3)ut)(NO(3))(OH(2))(2)]NO(3) (5). The crystal structures of these complexes have been determined by single-crystal X-ray diffraction. In 3 and 4, a similar pentacoordination is present; the copper atom is surrounded by the ligand SNO donor atoms and by two chloride ions. The structure of 5 consists of [Cu(Me-H(3)ut)(NO(3))(OH(2))(2)](+) cations and nitrate anions. The copper coordination (4 + 2) involves the SNO ligand atoms and a water oxygen in the basal plane; the apical positions are occupied by a second water oxygen and by an oxygen of a monodentate nitrate group. Two biochemical techniques, namely DNA titration in the UV-vis region and thermal denaturation, have been employed to probe the details of DNA binding of these compounds. Analysis of the results suggests that our compounds are able to interact with DNA by electrostatic and groove binding but not by intercalation. The compounds have been also tested in vitro on human leukemic cell line U937, but they are not able to inhibit significantly cell proliferation.

Nickel(II) complexes with the hexadentate ligand 1,3-propanediamine-N,N′-diacetate-N,N′-di-3-propionate (1,3-pddadp) have been prepared, chromatographically separated into the two geometrical isomers, trans(O5)-Na2[Ni(1,3-pddadp)]·2H2O (1) and trans(O5O6)-Na2[Ni(1,3-pddadp)]·3H2O (2), and characterized. The trans(O5) configuration of compound 1 was found to dominate and this geometry was verified crystallographically in the binuclear complex [Ni2(1,3-pddadp)(H2O)4]·4H2O (1). The complex crystallizes in the triclinic P 1 space group. The structure converged to R=0.0521 for 5210 reflections. The conformations of the chelate rings are those usually observed for these kinds of chelates [a six-membered diamine (T) ring in a twist-boat conformation, the two β-alaninate (G1 and G2) rings in an envelope-like conformation, and the two glycinate rings, R1 in a twist and R2 in an envelope conformation]. The structural data correlating an octahedral distortion are discussed with reference to those of related complexes. The IR and electronic absorption spectra are discussed in comparison with those of similar complexes.

In this paper we describe the synthesis of new copper complexes with alpha-ketoglutaric acid thiosemicarbazone. The crystal structures of the two compounds: [Cu(H(2)ct)Cl](n) [(Cu(H(2)ct)Cl)(2)] (1) and [Cu(Hct)](n).3nH(2)O (2) (H(3)ct=alpha-ketoglutaric acid thiosemicarbazone) have been determined by X-ray and spectroscopic methods. In 1 two independent copper atoms are present. Cu(1), in a nitrogen- and oxygen-bridged polymer, is a six-coordinated (4+2), Cu(2), five coordinated (4+1), is a chlorine-bridged dimer. In 2 the copper atom presents a penta-coordination, polymeric chains form layers and the -CH(2)CH(2)COO(-) groups bridge copper atoms. In 1 a monodentate and in 2 a syn-anti bidentate bridging carboxylate are present. The biological properties of 1 and 2 and also of the free ligand (H(3)ct) were tested in vitro and compared on Friend erythroleukemia cells (FLC) and on human leukemia cell lines K562 and U937. On the FLC cells the free ligand does not inhibit cell growth, but increases the DNA synthesis; complex 1 inhibits cell proliferation and increases the DNA synthesis; complex 2 inhibits cell growth, but induces a decrement of DNA synthesis and increases the reverse transcriptase activity. Regarding the human cell lines, both complexes show proliferation inhibition through an apoptosis mechanism on cell line U937, while they have no effects on the K562 line.

Novel ligands were obtained by condensation of pyridoxal with thiosemicarbazides substituted with alkyl and aryl moieties on the aminic and/or hydrazinic nitrogen. The spectrophotometric characteristics of the various species are reported. The X-ray structure of two different dimethylthiosemicarbazones of pyridoxal — pyridoxal N1,N2-dimethylthiosemicarbazone monohydrate and pyridoxal N1,N1-dimethylthiosemicarbazone monohydrate — was determined. The change of methyl group position determines in the solid state strong differences which affect the ligand behavior of these compounds. In the first ligand, characterized by X-ray diffraction, the pyridoxal ring is in a zwitterion form, with the phenolic oxygen and the sulfur atoms in trans position to the iminic N atom. The second compound, with both methyl groups on the aminic nitrogen, shows the donor atoms SNO on the same side, making it potentially suitable for coordination to the metal. Biological studies have involved both inhibition of cell proliferation ...

Pt(IV) complexes are usually prepared by oxidation of the corresponding Pt(II) counterparts, typically using hydrogen peroxide or chlorine. A different way to synthesize asymmetrical Pt(IV) compounds is the oxidative chlorination of Pt(II) counterparts with N-chlorosuccinimide. The reaction between cisplatin cis-[PtCl2(NH3)2], carboplatin, cis-[PtCl2(dach)] and cis-[Pt(cbdc)(dach)] (cbdc = cyclobutane-1,1'-dicarboxylato; dach = cyclohexane-1R,2R-diamine) with N-chlorosuccinimide in ethane-1,2-diol was optimized to produce the asymmetric Pt(IV) octahedral complexes [PtA2Cl(glyc)X2] (A2 = 2 NH3 or dach; glyc = 2-hydroxyethanolato; X2 = 2 Cl or cbdc) in high yield and purity. The X-ray crystal structure of the [Pt(cbdc)Cl(dach)(glyc)] complex is also reported. Moreover, the oxidation method proved to be versatile enough to produce other mixed Pt(IV) derivatives varying the reaction medium. The two trichlorido complexes easily undergo a pH-dependent hydrolysis reaction, whereas the dicarboxylato compounds are stable enough to allow further coupling reactions for drug targeting and delivery via the glyc reactive pendant. Therefore, the coupling reaction between the [Pt(cbdc)Cl(dach)(glyc)] and a model carboxylic acid, a model amine, and selectively protected amino acids is reported.

Modulation of the complex reactivity of cyclohexenylidene malononitriles using diverse β-aryl-substituted enals and proper organocatalytic modalities resulted in divergent asymmetric reaction patterns to furnish angularly fused or bridged carbabicyclic frameworks. In particular, use of remotely enolizable dicyanodienes 1, under one-pot sequential amine/NHC catalysis, led to [3 + 2] cycloaddition to afford ε,δ-bonded spiro[4.5]decanone structures 5. Alternatively, modifying the standard amine catalysis by adding a suitable chemical stimulus (p-nitrophenol cocatalyst) switched the reactivity decidedly toward a domino [4 + 2] cycloaddition to afford γ',δ-bonded bicyclo[2.2.2]octane carbaldehydes 8. Products invariably formed in good yields, with rigorous chemo-, regio-, diastereo-, and enantiocontrol. Experimental evidence, including carbon isotope effects measured by (13)C NMR, were indicative of the rate (and stereochemistry) determining step of these transformations and suggested a stepwise mechanism for the [4 + 2] cycloadditive pathway.

By reacting thiosemicarbazides substituted on the aminic nitrogen with both alkyl or aryl groups, and methyl pyruvate a new group of methylpyruvate thiosemicarbazones (Hmpt) derivatives was obtained. These ligands were then treated with copper and zinc inorganic salts. All isolated compounds were characterized using spectroscopic methods. The single crystal structural analysis of the ligands Me–Hmpt·0.5H 2 O 1 , Et–Hmpt·H 2 O 2 , Ph–Hmpt 5 , Meph–Hmpt 6 showed that only compound 6 presents significant deviation from planarity. The X-ray structure of [Zn(Me–Hmpt)Cl 2 ]·H 2 O 8 showed that in this complex Me–Hmpt behaves as a neutral ligand SNO terdentate and that the penta coordination is achieved by chloride ions according to spectroscopic and elemental analyses. On the basis of the analytical data the same behavior is proposed for the other zinc complexes. All the ligands in copper complexes seem to be monodeprotonated; nevertheless the same SNO behavior is expected. Tests on cell proliferation of human leukemic cell line U937 showed that the copper complex Cu(Et–mpt)Cl·H 2 O is the most active compound among those reported even though it is not able to induce apoptosis.

New thiosemicarbazone nickel complexes (1–7), derived from p-fluorobenzaldehyde and differently substituted thiosemicarbazides, were synthetized and characterized by means of NMR and IR techniques. The p-fluorobenzaldehyde 4-ethylthiosemicarbazone Et-Hfbt (1) and its complex [Ni(Et-fbt)2] (2) were also characterized by X-ray diffractometry. Molecule 1 consists of two units: the p-fluorobenzaldehyde residue and the thiosemicarbazonic chain. In the reaction of 1 with NiAc2·4H2O, complex 2 was afforded. The molecular structure of 2 consists of the neutral complexes [Ni(Et-fbt)2] with the metal not lying on a symmetry centre, with two consequently independent ligand molecules; the coordination results in a square planar geometry slightly twisted towards a tetrahedron, involving the sulfur and the hydrazine nitrogen atoms of the two ligands in a trans configuration.