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Fungi are ubiquitous in nature, and typically cause little or no environmental or pathogenic damage to their plant, animal, and human hosts. However, a small but growing number of pathogenic fungi are spreading world-wide at an alarming rate threatening global ecosystem health and proliferation. Many of these emerging pathogens have developed multi-drug resistance to front line therapeutics increasing the urgency for the development of new antifungal agents. This review examines the development of thiosemicarbazones, bis(thiosemicarbazones), and their metal complexes as potential antifungal agents against more than 65 different fungal strains. The fungistatic activity of the compounds are quantified based on the zone of inhibition, minimum inhibitory concentration, or growth inhibition percentage. In this review, reported activities were standardized based on molar concentrations to simplify comparisons between different compounds. Of all the fungal strains reported in the review, A. niger in particular was very resistant towards a majority of tested compounds. Our analysis of the data shows that metal complexes are typically more active than non-coordinated ligands with copper(II) and zinc(II) complexes generally displaying the highest activity.

Triapine, the most prominent anticancer drug candidate from the substance class of thiosemicarbazones, was investigated in >30 clinical phase I and II studies. However, the results were rather disappointing against solid tumors, which can be explained (at least partially) due to inefficient delivery to the tumor site. Hence, we synthesized the first biotin-functionalized thiosemicarbazone derivatives in order to increase tumor specificity and accumulation. Additionally, for Triapine and one biotin conjugate the iron(III) and copper(II) complexes were prepared. Subsequently, the novel compounds were biologically evaluated on a cell line panel with different biotin uptake. The metal-free biotin-conjugated ligands showed comparable activity to the reference compound Triapine. However, astonishingly, the metal complexes of the biotinylated derivative showed strikingly decreased anticancer activity. To further analyze possible differences between the metal complexes, detailed physico- and electrochemical experiments were performed. However, neither lipophilicity or complex solution stability, nor the reduction potential or behavior in the presence of biologically relevant reducing agents showed strong variations between the biotinylated and non-biotinylated derivatives (only some differences in the reduction kinetics were observed). Nonetheless, the metal-free biotin-conjugate of Triapine revealed distinct activity in a colon cancer mouse model upon oral application comparable to Triapine. Therefore, this type of biotin-conjugated thiosemicarbazone is of interest for further synthetic strategies and biological studies.

Four binuclear Ni(II) complexes [[Ni2(H-DEAsal-tsc)2(μ-dppm)]·2Cl (1), [Ni2(DEAsal-mtsc)2(μ-dppm)] (2), [Ni2(DEAsal-etsc)2(μ-dppm)] (3) and [Ni2(DEAsal-ptsc)2(μ-dppm)] (4)] were synthesized from the ligands namely 4(N,N)-diethylaminosalicylaldehyde-4(N)-thiosemicarbazone [H2-DEAsal-tsc] H2L1/4(N,N)-diethylaminosalicylaldehyde-4(N)-methyl thiosemicarbazone [H2-DEAsal-mtsc] H2L2/4(N,N)-diethylaminosalicylaldehyde-4(N)-ethyl thiosemicarbazone [H2-DEAsal-etsc] H2L3/4(N,N)diethylaminosalicylaldehyde-4(N)-phenyl thiosemicarbazone [H2-DEAsal-ptsc] H2L4 and 1,1'-bis(diphenylphosphino)methane (dppm) and characterized by a number of spectro analytical techniques. The molecular structure of complexes [Ni2(H-DEAsal-tsc)2(μ-dppm)]·2Cl (1) and [Ni2(DEAsal-ptsc)2(μ-dppm)] (4) have been confirmed by single crystal X-ray diffraction studies. The analysis indicated that in complex 1, the ligand [H2-DEAsal-tsc] coordinated as monobasic tridentate donor through phenolic oxygen, azomethine nitrogen and thione sulfur atoms. However, in complex 4, the ligand [H2-DEAsal-ptsc] behaved as dibasic tridentate donor with thiolate sulfur coordination. Their ability to bind with Calf Thymus Deoxyribonucleic acid (CT-DNA) and Bovine Serum Albumin (BSA) were analysed spectrometrically. Intercalative interaction of the complexes with DNA was confirmed by ethidium bromide (EB) displacement studies and DNA viscosity measurements. The interaction mechanism of the complexes with BSA was found as static. In vitro antiproliferative studies of the ligands and complexes in A549 (human lung carcinoma cancer), MCF-7 (human breast cancer) and HeLa (human cervical cancer) cell lines witnessed significant cytotoxic nature of the complexes with low IC50 values (in μM) than the standard metallo-drug cisplatin. Further, the results of Lactate Dehydrogenase (LDH) and Nitric oxide (NO) release assays supported the effectiveness of the complexes on the above said cancer cells.

Two types of α-N-heterocyclic piperidylthiosemicarbazone ligands and related Ga(III) complexes were synthesized. The structure of Ga4 and Ga5 were characterized by X-ray single crystal diffraction. We generated the related α-N-heterocycliperidinylthiosemicarbazone analogs to examine the effect of aldehydes or ketones in the Schiff base. The antitumor activity of both type ligands increased after coordination with gallium. Interestingly, the antitumor activity of gallium complexes containing pyridyl groups (first type ligands) is higher than that of pyrazine group-containing (second type ligands) complexes. Gallium complexes significantly depleted cellular iron, resulting in upregulation of transferrin receptor-1 and downregulation of ferritin. They also effectively activate the caspase family proteins (caspase-3/7/9), promote the release of cytochromes from the mitochondria, and ultimately lead to apoptosis.

An assessment study involving the use of the transglutaminase (TGase) conjugation method and the nitride-technetium-99m labelling on a bis(thiosemicarbazone) (BTS) bifunctional chelating agent is presented. The previously described chelator diacetyl-2-(N-4-methyl-3-thiosemicarbazone)-3-(N-4-amino-3-thiosemicarbazone), H(2)ATSM/A, has been functionalized with 6-aminohexanoic acid (epsilon-Ahx) to generate the bifunctional chelating agent diacetyl-2-(N-4-methyl-3-thiosemicarbazone)-3-[N-4-(amino)-(6-aminohexanoic acid)-3-thiosemicarbazone], H(2)ATSM/A-epsilon-Ahx (1), suitable for conjugation to glutamine (Gln) residues of bioactive molecules via TGase. The feasibility of the TGase reaction in the synthesis of a bioconjugate derivative was investigated using Substance P (SP) as model peptide. Compounds 1 and H(2)ATSM/A-epsilon-Ahx-SP (2) were labelled with nitride-technetium-99m, obtaining the complexes [Tc-99m] [Tc(N)(ATSM/A-epsilon-Ahx)] ((99m)Tc1)and [Tc-99m][Tc(N)(ATSM/ A-epsilon-Ahx-SP)] ((99m)Tc2). The chemical identity of (99m)Tc1 and (99m)Tc2 was confirmed by radio/UV-RP-HPLC combined with ESI-MS analysis on the respective carrier-added products (99g/99m)Tc1 and (99g/99m)Tc2. The stability of the radiolabelled complexes after incubation in various environments was investigated. All the results were compared with those obtained for the corresponding Cu-64-analogues, (64)Cu1 and (64)Cu2. The TGase reaction allows the conjugation of 1 with the peptide, but it is not highly efficient due to instability of the chelator in the required conditions. The SP-conjugated complexes are unstable in mouse and human sera. However, indeed the BTS system can be exploited as nitride-technetium-99m chelator for highly efficient technetium labelling, thus making compound 1 worthy of further investigations for new targeted technetium and copper radio-pharmaceuticals encompassing Single Photon Emission Computed Tomography and Positron Emission Tomography imaging.

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.

The solution chemical properties such as proton dissociation, complex formation with copper(II) and gallium(III) ions in addition to antibacterial and antitumor activity of a novel tridentate salicyaldehyde semicarbazone-estrone hybrid (estrone-SC) and a related bicyclic compound (thn-SC) were investigated. The crystal structure of complex [Cu(thn-SCH−1)Cl] was studied by single crystal X-ray diffraction method. Estrone-SC and thn-SC form mono-ligand complexes with Cu(II) characterized by relatively high stability, however, they are much less stable than their thiosemicarbazone analogues. The neutral Cu(II) complexes with (O−,N,O−)(H2O) coordination mode predominate at physiological pH. Estrone-SC and thn-SC are more efficient Ga(III) binders in comparison with thiosemicarbazones, although the complexes also suffer dissociation at pH 7.4. The Cu(II) complex of estrone-SC displayed significant cytotoxicity in A549, SW480 and CH1/PA cancer cells, and moderate apoptosis induction and ROS formation. The semicarbazone compounds did not exhibit antibacterial effect; unlike the related Cu(II)-thiosemicarbazone complexes represented by the fairly low MIC values (3–50 μM) obtained on the Gram-positive Staphylococcus aureus and Enterococcus faecalis bacteria.

Two new dimeric Zn(II) ([{ZnL1(DMSO2)}2]·DMSO (1), [{ZnL2Cl}2] (2)) and a novel tetrameric Zn(II) complex ([(Zn2L3)2(μ–OAc)2(μ3–O)2] (3)), where H2L1 = 4–(p–methoxyphenyl) thiosemicarbazone of o–hydroxynapthaldehyde, HL2 = 4–(p–methoxyphenyl)thiosemicarbazone of benzoyl pyridine and H2L3 = 4–(p–chlorophenyl)thiosemicarbazone of o–vanillin are reported. Ligands and their complexes were characterized by spectroscopic and single crystal X–ray diffraction techniques. In addition, the complexes exhibited good binding affinity towards HSA (1012 M−1), which is supported by their ability to quench the tryptophan fluorescence emission spectra of HSA. The complexes were also screened for their DNA binding propensity through UV–vis absorption titration, circular dichroism and fluorescence spectral studies. Results show that they effectively interact with CT–DNA through an intercalative mode of binding, with binding constants ranging from 103 to 104 M−1. Among the three complexes 1 has the highest binding affinity towards CT–DNA. Further, the phosphatase activity was evaluated using bis(2,4–dinitrophenyl)phosphate (BDNPP) as substrate, however, the complexes did not yield any measurable catalytic activity. Nevertheless the complexes showed significant cytotoxic potential against HeLa and HT–29 cancer cell lines that was assessed through MTT assay and DAPI staining. Remarkably, complex 1 showed better activity than cisplatin against HT–29 cell line.

Five thiosemicarbazones (H2Ln) derived from 4,6-diacetylresorcinol (n = 1–4) and salicylaldehyde (n = 5) have been synthesized and spectroscopically characterized. Single crystal X-ray diffraction studies on some of the complexes show that the molecular structure is dominated by intramolecular hydrogen bonds involving the O(1)–H group of the resorcinol/salicylaldehyde group and the azomethinic nitrogen atom and sulfur atom of the thiosemicarbazone arm. All of the ligands react with fac-[ReCl(CO)3(CH3CN)2] in the presence of NEt3 to form the stable anionic complexes [NHEt3][fac-[Re(Ln)(CO)3] (1–5). The thiosemicarbazonate ligand, as suggested by spectroscopic data and confirmed by X-ray diffraction, acts as a tridentate S,N,O system. The complexes are stable in solution for weeks, although other dimeric species were also detected by X-ray diffraction analysis. The reaction of fac-[99mTc(CO)3(H2O)3]+ with the appropriate ligand at 100 °C for 30 min yielded the complexes [fac-[99mTc(Ln)(CO)3]− (Tc1–Tc5). The radiochemical yield and purity were determined by HPLC and their chemical identity was ascertained by comparing their radiochromatogram with the chromatogram of the rhenium congeners (1–5). The results of biodistribution studies in mice on the five technetium compounds showed rapid blood clearance and fast liver uptake that slowly cleared into the intestines, a finding that indicates the hepatobiliary tract as the major excretory pathway. HPLC analysis of urine and blood serum samples from mice injected with the 99mTc complexes confirmed their in vivo stability since the predominant radiochemical species had the same retention time as the corresponding injected compound.

In this study, 9-anthraldehyde-N(4)-methylthiosemicarbazone (MeATSC) 1 and [Co(phen)(2)(O(2)CO)]Cl·6H(2)O 2 (where phen = 1,10-phenanthroline) were synthesized. [Co(phen)(2)(O(2)CO)]Cl·6H(2)O 2 was used to produce anhydrous [Co(phen)(2)(H(2)O)(2)](NO(3))(3) 3. Subsequently, anhydrous [Co(phen)(2)(H(2)O)(2)](NO(3))(3) 3 was reacted with MeATSC 1 to produce [Co(phen)(2)(MeATSC)](NO(3))(3)·1.5H(2)O·C(2)H(5)OH 4. The ligand, MeATSC 1 and all complexes were characterized by elemental analysis, FT IR, UV–visible, and multinuclear NMR ((1)H, (13)C, and (59)Co) spectroscopy, along with HRMS, and conductivity measurements, where appropriate. Interactions of MeATSC 1 and complex 4 with calf thymus DNA (ctDNA) were investigated by carrying out UV–visible spectrophotometric studies. UV–visible spectrophotometric studies revealed weak interactions between ctDNA and the analytes, MeATSC 1 and complex 4 (K(b) = 8.1 × 10(5) and 1.6 × 10(4) M(−1), respectively). Topoisomerase inhibition assays and cleavage studies proved that complex 4 was an efficient catalytic inhibitor of human topoisomerases I and IIα. Based upon the results obtained from the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay on 4T1-luc metastatic mammary breast cancer cells (IC(50) = 34.4 ± 5.2 μM when compared to IC(50) = 13.75 ± 1.08 μM for the control, cisplatin), further investigations into the molecular events initiated by exposure to complex 4 were investigated. Studies have shown that complex 4 activated both the apoptotic and autophagic signaling pathways in addition to causing dissipation of the mitochondrial membrane potential (ΔΨ(m)). Furthermore, activation of cysteine-aspartic proteases3 (caspase 3) in a time- and concentration-dependent manner coupled with the ΔΨ(m), studies implicated the intrinsic apoptotic pathway as the major regulator of cell death mechanism.

The present work is devoted to reveal physicochemical properties and several biological actions of a new thiosemicarbazone (NTSC) derived from naringenin, a natural flavanone, and its Cu-complexes formed in mixed solvent solutions. Equilibrium solution studies were carried out on the NTSC and Cu-NTSC complexes in DMSO/water mixture. The proton-dissociation constants of the ligand, the stability constants and the coordination modes of the metal complex species were determined by means of pH-potentiometric, UV–vis and EPR methods. Mono- and bis-ligand complexes in different protonation states were identified. Circular dichroism, fluorimetric and gel electrophoresis studies demonstrated that both NTSC and copper complex interact with CT DNA and plasmid pEGFP-C1. Fluorimetric experiments allowed to confirm that both NTSC and its Cu(II)-complex bind to human serum albumin (HSA), the Cu-NTSC giving a stronger quenching effect than NTSC at similar molar ratios. Investigations of antibacterial and antifungal properties were carried out on selected strains of bacteria and fungi. The cytotoxic effects were studied on the cancer A2780 and the non-cancer HEK cells, both compounds being found non-toxic.

A novel binuclear palladium(II) complex [(AsPh3)2ClPd(L)PdCl] (LPd2) has been synthesized by reacting 2-oxo-1,2-dihydroquinoline-3-carbaldehyde-4(N,N)-dimethylthiosemicarbazone (HL) with [PdCl2(AsPh3)2], and the molecular structure was confirmed by single crystal X-ray diffraction studies. The DNA interactions of the free ligand and of the complex have been evaluated by absorption and ethidium bromide (EB) competitive studies which revealed that the complex could interact with calf thymus DNA (CT-DNA) through intercalation. In addition, the interactions with bovine serum albumin (BSA) were also studied showing that the new binuclear palladium complex had a strong binding affinity with BSA.

The basic aim of this study pertains to developing antimicrobial or anticancer agents based on N, S-donor organic ligands bonded to metals. In the present investigation, di-2-pyridylketone-N1-substituted thiosemicarbazone (py2tscH-N1HR2, Chart 2) thio-ligands were reacted with copper(I) halides in organic solvents yielding copper(II) complexes of stoichiometry, [Cu(N,N,S-py2tsc-N1HR2)X] (X = I, R2 = H, 1; Me, 2; Et, 3; Ph, 4; X = Br, R2 = H, 5; Me, 6; Et, 7; Ph, 8; X = Cl, R2 = H, 9; Me, 10; Et, 11; Ph, 12); the formation of CuII probably occurs through a proton coupled electron transfer (PCET) process. Electron spin resonance, ultraviolet-visible spectroscopy and X-ray crystallography (2, 3, 5, 7, 11) supported a distorted square planar geometry of these complexes. Moderate to high antimicrobial activities of these complexes against methicillin resistant Staphylococcus aureus, Gram positive bacteria, Staphylococcus aureus and Gram negative bacteria, Klebsiella pneumoniae 1, Salmonella typhimurium 2 and one yeast Candida albicans were recorded. Complexes were found to be biosafe with 88–91% cellular viability. All complexes have shown high anticancer activity against the immortalized L6 rat skeletal muscle cell line with very low IC50 values.

Being a structural and catalytic cofactor in a number of biological pathways, copper accumulates in tumors owing to selective permeability of the cancer cell membranes. Copper(II) ion forms the active centers in a large number of metalloproteins. The coordination of Schiff's base ligands to the metal ion results in the high extent of increase in anticancer activity. The copper(II) complexes can cleave DNA through oxidative and hydrolytic pathways, cell apoptosis via intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway due to excessive production of ROS and hence, are found more active than Ni and Pt complexes. Flexible Cu(I/II) redox behavior helps the copper complexes to form more potent, clinically effective and less toxic copper based antiproliferative drugs of lower IC50 value and higher growth inhibitory activity. Copper(II) complexes of thiosemicarbazones of Isatin, Pyridine, Benzoyl pyridine, Diacetyl/Dimethyl glyoxal, Acetophenone/Acetoacetanalide, Thiazole/Pyrazole, Quinoline, Carboxybenzaldehyde, Cinnamaldehyde/Cuminaldehyde, Citronellal, Chromone, Pyridoxal, 8-Ethyl-2-hydroxytricyclo (7.3.1.02,7) tridecan-13-one, Acyl Diazines, Naphthalene, Proline, 5-Formyluracil, 2-Hydroxy-8-propyltricyclo (7.3.1.02,7) tridecan-13-one, 9-cis-Retinal, Curcumin, Helicin (Salicylaldehyde-β-D-glucoside), Thiophene carboxaldehyde, Salicylaldehyde, Iminodiacetate, and 3-Formyl-4-hydroxy benzenesulfonic acid have been found to exhibit more anticancer activity toward HCT116, MCF7, A549, U937, HeLa, HepG2, SGC-7901, A2780 cell lines than that of their corresponding thiosemicarbazones and standard topoisomerase-II inhibitors.

Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdCl(PPh3)(C14H10NO2S-pz)] (2) [pz = pyrazole (C3H2N2)] have been obtained unexpectedly from chromone thiosemicarbazones (L1 and L2) and [PdCl2(PPh3)2]. The compounds have been fully characterized by physicochemical studies. The single crystal X-ray diffraction and spectral studies revealed square planar geometry for the complexes. The conversion of chromone thiosemicarbazone into pyrazole based thiourea might have happened through coordination to palladium(II) ion after enolization, Michael addition and ring opening followed by cyclization. To the best of our knowledge, this is the first report for the conversion of chromone thiosemicarbazone into pyrazole based thiourea moiety. Plausible mechanism was proposed based on the spectroscopic studies. Calf thymus (CT) DNA binding of the compounds was explored using various spectroscopic and molecular docking methods. DNA cleavage studies suggested that complexes 1 and 2 had the capacity to cleave the supercoiled DNA (pUC19) to its naked form. In vitro cytotoxic property of the ligands and complexes has been evaluated against three human cancer cells such as A549, HepG-2 and U937. Complex 2 exhibited potent cytotoxic activity against HepG-2 cells with the IC50 value of 10.4 μM. In addition, mechanistic studies showed that complex 2 induced apoptosis through mitochondrial signaling pathway in HepG-2 cells. Beneficially, complex 2 showed less toxicity against human lung (IMR90) normal cells and hence it emerges as a potential candidate for further studies.

One mononuclear and another dinuclear Pd(II) complexes bearing a α-N-heterocyclic thiosemicarbazone ligand have been synthesized, fully characterized and studied as biological agents. In both complexes, the palladium center is coordinated to 3,5-diacetyl-1,2,4-triazol bis(N4,N4-dimethylthiosemicarbazone) via three sites (N, N and S). Their binding ability to DNA has been evaluated using spectroscopic and biophysical techniques. Molecular docking and molecular dynamics calculations supports the existence of a minor groove binding mode between the studied compounds and DNA.

Solution chemical properties of two bidentate pyrazolyl thiosemicarbazones 2-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Me-pyrTSC), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Ph-pyrTSC), stability of their Cu(II) and Ru(η6-p-cymene) complexes were characterized in aqueous solution (with 30% DMSO) by the combined use of UV–visible spectrophotometry, 1H NMR spectroscopy and electrospray ionization mass spectrometry in addition to their solid phase isolation. The solid phase structures of Me-pyrTSC∙H2O, [Ru(η6-p-cymene)(Me-pyrTSC)Cl]Cl and [Cu(Ph-pyrTSCH−1)2] were determined by single crystal X-ray diffraction. High stability mononuclear Ru(η6-p-cymene) complexes with (N,S) coordination mode are formed in the acidic pH range, and increasing the pH the predominating dinuclear [(Ru(η6-p-cymene))2(L)2]2+ complex with μ2-bridging sulphur donor atoms is formed (where L− is the deprotonated thiosemicarbazone). [CuL]+ and [CuL2] complexes show much higher stability compared to that of complexes of the reference compound benzaldehyde thiosemicarbazone. [CuL2] complexes predominate at neutral pH. Me-pyrTSC and Ph-pyrTSC exhibited moderate cytotoxicity against human colonic adenocarcinoma cell lines (IC50 = 33–76 μM), while their complexation with Ru(η6-p-cymene) (IC50 = 11–24 μM) and especially Cu(II) (IC50 = 3–6 μM) resulted in higher cytotoxicity. Cu(II) complexes of the tested thiosemicarbazones were also cytotoxic in three breast cancer and in a hepatocellular carcinoma cell line. No reactive oxygen species production was detected and the relatively high catalase activity of SUM159 breast cancer cells was decreased upon addition of the ligands and the complexes. In the latter cell line the tested compounds interfered with the glutathione synthesis as they decreased the concentration of this cellular reductant.

Six gallium(III) complexes (Ga1–Ga6) with 2‑quinolinecarboxaldehyde thiosemicarbazone analogues were synthesized and characterized. These gallium(III) complexes exhibited potent anticancer activity and exceeded that of the corresponding metal free ligands. Importantly, these gallium(III) complexes have a strong selectivity for tumor cells. Through the study of cellular mechanisms, we have found that the lipophilicity of ligands is closely linked to the antitumor activity of gallium(III) complexes. Additionally, we have chosen Ga6 with the best anti-tumor activity to study the mechanism of apoptosis. Caspase-3 and 9 activation and Annexin V-FITC/Propidium iodide (PI) dual-staining studies revealed that Ga6 promote apoptosis in A549 cells lines. Ga6 induces intracellular reactive oxygen species (ROS) and disrupts mitochondrial membrane potential.

Searching for prospective vanadium-based drugs for the treatment of Chagas disease, a new series of heteroleptic [V(IV)O(L-2H)(NN)] compounds was developed by including the lipophilic 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) NN ligand and seven tridentate salicylaldehyde semicarbazone derivatives (L1-L7). The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligand is bidentate bound through both nitrogen donor atoms in an axial-equatorial mode. The EPR and (51)V-NMR spectra of aerated solutions at room temperature indicate that the compounds are stable to hydrolysis and that no significant oxidation of V(IV) to V(V) takes place at least in 24h. The complexes are more active in vitro against Trypanosoma cruzi, the parasite responsible for Chagas disease, than the reference drug Nifurtimox and most of them are more active than previously reported [V(IV)O(L-2H)(NN)] complexes of other NN co-ligands. Selectivity towards the parasite was analyzed using J-774 murine macrophages as mammalian cell model. Due to both, high activity and high selectivity, L2, L4, L5 and L7 complexes could be considered new hits for further drug development. Lipophilicity probably plays a relevant role in the bioactivity of the new compounds. The [V(IV)O(L-2H)(NN)] compounds were designed aiming DNA as potential molecular target. Therefore, the novel L1-L7 tmp complexes were screened by computational modeling, comparing their DNA-binding features with those of previously reported [V(IV)O(L-2H)(NN)] compounds with different NN co-ligands. Whereas all the complexes interact well with DNA, with binding modes and strength tuned in different extents by the NN and semicarbazone co-ligands, molecular docking suggests that the observed anti-T. cruzi activity cannot be explained upon DNA intercalation as the sole mechanism of action.

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.

Thiosemicarbazone Ga(III) complexes (C3-C5) were synthesized and characterized by X-ray single crystal diffraction, and they were all 1:1 ligand/Ga(III) complexes. The antiproliferative activity of these Ga(III) complexes was tested against three cancer cell lines, demonstrating that Ga(III) complexes showed about 3-10 folds more anticancer activity than their ligands alone. Importantly, thiosemicarbazones and Ga(III) complexes have a low toxicity to human fetal lung fibroblast cells (MRC-5) and exhibit a high therapeutic index for tumor cells. The results of UV-visible spectroscopy showed that the binding constant of C4 with Topo-I-DNA was significantly higher than that of L4. The Ga(III) complex (C4) caused Topo-I inhibition and distinct DNA cleavage. Moreover, Ga(III) complex and thiosemicarbazone ligand prolonged the G1 phase in NCI-H460 cell cycle, which might be depended on the ability of these compounds to affect the expression of cell cycle related proteins.

Thiosemicarbazone chelators represent an exciting class of biologically active compounds that show great potential as anti-tumor agents. Our previous studies demonstrated the potent anti-tumor activity of the 2′-benzoylpyridine thiosemicarbazone series. While extensive studies have been performed on monomeric thiosemicarbazone compounds, dimeric thiosemicarbazone chelators have received comparatively less attention. Thus, it was of interest to investigate the anti-proliferative activity and iron chelation efficacy of dimeric thiosemicarbazones. Two classes of dimeric thiosemicarbazones were designed and synthesized. The first class consisted of two benzoylpyridine-based thiosemicarbazone units connected via a hexane or dodecane alkyl bridge, while the second class of dimer consisted of two thiosemicarbazones attached to a 2,6-dibenzoylpyridine core. These dimeric ligands demonstrated greater anti-proliferative activity than the clinically used iron chelator, desferrioxamine. This study highlights the importance of optimal lipophilicity as a factor influencing the cytotoxicity and iron chelation efficacy of these chelators.

The binding affinities towards estrogen receptors (ERs) α and β of a set of thiosemicarbazone ligands (HL n ) and their rhenium(I) carbonyl complexes [ReX(HL n )(CO) 3 ] (X = Cl, Br) were determined by a competitive standard radiometric assay with [ 3 H]-estradiol. The ability of the coordinated thiosemicarbazone ligands to undergo deprotonation and the lability of the Re X bond were used as a synthetic strategy to obtain [Re(hpy)(L n )(CO) 3 ] (hpy = 3- or 4-hydroxypyridine). The inclusion of the additional hpy ligand endows the new thiosemicarbazonate complexes with an improved affinity towards the estrogen receptors and, consequently, the values of the inhibition constant (K i ) could be determined for some of them. In general, the values of K i for both ER subtypes suggest an appreciable selectivity towards ERα.

One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-β (Aβ) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Aβ peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Aβ plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H 2 QH), a thiosemicarbazone (8-H 2 QT), and a semicarbazone (8-H 2 QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH 7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cu II , 8-H 2 QT in a 1:1 metal:ligand ratio, and 8-H 2 QH and 8-H 2 QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Aβ 1–40 peptide showed that 8-H 2 QS and 8-H 2 QH inhibit peptide aggregation in the presence of Cu II . Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Aβ aggregation using the more neurotoxic Aβ 1 −42 in the presence and absence of Cu II , 8-H 2 QH, 8-H 2 QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of Cu II . However, in the presence of ligands and Cu II , the results match those for the peptide alone, suggesting that the ligands function by sequestering Cu II and limiting oligomer formation in this assay.

Four novel thiosemicarbazone metal complexes, [Cu(Am4M)(OAc)]·H2O (1), [Zn(HAm4M)Cl2] (2), [Zn2(Am4M)2Br2] (3) and [Zn2(Am4M)2(OAc)2]·2MeOH (4) [HAm4M=(Z)-2-(amino(pyridin-2-yl)methylene)-N-methylhydrazinecarbothioamide], have been synthesized and characterized by X-ray crystallography, elemental analysis, ESI-MS and IR. X-ray analysis revealed that complexes 1 and 2 are mononuclear, which possess residual coordination sites for Cu(II) ion in 1 and good leaving groups (Cl(-)) for Zn(II) ion in 2. Both 3 and 4 displayed dinuclear units, in which the metal atoms are doubly bridged by S atoms of two Am4M(-) ligands in 3 and by two acetate ions in bi- and mono-dentate forms, respectively, in 4. Their antiproliferative activities on human epithelial cervical cancer cell line (HeLa), human liver hepatocellular carcinoma cell line (HepG-2) and human gastric cancer cell line (SGC-7901) were screened. Inspiringly, IC50 value (11.2±0.9 μM) of complex 1 against HepG-2 cells was nearly 0.5 fold of that against human hepatic cell lines LO2, showing a lower toxicity to human liver cells. Additionally, it displayed a stronger inhibition on the viability of HepG-2 cells than cisplatin (IC50=25±3.1 μM), suggesting complex 1 might be a potential high efficient antitumor agent. Furthermore, fluorescence microscopic observation and flow cytometric analysis revealed that complex 1 could significantly suppress HepG-2 cell viability and induce apoptosis. Several indexes, such as DNA cleavage, reactive oxygen species (ROS) generation, comet assay and cell cycle analysis indicated that the antitumor mechanism of complex 1 on HepG-2 cells might be via ROS-triggered apoptosis pathway.

Aiming to explore alternative mechanisms of cellular uptake and cytotoxicity, we have studied a new family of copper(II) complexes (CuL1-CuL4) with bis(thiosemicarbazone) (BTSC) ligands containing pendant protonable cyclic amines (morpholine and piperidine). Herein, we report on the synthesis and characterization of these new complexes, as well as on their biological performance (cytotoxic activity, cellular uptake, protein and DNA binding), in comparison with the parental CuIIATSM (ATSM = diacetyl-bis(N4-methylthiosemicarbazonate) complex without pendant cyclic amines. The new compounds have been characterized by a range of analytical techniques including ESI-MS, IR spectroscopy, cyclic voltammetry, reverse-phase HPLC and X-ray spectroscopy. In vitro cytotoxicity studies revealed that the copper complexes are cytotoxic, unlike the corresponding ligands, with a similar potency to that of CuATSM. Unlike CuATSM, the new complexes were able to circumvent cisplatin cross-resistance. The presence of the protonable cyclic amines did not lead to an enhancement of the interaction of the complexes with human serum albumin or calf thymus DNA. However, CuL1–CuL4 showed a remarkably augmented cellular uptake compared with CuATSM, as proved by uptake, internalization and externalization studies that were performed using the radioactive congeners 64CuL1-64CuL4. The enhanced cellular uptake of CuL1-CuL4 indicates that this new family of CuIIBTSC complexes deserves to be further evaluated in the design of metallodrugs for cancer theranostics.

Four novel ligands derived from 2,3-butanedione have been synthesized, two dissymmetric thiosemicarbazone/3-hydroxy-2-naphthohydrazone ligands, H2L1 (bearing 4-isopropyl-3-thiosemicarbazone) and H2L2 (containing 4-cyclohexyl-3-thiosemicarbazone) and the symmetric H2L3, diacetyl bis(3-hydroxy-2-naphthohydrazone), and H2L4, diacetyl bis(4-cyclohexyl-3-thiosemicarbazone). Their reactivity with SnR2Cl2 (R=methyl, n-butyl and phenyl) was explored and the resulting complexes were characterized by elemental analysis, molar conductivity, mass spectrometry, IR, 1H, 13C and 119Sn NMR and seven of them also by single crystal X-ray diffraction. The results showed that the reactivity of the dissymmetric ligands is strongly different and while the cyclohexyl derivative is very stable, with isopropyl easily undergoes a symmetrization reaction to yield the corresponding symmetric ligands. The antimicrobial activity of the ligands and the corresponding diorganotin(IV) complexes was investigated in vitro against seven species of microorganisms and minimum inhibitory concentrations (MICs) were determined. The results showed that the ligand H2L2 and several of its derivatives, together with methyl and phenyl complexes of H2L1, have the ability of inhibiting the growth of tested bacteria and fungi to different extents. Bacillus subtilis and Staphylococcus aureus Gram positive strains were the most sensitive microorganisms.

American trypanosomiasis or Chagas disease, caused by the protist parasite Trypanosoma cruzi (T. cruzi), is a major health concern in Latin America. In the search for new bioactive compounds, eight Pd(II) and Pt(II) complexes of thiosemicarbazones derived from 1-indanones (HL) were evaluated as potential anti-T. cruzi compounds. Their unspecific cytotoxicity was determined on human erythrocytes. Two physicochemical features, lipophilicity and redox behavior, that could be potentially relevant for the biological activity of these complexes, were determined. Crystal structure of [Pd(HL1)(L1)]Cl·CH3OH, where HL1 = 1-indanone thiosemicarbazone, was solved by X-ray diffraction methods. Five of the eight metal complexes showed activity against T. cruzi with IC50 values in the low micromolar range and showed significantly higher activity than the corresponding free ligands. Four of them resulted more active against the parasite than the reference antitrypanosomal drug Nifurtimox. Anti-T. cruzi activity and selectivity towards the parasite were both higher for the Pd(II) compounds than for the Pt(II) analogues, showing the effect of the metal center selection on the biological behavior. Among both physicochemical features tested for this series of compounds, lipophilicity and redox behavior, only the former seemed to show correlation with the antiproliferative effects observed. Metal coordination improved bioactivity but lead to an increase of mammalian cytotoxicity. Nevertheless, some of the metal complexes tested in this work still show suitable selectivity indexes and deserve further developments. Fil: Santos, Diego. Universidad de la Republica; Uruguay Fil: Parajon Costa, Beatriz Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Química Inorgánica; Argentina; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; Argentina Fil: Rossi, Miriam. Vassar College. Department of Chemistry; Estados Unidos Fil: Caruso, Francesco. Università di Roma La Sapienza; Italia. Consiglio Nazionale delle Ricerche; Italia Fil: Benítez, Diego. Universidad de la Republica; Uruguay Fil: Varela, Javier. Universidad de la Republica; Uruguay Fil: Cerecetto, Hugo. Universidad de la Republica; Uruguay Fil: González, Mercedes. Universidad de la Republica; Uruguay Fil: Gómez, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina Fil: Caputto, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina Fil: Moglioni, Albertina Gladys. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina Fil: Moltrasio, Graciela Y.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina Fil: Finkielsztein, Liliana M.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina Fil: Gambino, Dinorah. Universidad de la Republica; Uruguay

The synthesis and characterization of a number of organometallic ruthenium(II) complexes containing a series of bidentate thiosemicarbazone ligands derived from piperonal is reported. The structure of compounds have been confirmed by spectroscopic analysis (IR and NMR) as well as X-ray crystallographic analysis of [(η 6 - p -cymene)Ru(pPhTSC)Cl]Cl ( 4 ) (pPhTSC is piperonal-N(4)-phenylthiosemicarbazone). The interaction of the complexes ([(η 6 - p -cymene)Ru(pEtTSC)Cl]Cl) ( 3 ) (pEtTSC is piperonal-N(4)-ethylthiosemicarbazone) and 4 with calf thymus DNA, human serum albumin (HSA) and pBR322 plasmid DNA were studied by spectroscopic, gel electrophoresis and hydrodynamic methods. The apparent binding constant for the interaction with DNA was determined to be 3.97 × 10 3 M − 1 and 4.07 × 10 3 M − 1 at 293 K for 3 and 4 respectively. The complexes bind strongly to HSA with binding constants of 2.94 × 10 4 M − 1 and 12.2 × 10 4 M − 1 at 296 K for 3 and 4 respectively. The in vitro anticancer activity of 3 and 4 has been evaluated against two human colon cancer cell line (HCT-116 and Caco-2) with IC 50 values in the range of 26–150 μM. Both 3 and 4 show good activity as a catalytic inhibitor of human topoisomerase II at concentrations as low as 20 μM. The proficiency of 3 and 4 to act as antibacterial agents was also evaluated against six pathogenic bacterial strains with the best activity seen against Gram-positive strains.

In the search for new therapeutic tools against diseases produced by kinetoplastid parasites five vanadyl complexes, [V(IV)O(L-2H)(phen)], including 1,10-phenanthroline (phen) and tridentate salicylaldehyde semicarbazone derivatives as ligands have been synthesized and characterized in the solid state and in solution by using different techniques. EPR suggested a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and phen coordinated in an equatorial/axial mode. The compounds were evaluated in vitro on epimastigotes of Trypanosoma cruzi, causative agent of Chagas disease, Leishmania panamensis and Leishmania chagasi and on tumor cells. The complexes showed higher in vitro anti-trypanosomal activities than the reference drug Nifurtimox (IC(50) values in the range 1.6-3.8 μM) and increased activities in respect to the free semicarbazone ligands. In vitro activity on promastigote and amastigote forms of Leishmania showed interesting results. The compounds [VO(L1-2H)(phen)] and [VO(L3-2H)(phen)], where L1 = 2-hydroxybenzaldehyde semicarbazone and L3 = 2-hydroxy-3-methoxybenzaldehyde semicarbazone, resulted active (IC(50) 2.74 and 2.75 μM, respectively, on promastigotes of L. panamensis; IC(50) 19.52 and 20.75 μM, respectively, on intracellular amastigotes of L. panamensis) and showed low toxicity on THP-1 mammalian cells (IC(50) 188.55 and 88.13 μM, respectively). In addition, the complexes showed cytotoxicity on human promyelocytic leukemia HL-60 cells with IC(50) values of the same order of magnitude as cisplatin. The interaction of the complexes with DNA was demonstrated by different techniques, suggesting that this biomolecule could be a potential target either in the parasites or in tumor cells.

In the search for new therapeutic tools against Chagas’ disease (American Trypanosomiasis) four novel mixed-ligand vanadyl complexes, [V IV O(L 2 -2H)(L 1 )], including a bidentate polypyridyl DNA intercalator (L 1 ) and a tridentate salycylaldehyde semicarbazone derivative (L 2 ) as ligands were synthesized, characterized by a combination of techniques, and in vitro evaluated. EPR suggest a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and the polypyridyl ligand coordinated in an equatorial/axial mode. Both complexes including dipyrido[3,2-a: 2′,3′-c]phenazine (dppz) as polypyridyl coligand showed IC 50 values in the μM range against Dm28c strain (epimastigotes) of Trypanosoma cruzi , causative agent of the disease, being as active as the anti-trypanosomal reference drug Nifurtimox. To get an insight into the trypanocidal mechanism of action of these compounds, DNA was evaluated as a potential parasite target and EPR, and 51 V NMR experiments were also carried out upon aging aerated solutions of the complexes. Data obtained by electrophoretic analysis suggest that the mechanism of action of these complexes could include DNA interactions.

Substituted semicarbazones/thiosemicarbazones and their copper complexes have been prepared and several single crystal structures examined. The copper complexes of these semicarbazone/thiosemicarbazones were prepared and several crystal structures examined. The single crystal X-ray structure of the pyridyl-substituted semicarbazone showed two types of copper complexes, a monomer and a dimer. We also found that the p-nitrophenyl semicarbazone formed a conventional 'magic lantern' acetate-bridged dimer. Electron Paramagnetic Resonance (EPR) of several of the copper complexes was consistent with the results of single crystal X-ray crystallography. The EPR spectra of the p-nitrophenyl semicarbazone copper complex in dimethylsulfoxide (DMSO) showed the presence of two species, confirming the structural information. Since thiosemicarbazones and semicarbazones have been reported to exhibit anticancer activity, we examined the anticancer activity of several of the derivatives reported in the present study and interestingly only the thiosemicarbazone showed activity while the semicarbazones were not active indicating that introduction of sulphur atom alters the biological profile of these thiosemicarbazones.

Bis(thiosemicarbazones) and their copper (Cu) complexes possess unique anti-neoplastic properties. However, their mechanism of action remains unclear. We examined the structure-activity relationships of twelve bis(thiosemicarbazones) to elucidate factors regarding their anti-cancer efficacy. Importantly, the alkyl substitutions at the diimine position of the ligand backbone resulted in two distinct groups, namely, unsubstituted/monosubstituted and disubstituted bis(thiosemicarbazones). This alkyl substitution pattern governed their: (1) Cu(II/I) redox potentials; (2) ability to induce cellular (64)Cu release; (3) lipophilicity; and (4) anti-proliferative activity. The potent anti-cancer Cu complex of the unsubstituted bis(thiosemicarbazone) analog, glyoxal bis(4-methyl-3-thiosemicarbazone) (GTSM), generated intracellular reactive oxygen species (ROS), which was attenuated by Cu sequestration by a non-toxic Cu chelator, tetrathiomolybdate, and the anti-oxidant, N-acetyl-l-cysteine. Fluorescence microscopy suggested that the anti-cancer activity of Cu(GTSM) was due, in part, to lysosomal membrane permeabilization (LMP). For the first time, this investigation highlights the role of ROS and LMP in the anti-cancer activity of bis(thiosemicarbazones).

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.

Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(η(5)-C5H5)(PPh3)L], with HL=bioactive 5-nitrofuryl containing thiosemicarbazones were synthesized and characterized in the solid state and in solution. The compounds were evaluated in vitro on the blood circulating trypomastigote form of Trypanosoma cruzi (Dm28c strain), the infective form of Trypanosoma brucei brucei (strain 427) and on J774 murine macrophages and human-derived EA.hy926 endothelial cells. The compounds were active against both parasites with IC50 values in the micromolar or submicromolar range. Interestingly, they are much more active on T. cruzi than previously developed Ru(II) classical and organometallic compounds with the same bioactive ligands. The new compounds showed moderate to very good selectivity towards the parasites in respect to mammalian cells. The global results point at [RuCp(PPh3)L2] (L2=N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp=cyclopentadienyl) as the most promising compound for further developments (IC50T. cruzi=0.41μM; IC50T. brucei brucei=3.5μM). Moreover, this compound shows excellent selectivity towards T. cruzi (SI>49) and good selectivity towards T. brucei brucei (SI>6). In order to get insight into the mechanism of antiparasitic action, the intracellular free radical production capacity of the new compounds was assessed by ESR. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and to redox cycling processes were characterized. In addition, DNA competitive binding studies with ethidium bromide by fluorescence measurements showed that the compounds interact with this biomolecule.

Five novel antimony(III) complexes with the mono- and bis(thiosemicarbazone) ligands of 2N1S or 4N2S donor atoms, N'-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide (Hmtsc, L1) and bis[N'-[1-(2-pyridyl)ethylidene]]-1,4-piperazinedicarbothiohydrazide (H(2)ptsc, L7), and the tridentate semicarbazone ligand of 2N1O donor atoms, 2-acetylpyridine semicarbazone (Hasc, L2b), were prepared by reactions of SbCl(3) or SbBr(3), and characterized by elemental analysis, TG/DTA, FT-IR and (1)H NMR spectroscopy. The crystal and molecular structures of five antimony(III) complexes were determined by single-crystal X-ray structure analysis. The neutral, 6-coordinate antimony(III) complexes ([Sb(mtsc)Cl(2)] 1, [Sb(mtsc)Br(2)] 2, [Sb(asc)Cl(2)] 3 and [Sb(asc)Br(2)] 4) are depicted with one electron pair (5s(2)) of the antimony(III) atom, deprotonated forms of multidentate thiosemicarbazone or semicarbazone ligands, and two monodentate halogen ligands, respectively. In the dimer complex 5 ([Sb(2)(ptsc)Cl(4)]) with the ligand in which two tridentate thiosemicarbazone moieties are connected by the piperazine moiety, each antimony(III) was also described as a neutral 6-coordinate structure. These antimony(III) complexes were thermally stable around 200 degrees C. Water-soluble antimony(III) complexes 1 and 2 showed moderate antimicrobial activities against Gram-positive (Bacillus subtilis and Staphylococcus aureus) and -negative bacteria (Escherichia coli and Pseudomonas aeruginosa), yeasts (Candida albicans and Saccharomyces cerevisiae) and molds (Aspergillus niger and Penicillium citrinum). Complex 5 showed moderate antimicrobial activities against four bacteria, and two molds, while the ligand itself showed only modest antimicrobial activities against selected bacteria (B. subtilis, E. coli and S. aureus). The molecular structures and antimicrobial activities of antimony(III) complexes were compared with those of bismuth(III) complexes in the same 15 group in the periodic table.

The thiosemicarbazone derivative of 9,10-phenanthrenequinone, 1, and its metal complexes were synthesized. The X-ray crystal structure for 1 confirms the presence of the E tautomeric arrangement in this compound. Its copper complex shows 1:1 stoichiometry while nickel and cobalt compounds show 1:2 stoichiometry. The X-ray crystal structure of the nickel complex indicates two tridentate ligands coordinating in the thiolato form yielding an octahedral geometry for the 'mer' isomer. The copper complex exhibits maximum antiproliferative activity against human breast cancer cell-line, T47D probably due to inhibition of steroid binding to the cognitive receptor or by preventing dimerization of the estrogen receptor.

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.

NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Inorganic Biochemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Inorganic Biochemistry 138 (2014): 16-23 DOI http://dx.doi.org/10.1016/j.jinorgbio.2014.04.017, Preparation and characterization of 2,6-diacetylpyridine bis(4N-p-chlorophenylthiosemicarbazone) ligand, H2L, and its palladium(II) and platinum(II) complexes [PdL] and [PtL], is described. The molecular structure of the two new complexes has been determined by single crystal X-ray diffraction. The ligand acts as dianionic tetradentate donor coordinating to the metal center in a square planar geometry through the pyridine nitrogen atom and the azomethine nitrogen and thione sulfur atoms from one thiosemicarbazone arm, the fourth coordination position is occupied by the hydrazine nitrogen atom of the other arm. New free ligand and its metal complexes have been evaluated for antiproliferative activity in vitro against NCI-H460, T-47D, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumor properties, especially H2L and [PtL] since they are capable of not only circumvent cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in breast cancer T-47D cells. The interaction of H2L with calf thymus DNA was also investigated and its binding constant (Kb) determined, We are grateful to Ministerio de Economía y Competitividad, Instituto de Salud Carlos III of Spain (PI1100659) for financial support

An interesting series of new platinum complexes has been synthesized by the reaction of Na(2)ptCl(4) with 2-acetyl pyridine thiosemicarbazone, HAcTsc. The new complexes, [Pt(AcTsc)CI], [Pt(HAcTsc),]Cl-2 and [Pt(AcTsc)(2)], have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(AcTsc)CI] has been solved by single-crystal X-ray diffraction. The anion of HAcTsc coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. Double intermolecular hydrogen bonds (NH-CI), pi-pi and weak Pt-Pt and Pt-pi contacts lead to aggregation and to a two-dimensional supramolecular assembly. The antibacterial and antifungal effect of the novel platinum(II) complexes and the related palladium(fl) complexes, [Pd(AcTsc)CI], [d(HAcTsc),]Cl, and [Pd(AcTsc),], were studied in vitro. The complexes were found to have a completely lethal effect on Gram+ bacteria, while the same complexes showed no bactericidal effect on Gram- bacteria. Additionally, the complexes [Pt(AcTsc),] and [Pd(AcTsc),] showed effective antifungal activity towards yeast. Among these compounds [33], the most effective in inducing antitumour and cytogenetic effects are the complexes [Pt(AcTsc)(2)] and [Pd(AcTsc)(2)] while the rest, display marginal cytogenetic and antitumour effects. (C) 2001 Elsevier Science BY All rights reserved. J Inorg Biochem

The crystal structure of [Ni(L(III))(2)] (1), where HL(III)=thiophene-2-carbaldehyde thiosemicarbazone, consists of monomeric entities where the nickel(II) ions exhibit distorted square planar geometry. The two bidentate thiosemicarbazone ligands are centrosymmetric. C...S van der Waals' links and nonbonded intramolecular interactions are present in the structure. The biological activity of 1 is compared to that of the free ligand, and the cobalt(III) (2) and copper(II) (3) derivatives. The observed order of cytotoxicity against melanoma B16F10 and Friend erythroleukemia cells is: 1< or =ligand

Biological studies on [Fe(L)2](NO3).0.5H2O (1), [Fe(L)2][PF6] (2), [Co(L)2](NCS) (3), [Ni(HL)2]Cl2.3H2O (4) and Cu(L)(NO3) (5), where HL=C7H8N4S, pyridine-2-carbaldehyde thiosemicarbazone, have been carried out. The crystal structure of compound 3 has been solved. It consists of discrete monomeric cationic entities containing cobalt(III) ions in a distorted octahedral environment. The metal ion is bonded to one sulfur and two nitrogen atoms of each thiosemicarbazone molecule. The thiocyanate molecules act as counterions. The copper(II) and iron(III) complexes react with reduced glutathione and 2-mercaptoethanol. The reaction of compound 1 with the above thiols causes the reduction of the metal ion and bis(thiosemicarbazonato)iron(II) species are obtained. The redox activity, and in particular the reaction with cell thiols, seems to be related to the cytotoxicity of these complexes against Friend erithroleukemia cells and melanoma B16F10 cells.

To investigate the relationship between antimicrobial activities and the molecular structures of nickel(II) complexes with thiosemicarbazone and semicarbazone ligands, nickel(II) complexes with ligands Hmtsc, Hatsc, Hasc and H2dmtsc, were prepared and characterized by elemental analysis, FT-IR, 1H and 13C NMR spectroscopies, magnetic susceptibility measurements, UV-Vis absorption spectra, TG/DTA and single-crystal X-ray analysis. Their antimicrobial activities were evaluated by the MIC against four bacteria (B. subtilis, S. aureus, E. coli and P. aeruginosa), two yeasts (C. albicans and S. cerevisiae) and two molds (A. niger and P. citrinum). The 4-coordinate, diamagnetic nickel(II) complexes showed antimicrobial activities which were different from those of free ligands or the starting nickel(II) compounds; [Ni(mtsc)(OAc)] 1 showed selective and effective antimicrobial activities against two Gram-positive bacteria (B. subtilis and S. aureus) and modest activities against a yeast (S. cerevisiae), [Ni(mtsc)Cl] 3 exhibited moderate activities against a Gram-positive bacterium (S. aureus), and [Ni(atsc)(OAc)] 5 showed modest activities against two Gram-positive bacteria (B. subtilis and S. aureus). On the other hand, the 6-coordinate, paramagnetic nickel(II) complexes with two protonated or deprotonated ligands ([Ni(mtsc)2] 2, [Ni(atsc)(mtsc)] 4, [Ni(atsc)2] 6, [Ni(Hatsc)2](NO3)(2)7, [Ni(Hatsc)2]Cl(2)8 and [Ni(Hasc)2](OAc)(2)9) and the sterically crowded 4-coordinate, diamagnetic nickel(II) complex ([Ni(dmtsc)] 10) did not inhibit the growth of the test organisms. The structure-activity correlation in this series of nickel(II) complexes was discussed based on their ligand-replacement abilities.

Vitamin K-3-thiosemicarbazone (C12H11N3NaO4S2. 5H(2)O, abbreviated as VT), a new Schiff base derivative, has been synthesized. Its crystal structure, determined by X-ray diffraction, is triclinic, space group P (1) over bar. We have also prepared five novel complexes of VT with transition metals: [M(VT)(2)2H(2)O]. nH(2)O, (n = 1 and 2 for M = Cu(n) and Zn(II), respectively) and [M'(HVT)(2)Cl-2]. mH2O, (m =4, 5, and 7 for M' =Co(II), Mn(II), and Ni(n), respectively). These compounds were characterized by IR and UV-Vis spectroscopy, molar conductivity, thermal analyses, complexometric titration, and elemental analysis. In all the complexes, the VT ligand coordinates through sulfur and oxygen atoms, and the geometry around metal atom is best described as octahedral, in vitro tests of antibacterial activity showed that VT and its complexes with Mn(II), Co(n),Ni(II), Cu(II), and Zn(II) all had strong inhibitory actions against G(+) Staphylococcus aureus, G(+) Hay bacillus, and G(-) Escherichia coli. (C) 2000 Elsevier Science Inc. All rights reserved.

It is known that metallic complexes of methyl 2-pyridyl ketone thiosemicarbazone (HL1) and p-isopropyl benzaldehyde thiosemicarbazone (HL2) may have potential antitumor activity. We have prepared complexes of HL1 and HL2 with Zn(II) and Cd(II). The cytotoxic activity shown by these compounds against cell lines sensitive and resistant to cis-diamminedichloroplatinum(II) (cis-DDP) indicates that coupling of HL1 and HL2 to Zn(II) and Cd(II) centers may result in metallic complexes with important biological properties since they display IC50 values in a microM range similar to that of the antitumor drug cis-DDP. Moreover, it is interesting to note that the Zn/HL2 complex exhibits specific cytotoxic activity against Pam-ras cells (cis-DDP resistant cells which over-express the H-ras oncogene) with an in vitro therapeutic index of 3.26 versus 0.78 for cis-DDP. Treatment of Pam-ras cells with the IC50 value of the Zn/HL2 compound induces a 'DNA ladder' (fragmentation of genomic DNA in nucleosome units) indicative of apoptosis in this ras-transformed cell line. In contrast, a 'DNA smear' (non-specific fragmentation of genomic DNA) is observed in Pam 212 normal cells treated with the IC50 of this compound. The analysis by circular dichroism (CD) spectroscopy of the interaction of the Zn/HL2 compound with calf thymus DNA (CT DNA) indicates that it produces stronger alterations on the double helix conformation than cis-DDP. So, these results suggest that Zn/HL2 may be considered a potential antitumor agent.

The synthesis, structure and spectroscopic properties on complexes with the formula [Cu(L III ) 2 ] ( 1 ) and Cu(NO 3 ) 2 (HL III ) 2 ( 2 ), where HL III = thiophene-2-carbaldehyde thiosemicarbazone, have been developed. The molecular structure of compound 1 consists of monomeric entities. The copper(II) ions exhibit distorted square-planar geometry with both bidentate thiosemicarbazone ligands placed in a centrosymmetric way. Metal to ligand π-backdonation is proposed to explain several structural and spectroscopic features in these complexes. The EPR spectra of compound 1 show an orthorhombic g tensor indicating the presence of weak magnetic exchange interactions. The reaction of compound 1 with glutathione causes the reduction of the metal ion and the substitution of the thiosemicarbazone ligand by the thiol ligand. This mechanism seems to be related to the cytotoxicity of this complex against Friend Erithroleukemia cells (FLC) and melanome B16F10 cells.

Reaction of the vitamin K(3) derivative menadione sodium bisulfite thiosemicarbazone (NaK(3)TSC) with chloro(triethylphosphine)gold(I) afforded the complex [AuPEt(3)(K(3)TSC)]. This compound consists of discrete molecules in which the metal is almost linearly coordinated to P and S. Preliminary in vitro screening showed significant anti-cancer activity, notably against the cisplatin-resistant cell line A2780cis.