Ketone Thiosemicarbazone Research Articles

Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin-Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment.

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)-indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA-IND-C4 complex (HSA-IND-C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA-IND-C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.

Methyl 4-pyridyl ketone thiosemicarbazone (4-PT) as an effective and safe inhibitor of mushroom tyrosinase and antibrowning agent

Enzymatic browning is of concern as it can affect food safety and quality. In this study, an effective and safe tyrosinase inhibitor and anti-browning agent, methyl 4-pyridyl ketone thiosemicarbazone (4-PT), was synthesised and characterised using Fourier-transform infrared (FTIR) spectroscopy, CHNS elemental analysis, and proton (1H) and carbon-13 (13C) nuclear magnetic resonance (NMR) spectroscopy. The vibrational frequencies of 4-PT were studied theoretically using vibrational energy distribution analysis (VEDA). Density functional theory (DFT) was applied to elucidate its chemical properties, including the Mulliken atomic charges, molecular electrostatic potential (MEP), quantum theory of atoms in molecules (QTAIM) and reduced density gradient non-covalent interactions (RDG-NCIs). Moreover, 4-PT was compared with kojic acid in terms of its effectiveness as a tyrosinase inhibitor and anti-browning agent. The toxicity and physicochemical properties of 4-PT were predicted via ADME evaluation, which proved that 4-PT is safer than kojic acid. Experimentally, 4-PT (IC50 = 5.82 μM, browning index (10 days) = 0.292 ± 0.002) was proven to be an effective tyrosinase inhibitor and anti-browning agent compared to kojic acid (IC50 = 128.17 μM, browning index (10 days) = 0.332 ± 0.002). Furthermore, kinetic analyses indicated that the type of tyrosinase inhibition is a mixed inhibition, with Km and Vmax values of 0.85 mM and 2.78 E-09 μM/s, respectively. Finally, the mechanism of 4-PT for tyrosinase inhibition was proven by 1D, second derivative and 2D IR spectroscopy, molecular docking and molecular dynamic simulation approaches.

Optical and Electrochemical Sensing of Co(II), Ni(II) and Cu(II) in DMSO. Pyridyl Thiazole and (Thio)Amide Pincer Ligands versus Di‐2‐pyridyl Ketone Hydrazones

AbstractThe ability of six pincer type molecules (di‐2‐pyridyl ketone acetic acid hydrazone (1), N‐(2,5‐dimethoxyphenyl)‐6‐[(2,5‐dimethoxyphenyl)carbamothioyl]pyridine‐2‐carboxamide (2), 6‐(4,7‐dimethoxy‐2‐benzothiazolyl)‐N‐(2,5‐dimethoxyphenyl)‐2‐pyridinecarboxamide (3), di‐2‐pyridyl ketone thiosemicarbazone (4), bis‐N‐(2,5‐dimethoxyphenyl)pyridine‐2,6‐dicarbothioamide (5), and 6‐(4,7‐dimethoxy‐2‐benzothiazolyl)‐N‐(2,5‐dimethoxyphenyl)‐2‐pyridinecarbothioamide (6)), to detect MBr2 (where M=Co, Ni, and Cu) in DMSO was quantified via formation constants determined from spectrophotometric and voltammetric titrations. The limit of detection (from electronic spectroscopy) of 1–6 ranged from 0.9‐9.5 ppm. The values of β (=log K) for the six species were found to be in the ranges of 4.3–4.9 and 4.0–6.3 for Co(II), 3.9–5.5 and 3.5–4.3 for Ni(II), and 4.0–4.3 and 3.7–5.0 for Cu(II) by UV‐visible and voltammetric methods, respectively. The results suggested that κ3‐NNS (6) and the κ3‐NNO (3) had good affinity for Ni(II) and Cu(II), whereas the κ3‐SNS (5) had greater affinities for Co(II) and Ni(II). The hydrazones (κ3‐NNO, 1 and κ3‐NNS, 4) were generally in the middle of the pack, displaying good affinity for the three metal ions. In a contrasting vein, the κ3‐ONS species (2) was generally the lowest across the pincers. DFT calculations (PBE0/6‐31G(d,p)/SMD) suggested that stable complexes of coordination numbers=4 to 6 were plausible in solution.

Novel κ2-Nim,S- and κ4-C,Nim,(μ-S),(μ-S)-coordination of di-2-thienyl ketone thiosemicarbazone (dtktsc). Hydrogen evolution and catalytic properties of palladacyclic [Pd(κ4-C,Nim,(μ-S),(μ-S)-dtktsc-2H)

The reaction between di-2-thienyl ketone thiosemicarbazone, dtktsc, (1) and Zn(OAc)2·2H2O in ethanol produced [Zn(κ2-Nim,S-dtktsc-H)2] (2). When PdCl2(CH3CN)2 was used in place Zn(OAc)2·2H2O novel [Pd(κ4-C,Nim,(μ-S),(μ-S)-dtktsc-2H)]4 (3) was isolated. These reactions are in contrast with those reported for the synthesis of [Zn(κ3-Npy,Nim,S-dpktsc-H)2] and [PdCl(κ3-Npy,Nim,S),PdCl2(κ2-Npy,Nam)-dpktsc-H)] • CH3CN when di-2-pyridyl ketone thiosemicarbazone (dpktsc) was used in place of 1. The identities of 2 and 3 were established from results of their elemental compositions, spectroscopic and electrochemical properties. The κ2-Nim,S-coordination of the imide deprotonated dtktsc (dtktsc-H)– to the Zn(II) ion was established from 13C and 1H NMR measurements. X-ray structural analysis on a single crystal of 3 • dmf confirmed the κ4-Nim,C,(μ-S),(μ-S)-coordination of amide deprotonated and thienyl metallated dtktsc (dtktsc-2H)2- to the Pd(II) ion. In acidic or basic media 2 suffers dissociation, while 3 is stable under similar conditions. Electrochemical measurements on dmf solutions of 2 and 3, along with electrochemical reactions of dtktsc with Zn(OAc)2·2H2O and PdCl2(CH3CN)2 revealed facile coordination of dtktsc to the metal ions. The palladacyclic 3 shows good electro-catalytic behavior toward proton reduction and moderate catalytic activity toward CC cross-coupling reactions.

Spectroscopic, electrochemical and X-ray crystallographic properties of a novel palladium(II) complex of thioamide deprotonated di-2-pyridyl ketone thiosemicarbazone (dpktsc-H)−

The reaction between di-2-pyridyl ketone thiosemicarbazone (dpktsc) and PdCl2(CH3CN)2, generated in situ from the reaction between PdCl2 and CH3CN, gave the unprecedented [Pd2Cl3(κ5-Npy,Nim,S,Npy,Nam-dpktsc-H)]·2CH3CN (1) complex (py = pyridine, im = imine and am = amide). The identity of 1 was confirmed via its elemental analysis and spectroscopic properties. Infrared and 1H-NMR spectra confirmed the coordination of (dpktsc-H)− to the palladium ions. The electronic absorption spectra measured in dmso and dmf and density functional theory (DFT) calculations revealed metal-to-ligand charge-transfer (MLCT), d–d and intra-ligand charge-transfer (ILCT) electronic transitions. X-ray structural analysis on a crystal of [Pd2Cl3(κ5-Npy,Nim,S,Npy,Nam-dpktsc-H)]·H2O (2) grown from dmf solution of 1 confirmed its formulation and showed the solid-state structure contains a web of molecules locked via a network of non-covalent interactions. Electrochemical measurements on 1 in dmf revealed metal- and ligand-based redox processes. In contrast to the electrochemical decomposition of uncoordinated dpktsc, coordinated (dpktsc-H)− in 1 does not undergo electrochemical decomposition. Electrochemical titrations of 1 with p-toluenesulfonic acid monohydrate (p-TSOH) revealed electro-catalytic proton reduction. Over-potential (η) of 180 mV for the H2 evolution was observed and is comparable to several molecular electro-catalysts for proton reduction. Controlled-potential electrolysis confirmed the electro-catalytic proton reduction by the Pd-complex. Electrochemical reactions of CO2 in the presence of 1 exhibited a proton dependence, and metal- and ligand-based electrochemical reaction.

Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L

The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.

Spectroscopic and electrochemical properties of di-2-thienyl ketone thiosemicarbazone (dtktsc): electrochemical reactions with electrophiles (H+ and CO2)

The first di-2-thienyl ketone thiosemicarbazone (dtktsc) and its di-2-thienyl ketone (dtk) hybrid (dtktsc-dtk) were isolated and characterized from the results of their elemental analyses, spectroscopic measurements and X-ray structural analyses. Spectroscopic and electrochemical measurements disclosed sensitivity of dtktsc to changes in its surroundings. Electronic absorption measurements in protophilic solvents (dmso and dmf) in the presence and absence of a base disclosed deprotonation of the thioamide (NH) proton. Variable temperature 1H NMR measurements divulged entropy driven exchange of NH and NH2 protons with the residual water protons. X-ray structure analyses confirmed the identities of dtktsc and dtktsc-dtk. Electrochemical measurements on dtktsc in the presence and absence of an electrophile (CO2 or H+) revealed irreversible redox processes pointing to electrochemical decomposition, reactions with electrophiles and electro-polymerization. On GC-electrode electro-polymerization of dtktsc occurs in CH3CN on oxidative scans. On reductive scans at a Pt-electrode, electro-catalytic decomposition of dtktsc occurs. Plausible mechanisms for the electrochemical decomposition and reactions of dtktsc with electrophiles are proposed.

Synthesis of diazahomoadamantanones thiosemicarbazones

Thiosemicarbazones of ketones from 3,6-diazahomoadamantane series were prepared by two procedures: by treating 3,6-diazahomoadamantan-9-ones with thiosemicarbazide and by a reaction of substituted (3,6-diazahomoadamantan-9-ylidene)hydrazines with versatile isothiocyanates.

Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis

Cancer cell resistance to chemotherapy is still a heavy burden that impairs the response of many cancer patients to conventional chemotherapy. Using drug combinations is one therapeutic approach to overcome the developing resistance to any one drug. Oxidative stress is now a generally regarded hallmark of cancer that can be one approach to selectively target cancer cells while sparing normal cells. With the aim of increasing oxidative stress in cancer cells to a lethal set point, we have generated and combined several series of redox active compounds that act at different points of the cellular oxidative cascade. The premise of such combinations is to deplete of endogenous antioxidant defence proteins (e.g., Glutathione) while concomitantly increasing the generation of ROS via metal redox recycling and Fenton chemistry which eventually leads to the disruption of cellular redox homeostasis and induction of cell death. Through this approach, we have identified highly synergistic combinations of two distinctive classes of compounds (Azines and Copper(II) complexes of 2-pyridyl ketone thiosemicarbazones) which are capable of eliminating cancer cells without concomitant increase in toxicity toward normal cells. In one of our most potent combinations, a combination index (CI) value of 0.056 was observed, representing a 17 fold enhancement in activity beyond additive effects. Such new combination regimen of redox active compounds can be one step closer to potentially safer low dose chemotherapy.

Synthesis, Characterization and Anti Microbial Activity of Some Heterocyclic Ketone Thiosemicarbazones

Synthesis, Characterization and Anti Microbial Activity of Some Heterocyclic Ketone Thiosemicarbazones

Novel Second-Generation Di-2-Pyridylketone Thiosemicarbazones Show Synergism with Standard Chemotherapeutics and Demonstrate Potent Activity against Lung Cancer Xenografts after Oral and Intravenous Administration in Vivo

We developed a series of second-generation di-2-pyridyl ketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands to improve the efficacy and safety profile of these potential antitumor agents. Two novel DpT analogues, Dp4e4mT and DpC, exhibited pronounced and selective activity against human lung cancer xenografts in vivo via the intravenous and oral routes. Importantly, these analogues did not induce the cardiotoxicity observed at high nonoptimal doses of the first-generation DpT analogue, Dp44mT. The Cu(II) complexes of these ligands exhibited potent antiproliferative activity having redox potentials in a range accessible to biological reductants. The activity of the copper complexes of Dp4e4mT and DpC against lung cancer cells was synergistic in combination with gemcitabine or cisplatin. It was demonstrated by EPR spectroscopy that dimeric copper compounds of the type [CuLCl](2), identified crystallographically, dissociate in solution to give monomeric 1:1 Cu:ligand complexes. These monomers represent the biologically active form of the complex.

ChemInform Abstract: Reactions of Flavonoid Thiosemicarbazones Under Acetylating Conditions.

Abstract Upon acetylation, (2-phenyl)dihydrobenzopyrone- and 2′-hydroxychalcone thiosemicarbazones (1c, 2c, 3c, and 7c) form 2,2-disubstituted 5-acetamido-3-acetyl-2,3-dihydro-1,3,4-thiadiazoles (1i, 2i, 4i, and 8i) instead of the diacetylthiosemicarbazones (2e, 8e) claimed in the literature. Similarly, the reactions of the aromatic ketone thiosemicarbazones 9c, 10c and 11d result in the formation of thiadiazolines (9i, 10i, and 11k, respectively), flavone thiosemicarbazone (6c), however, is degraded to flavone diacetylhydrazone (6g) under the same conditions. The synthesis of the flavanone spiro-1,3,4-oxadiazoline 2h is also described.

Vibrational spectroscopic studies and computational study of ethyl methyl ketone thiosemicarbazone

FT-IR and FT-Raman spectra of ethyl methyl ketone thiosemicarbazone were recorded and analyzed. The crystal structure is also described. The vibrational wavenumbers were computed using HF/6–31G(d) and B3LYP/6–31G(d) basis sets and are assigned with the aid of MOLEKEL program. The first hyperpolarizability, infrared intensities and Raman activities are also reported. The calculated first hyperpolarizability is comparable with the reported values of similar derivatives and is an attractive molecule for future applications in non-linear optics. The geometrical parameters of the title compound obtained from XRD studies are in agreement with the calculated values. The red shift of the NH stretching wavenumber in the infrared spectrum compared to the computed wavenumber indicates the weakening of the N–H bond resulting in proton transfer to the neighbouring sulfur atom.

Synthesis, characterization and molecular sensing capability of fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] where dpktsc = di-2-pyridylketone thiosemicarbazone

When di-2-pyridyl ketone thiosemicarbazone (dpktsc) was allowed to react with [Re(CO) 5Cl] in toluene under reflux, fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] was isolated in good yield. The identity of fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] was established from the results of its elemental analysis, spectroscopic, and electrochemical properties. The infrared spectra of fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] show the facial coordination of the carbonyl groups, and the pyridyl N,N-coordination of dpktsc. 1H NMR measurements on fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] in d 6-dmso and d 6-acetone confirmed the pyridyl N,N-coordination of dpktsc, and showed strong solvent dependence as manifested by the sensitivity of thioamide and ammine protons to their surroundings. The electronic absorption spectra of fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] in protophilic solvents (dmso and dmf) display two intra-ligand charge transfer (ILCT) transitions at 476 and 360 nm and in non-protophilic solvents a single ILCT transition at 346 nm in CH 3CN and 342 nm in CH 2Cl 2. Reversible interconversion between fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] and its conjugate base was established in protophilic solvents using a base to shift the equilibrium to the conjugate base and an acid to shift the equilibrium or conjugate base to the neutral form. Substrates in concentrations as low as 1 × 10 −10 M can be detected and determined using protophilic solutions of fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl]. When MCl 2 (M = Zn, Cd or Hg) was allowed to interact with fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] in protophilic solvents, the intensity of the low energy ILCT band disappeared and a shift in the high energy ILCT electronic transition was observed that hints to the coordination of MCl 2 to fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl]. Electrochemical measurements on fac-[Re(CO) 3(κ 2-N,N-dpktsc)Cl] in dmf showed sequential irreversible redox processes in accord with the electrochemical reduction or oxidation of the thiosemicarbazone moiety.

Liquid Chromatographic Determination of Co(II), Cu(II), Ni(II), and Fe(II) using Di‐2‐pyridylketon Thiosemicarbazone (DPKT) as Derivatizing Reagent

Di‐2‐pyridyl ketone thiosemicarbazone (DPKT) was examined as a precolumn chelating reagent for high performance liquid chromatographic separation of Co(II), Cu(II), Ni(II), and Fe(II) ions as metal chelates on a 10 µm Bondapak C18 (300 mm×3.9 mm) RP column. A gradient program with a mobile phase of acetonitrile and 0.01 M pH:6.0 acetate buffer is used. Acetonitrile composition is increased from 25 to 40% at 18 min and held at 40% for 18 min. A UV detector was used at 400 nm. The flow rate was 1.5 mL · min−1. Limit of detection was determined on a 3σ blank basis. Interference effects from other metal ions were also investigated. The method was applied for the determination of Co(II), Cu(II), Ni(II), and Fe(II) ions in drinking and tap water samples.

Dipyridyl Thiosemicarbazone Chelators with Potent and Selective Antitumor Activity Form Iron Complexes with Redox Activity

There has been much interest in the development of iron (Fe) chelators for the treatment of cancer. We developed a series of di-2-pyridyl ketone thiosemicarbazone (HDpT) ligands which show marked and selective antitumor activity in vitro and in vivo. In this study, we assessed chemical and biological properties of these ligands and their Fe complexes in order to understand their marked activity. This included examination of their solution chemistry, electrochemistry, ability to mediate redox reactions, and antiproliferative activity against tumor cells. The higher antiproliferative efficacy of the HDpT series of chelators relative to the related di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues can be ascribed, in part, to the redox potentials of their Fe complexes which lead to the generation of reactive oxygen species. The most effective HDpT ligands as antiproliferative agents possess considerable lipophilicity and were shown to be charge neutral at physiological pH, allowing access to intracellular Fe pools.

Synthesis, characterization and in vitro antibacterial activity of new steroidal thiazolo quinoxalines

Herein, we report the synthesis of different steroidal thiazolo quinoxaline derivatives as antibacterial agents against Escherichia coli. Steroidal ketone thiosemicarbazones ( 4–6) were obtained from corresponding ketones ( 1–3) by refluxing with thiosemicarbazide. The thiosemicarbazones on reaction with 2,3-dichloroquinoxalines at 80 °C gives 3β-acetoxy-5α-cholestan-6-[thiazolo(4,5- b)quinoxaline-2-yl-hydrazone] ( 7), 3β-chloro-cholestan-6-[thiazolo(4,5- b)quinoxaline-2-yl-hydrazone] ( 8), and 5α-cholestan-6-[thiazolo(4,5- b)quinoxaline-2-yl-hydrazone] ( 9). The structures of the compounds were evident by elemental, IR, 1H NMR and FAB mass spectral analyses. The antibacterial activities of these compounds were evaluated by disk diffusion method against the culture of E. coli and the results were compared with the standard drug amoxicillin. The results reveal that the compounds are better antibacterial agents as compared to amoxicillin. Among all the three compounds ( 7–9), compound 8 showed better zone of inhibition.

Preconcentration of Some Trace Metal Ions from Drinking and Tap Water Samples by Sorption on Amberlite XAD‐4 after Complexation with Di‐2‐Pyridyl Ketone Thiosemicarbazone

A method was established for enrichment of trace levels of Co(II), Ni(II), Fe(II), and Cu(II) ions in aqueous solutions. These metals were quantitatively retained on an Amberlite XAD‐4 column, after complexation with di‐2‐pyridyl ketone thiosemicarbazone (DPKT). After elution with 1 M HNO3 in acetone, concentration of metals were measured by atomic absorption spectrometry. The effect of major cations of drinking and tap water samples on the sorption of metal ions also were investigated. The amount of the analyte metal ions determined after preconcentration was basically in agreement with the added amount. The developed method was used for the determination of trace amounts of metal ions in drinking and tap water samples with good results, such as relative standart deviations below 2% (N=6) and recoveries greater than >95%.

Spectroscopic and biological studies on newly synthesized nickel(II) complexes of semicarbazones and thiosemicarbazones

Nickel(II) complexes, having the general composition Ni(L) 2X 2, have been synthesized [where L: isopropyl methyl ketone semicarbazone (LLA), isopropyl methyl ketone thiosemicarbazone (LLB), 4-aminoacetophenone semicarbazone (LLC) and 4-aminoacetophenone thiosemicarbazone (LLD) and X = Cl −, 1/2SO 4 2−]. All the Ni(II) complexes reported here have been characterized by elemental analyses, magnetic moments, IR, electronic and mass spectral studies. All the complexes were found to have magnetic moments corresponding to two unpaired electrons. The possible geometries of the complexes were assigned on the basis of electronic and infrared spectral studies. Newly synthesized ligand and its nickel(II) complexes have been screened against different bacterial and fungal growth.

Spectroscopic evaluation of manganese(II) complexes derived from semicarbazones and thiosemicarbazones

Manganese(II) complexes having the general composition Mn(L) 2X 2 [where L = isopropyl methyl ketone semicarbazone (LLA), isopropyl methyl ketone thiosemicarbazone (LLB), 4-aminoacetophenone semicarbazone (LLC) and 4-aminoacetophenone thiosemicarbazone (LLD) and X = Cl −, 1/2SO 4 2−] have been synthesized. All the complexes were characterized by elemental analyses, molar conductance, magnetic moment susceptibility, EI-mass, 1H NMR, IR, EPR and electronic spectral studies. All the complexes show magnetic moments corresponding to five unpaired electrons. The possible geometries of the complexes were assigned on the basis of EPR, electronic and infrared spectral studies.