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PubMed1999

Synthesis and spectroscopic properties of copper(II) complexes derived from thiophene-2-carbaldehyde thiosemicarbazone. Structure and biological activity of [Cu(C6H6N3S2)2].

The synthesis, structure and spectroscopic properties on complexes with the formula [Cu(Lm)2] (1) and Cu(NO3)2(HLm)2 (2), where HLm = 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 pi-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.

Animals↗
PubMed1999

Synthesis and evaluation of copper radiopharmaceuticals with mixed bis(thiosemicarbazone) ligands.

Four "mixed" bis(thiosemicarbazone) derivatives of pyruvaldehyde were synthesized that incorporate two dissimilar thiosemicarbazone functions. The corresponding [67Cu]copper(II) complexes were prepared and evaluated as possible copper radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands, CH3C[=NNHC(S)NHMe]CH[=NNHC(S)NHEt] (1), CH3C[=NNHC(S)NHMe] CH[=NNHC(S)NEt2] (2), CH3C[=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)5] (3), and CH3C [=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)6] (4), were obtained by reaction of the appropriate thiosemicarbazide derivative with pyruvaldehyde-2-N4-methylthiosemicarbazone (CH3C[=NNHC(S) NHMe]CHO). The 67Cu-labeled copper(II) complexes of ligands 1-4 were prepared and screened in a rat model to assess the potential of each chelate as a 62Cu-radiopharmaceutical for imaging with positron emission tomography. The 67Cu-complexes of ligands 1-4 exhibit significant uptake into the brain and heart 1 min following intravenous administration to rats. For the 67Cu-complexes of ligands 2, 3, and 4, the cerebral and myocardial uptake of 67Cu is two-to-threefold lower at 2 h than at 1 min postinjection, due to significant biological clearance of these 67Cu-chelates. However, the 67Cu-complex of 1 affords cerebral and myocardial uptake and retention comparable to that of [67Cu]Cu-PTSM in this model. Although the kinetics of this new agent appear attractive, ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu-complex of ligand 1, like Cu-PTSM, interacts more strongly with human albumin than dog albumin. Thus, this new agent would appear to offer no advantage over Cu-PTSM as a 62Cu-labeled tracer for evaluation of regional tissue perfusion.

Animals↗
PubMed1989

Hybrid molecules: growth inhibition of Leishmania donovani promastigotes by thiosemicarbazones of 3-carboxy-beta-carbolines.

The thiosemicarbazones of beta-carboline-3-carboxaldehyde (compound 2) and 3-acetyl-beta-carboline (compound 3) were found to effectively inhibit the in vitro growth of the promastigote form of Leishmania donovani, 50% inhibition being obtained at concentrations of 5.0 and 2.5 microM, respectively, while irreversible growth inhibition was achieved at 40 (compound 2) and 17.5 microM (compound 3). The thiosemicarbazone of pyridine-2-carboxyaldehyde (compound 4) was considerably less active while both methyl beta-carboline-3-carboxylate (compound 1) and the thiosemicarbazone of ethyl 5-formyl-6-azaindole-2-carboxylate (compound 5) were inactive at the highest concentrations tested. At concentrations provoking approximately 50% growth inhibition of promastigotes, compound 2 was observed to preferentially block DNA rather than RNA synthesis, but for compound 3, the reverse was true. Compound 3, the most active analogue studied, may thus act, at least partially, via a novel, though as yet unelucidated, mechanism.

Animals↗
PubMed1979

2-Acetylpyridine thiosemicarbazones. 1. A new class of potential antimalarial agents.

Based on the antimalarial properties observed for 2-acetylpyridine 4-phenyl-3-thiosemicarbazone (1), an extensive series of related thiosemicarbazones was prepared and tested against Plasmodium berghei in mice. Screening results indicated that the presence of the 2-pyridylethylidene group was critical and that certain phenyl, benzyl, phenethyl, or cycloalkyl groups at N4 of the thiosemicarbazone moiety also contribute to antimalarial activity.

Animals↗
PubMed1979

2-Acetylpyridine thiosemicarbazones. 2. N4,N4-Disubstituted derivatives as potential antimalarial agents.

The most effective antimalarial agents among the N4-monosubstituted 2-acetylpyridine thiosemicarbazones recently described by us have a cyclohexyl or a phenyl substituent and produce cures in Plasmodium berghei infected mice at a dose of 160 and 320 mg/kg, respectively. We report here on a related series of N4,N4-disubstituted 2-acetylpyridine thiosemicarbazones. Several members of this group bearing alkyl or cycloalkyl substituents at N4 show activity superior to the most active monosubstituted 2-acetylpyridine thiosemicarbazones. However, the greatest improvement in potency was seen when the N4-nitrogen atom was incorporated into a six- or seven-membered ring, such as the piperidine, piperazine, or azabicyclo[3.2.2]nonane systems, to give compounds with curative properties at a dose level as low as 20 mg/kg.

Animals↗
PubMed1984

2-Acetylpyridine thiosemicarbazones. 9. Derivatives of 2-acetylpyridine 1-oxide as potential antimalarial agents.

In view of the antimalarial activity in mice of 2-acetylpyridine thiosemicarbazones, a series of analogous 1-oxides was prepared for evaluation. Their synthesis was achieved by the reaction of 2-acetylpyridine 1-oxide with methyl hydrazinecarbodithioate to give methyl 3-[1-(2-pyridinyl 1-oxide)ethylidene]hydrazinecarbodithioate (II). Reaction of the latter intermediate with secondary amines afforded the desired 2-acetylpyridine 1-oxide thiosemicarbazones (III). Reduction of the azomethine linkage of II with NaBH4 gave methyl 3-[1-(2-pyridinyl 1-oxide)ethyl]-hydrazinecarbodithioate (IV) whose S-methyl group was then displaced by amines to give a 1-[1-(2-pyridinyl 1-oxide)ethyl]thiosemicarbazide, V. Antimalarial activity of III was evaluated against both Plasmodium berghei in the mouse and Plasmodium falciparum in an automated in vitro test system. In both cases, 2-acetylpyridine 1-oxide thiosemicarbazones were found to be less active than the corresponding de-1-oxide analogues. When compounds V were evaluated against Plasmodium berghei in the mouse, a diminution of activity was similarly seen in comparison to the analogues not bearing the 1-oxide moiety.

Animals↗
PubMed2003

Platinum(II) and palladium(II) complexes with 2-acetyl pyridine 4N-ethyl thiosemicarbazone able to overcome the cis-platin resistance. Structure, antibacterial activity and DNA strand breakage.

The reactions of Pd(II) and Pt(II) with 2-Acetyl Pyridine N(4)-Ethyl-Thiosemicarbazones, HAc4Et and 2-Acetyl Pyridine N(4)-1-(2-pyridyl)-piperazinyl Thiosemicarbazone, HAc4PiPiz and 2-Formyl Pyridine N(4)-1-(2-pyridyl)-piperazinyl Thiosemicarbazone, HFo4PiPiz afforded the complexes, [Pd(Ac4Et)], 1, [Pd(HAc4Et)2]Cl2, 2 and [Pd(Ac4Et)2], 3 [Pt(Ac4Et)], 4, [Pt(HAc4Et)2]Cl2, 5, [Pt(Ac4Et)2], 6 and [Pd(Fo4PipePiz)Cl], 7, [Pd(Fo4PipePiz)2], 8, [Pd(Ac4PipePiz)Cl], 9 and [Pd(Ac4PipePiz)2], 10. The crystal structure of the complex [Pt(Ac4Et)2], 6 has been solved. The platinum(II) atom is in a square planar environment surrounded by two cis nitrogen atoms and two cis sulfur atoms. The ligands are not equivalent, one being tridentate with (N,N,S) donation, the other being monodentate using only the sulfur atom to coordinate to the metal. The tridentate ligand shows a Z, E, Z configuration while the monodentate ligand shows an E, E, Z. Inter-molecular hydrogen bonds stabilize the structure, while the crystal packing is determined by pi-pi, and Pt-C interactions. The antibacterial effect of Pd(II) and Pt(II) complexes were studied in vitro. The complexes were found to have effect on Gram(+) bacteria, while the same complexes showed no bactericidal effect on Gram(-) bacteria. The effect of the Pd(II) and Pt(II) complexes on the in vitro DNA strand breakage was studied by agarose gel electrophoresis. The complexes 1-6 were found to exhibit a cytotoxic potency in a very low micromolar range and to be able to overcome the cisplatin resistance of A2780/Cp8 cells.

Anti-Infective Agents↗
PubMed1977

Inactivation and inhibition of Rous sarcoma virus by copper-binding ligands: thiosemicarbazones, 8-hydroxyquinolines, and isonicotinic acid hydrazide.

We have shown that three types of copper-binding ligands, thiosemicarbazones, 8-hydroxyquinolines, and isonicotinic acid hydrazide and their copper complexes, inactivate the transforming ability of RSV and inhibit its RNA-dependent DNA polymerases. Three other compounds, 2-pyridine thiosemicarbazone, 1-formyl isoquinoline thiosemicarbazone, and diphenyl thiocarbazone inhibit transformation by RSV intracellularly. Most but not all of these compounds bind to nucleic acids in the presence of copper, which may be important in their mode of action.

Avian Sarcoma Viruses↗
PubMed1980

Activity of 2-acetylpyridine thiosemicarbazones against Trypanosoma rhodesiense in vitro.

Twenty-seven 2-acetylpyridine thiosemicarbazones and analogs were tested for antitrypanosomal activity against Trypanosoma rhodesiense using a semiautomated in vitro assay system. Activity was determined by relative inhibition of uptake of two radiolabeled macromolecular precursors, [methyl-3H]thymidine and L-[U-14C]leucine, as compared to untreated controls. It was observed that the nitrogen atom of the pyridyl moiety of the 2-acetylpyridine thiosemicarbazones was essential for antitrypanosomal activity. The 2-acetylpyridine thiosemicarbazones generally inhibited the uptake of L-[U-14C]leucine to a greater extent than they inhibited [methyl-3H]thymidine uptake. Twenty-four of the 27 compounds tested exhibited activity comparable to that found for the antitrypanosomal agent ethidium bromide.

Animals↗
PubMed1985

In vitro susceptibility of Neisseria gonorrhoeae to 2-acetylpyridine thiosemicarbazones.

MICs of 20 2-acetylpyridine thiosemicarbazones and penicillin were determined for 25 clinical isolates of beta-lactamase-positive and beta-lactamase-negative Neisseria gonorrhoeae strains. The compounds most active against the beta-lactamase-producing strains were the N4,N4-disubstituted derivatives and the thiosemicarbazone derivatives of the 2-acetylpyridines, followed by the other compounds related to the 2-acetylpyridine thiosemicarbazones.

Anti-Bacterial Agents↗
PubMed1973

Inhibition of granulocyte-macrophage colony formation in vitro by substituted isatin thiosemicarbazones.

The 1-methylisatin derivative of isatin thiosemicarbazone was previously shown to inhibit granulocyte-macrophage colony growth in vitro by an action at the early stages of colony development. The parent compound isatin thiosemicarbazone and 25 other derivatives were tested, and a wide range of activity was found (50% colony inhibition from 0.07 to > 100 mug per ml of culture). High activity was not associated with any specific substituent although 1-methyl or 1-ethyl isatin groups in association with 4'4' morpholino or 4'4' tetramethylene thiosemicarbazone substitutions were within the most active group. No correlation between the antimarrow and known antiviral activities of these compounds was apparent. Two of the more active compounds were compared with methisazone and were shown to have the same property of selective action on the early stages of granulocyte-macrophage differentiation in culture. It is suggested that this group of compounds might possibly provide some useful antileukemia agents.

Bone Marrow↗
PubMed1976

Inactivation of lambda phage infectivity and lambda deoxyribonucleic acid transfection by N-methyl-isatin beta-thiosemicarbazone-copper complexes.

The infectivity of intact lambda phage and transfection by lambda deoxyribonucleic acid were inactivated by exposure to the copper complexes of N-methyl-isatin beta-thiosemicarbazone, thiosemicarbazide, and semicarbazide, but not methyl-isatin. No inactivation was observed when these compounds were used in the absence of copper sulfate. This confirms our previous observation that the activity of N-methyl-isatin beta-thiosemicarbazone is mediated by its thiosemicarbazone moiety and that the presence of copper is required for action. This represents the first time, to our knowledge, that semicarbazide has been found to possess antiviral activity. It is clear that these compounds act directly on deoxyribonucleic acid; whether the compounds also act on proteins has not been determined.

Coliphages↗
PubMed1967

Use of thiosemicarbazone and para-nitrobenzoic acid in screening tests for anonymous mycobacteria.

In screening for anonymous mycobacteria the use of thiosemicarbazone (10mug./ml.) may give rise to false positive results. Although these can usually be overcome by further tests, additional time and effort is required, which seriously limits the value of thiosemicarbazone as a true screening agent. Para-nitrobenzoic acid (500 mug./ml.) has proved more satisfactory in our hands; no false positive results have been obtained and it has the additional advantage that strains of M. kansasii (usually thiosemicarbazone sensitive) are resistant to para-nitrobenzoic acid.

Animals↗
PubMed1990

Effect of 2,4-dihydro-3H-1,2,4-triazole-3-thiones and thiosemicarbazones on iodide uptake by the mouse thyroid: the relationship between their structure and anti-thyroid activity.

Antithyroid activity of 2,4-dihydro-3H-1,2,4-triazole-3-thiones and thiosemicarbazones was tested by measuring the uptake ratio of thyroid: serum (T/S) of 125I through the mouse thyroid. Substitution with an alkyl group at the 5-position of the triazole nucleus remarkably increased the activity but substitution at the N-2 and/or N-4 positions caused a significant decrease in the activity, indicating the necessity of unsubstituted thioureylene moiety for the antithyroid activity. Thiosemicarbazone derivatives which are an open ring structure of triazoles showed comparable antithyroid activities to those in a ring form, but one thiosemicarbazone showed a much higher toxicity than the corresponding ring form compound. This suggests that the ring structure is not essential for the activity but is necessary to reduce toxic effect. Of fourteen compounds tested, 5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione was the most potent antithyroid compound with low toxicity, with a potency tenfold that of propylthiouracil, a drug currently used.

Animals↗
PubMed1984

Site of action of N,N'-bis(methylisatin-beta-thiosemicarbazone)-2-methylpiperazine in the vaccinia virus replication cycle.

N,N'-Bis(methylisatin-beta-thiosemicarbazone)-2-methylpiperazine inhibits late function or synthesis of a late component in the replication cycle of vaccinia virus. The kinetics of formation of the component sensitive to the inhibition with N,N'-bis(methylisatin-beta-thiosemicarbazone)-2-methylpiperazine precedes that of appearance of infectious virus by 30 min. The finding is in accord with the site of action of unsubstituted isatin-beta-thiosemicarbazone.

Antiviral Agents↗
PubMed1981

Antimycobacterial activity of 2-acetylpyridine thiosemicarbazones in relation to their antileprosy activity.

Antimycobacterial assays were carried out on sixteen 2-acetylpyridine thiosemicarbazones using a number of culturable mycobacteria in vitro. The resulting MIC determinations were plotted against the lipophilicity (log P) values for the various test compounds. Plots of log MIC vs log P values conformed to a parabolic regression curve having a log Pmax of 4.0 for the slow-growing mycobacteria and 3.0 for the rapid grower, M. smegmatis. Ten thiosemicarbazone compounds covering a log P range of 1.0 to 4.5 were tested for their antileprosy activity in M. leprae-inoculated mouse foot pads. The resulting activity curve had a log Pmax of 2.0. The significance of these findings is discussed in terms of the role played by limiting diffusional factors within the tissue so far as the penetration of these thiosemicarbazones into the intracellular environment is concerned.

Animals↗