Synthesis of novel chiral metal complexes derived from chiral thiosemicarbazide ligands as potential antioxidant agents.

Two new chiral thiosemicarbazide ligands and their Cu (II), Ni (II), Pd (II), and Zn (II) complexes were synthesized and characterized by nuclear magnetic resonance (NMR) (only for ligand), Fourier transform infrared (FT-IR), ultraviolet visible (UV-Vis), mass, and elemental analysis. The antioxidant activity of ligands and their metal complexes was examined. It was found that the antioxidant activity of metal complexes was better than their ligands. In addition, the antioxidant activity, as reflected by free radical scavenging, was evaluated. Besides, Pd (II) complexes exhibited better antioxidant activity than Ni (II), Cu (II), and Zn (II) complexes. Therefore, complexes (3a-Pd and 3b-Pd) can be used as an antioxidant agent or antioxidant test standard.

Systematic Identification of Thiosemicarbazides for Inhibition of Toxoplasma gondii Growth In Vitro.

One of the key stages in the development of new therapies in the treatment of toxoplasmosis is the identification of new non-toxic small molecules with high specificity to Toxoplasma gondii. In the search for such structures, thiosemicarbazide-based compounds have emerged as a novel and promising leads. Here, a series of imidazole-thiosemicarbazides with suitable properties for CNS penetration was evaluated to determine the structural requirements needed for potent anti-Toxoplasma gondii activity. The best 4-arylthiosemicarbazides 3 and 4 showed much higher potency when compared to sulfadiazine at concentrations that are non-toxic to the host cells, indicating a high selectivity of their anti-toxoplasma activity.

NDMA formation from 4,4'-hexamethylenebis (HDMS) during ozonation: influencing factors and mechanisms.

N-nitrosodimethylamine (NDMA), a toxic disinfection byproduct commonly associated with chloramination, has recently been found to form from an anti-yellowing agent (4,4'-hexamethylenebis (1,1-dimethylsemicarbazide) (HDMS)) during ozonation but the mechanisms are unclear. In this paper, the potential roles of molecular ozone (O3) and hydroxyl radical (∙OH) on NDMA formation from HDMS were investigated under various oxidation conditions (ozone dosages, pH) and different components in water (bromide ion (Br-), bicarbonate ion (HCO3-), sulfate ion (SO42-), and humic acid (HA), as well as natural organic matter (NOM) from a lake). Moreover, HDMS transformation pathways by ozonation were determined. The results indicated that the formation of NDMA was enhanced through the combined effect of O3 and ∙OH compared to that by O3 alone (addition of tert-butyl alcohol (tBA) as ∙OH scavenger). ∙OH itself cannot generate NDMA directly; however, it can transform HDMS to intermediates with higher NDMA yield than parent compound. The NDMA generation was affected (small dosages promoted but high dosages inhibited) by HA or Br- no matter with or without tBA. The presence of SO42- and HCO3- ions lowered NDMA formation through ∙OH scavenging effect. Increasing pH not only increased degradation rate constant by enhancing ∙OH generation but also affected HDMS dissociation ratio, reaching the maximum NDMA formation at pH 7-8. Natural constituents in selected water matrix inhibited NDMA formation. Impacts of these influencing factors on NDMA formation by only O3 however were significantly less pronounced over that by the joint roles of O3 and ∙OH. Based on the result of Q-TOF, LC/MS/MS, and GC/MS, the possible transformation pathways of HDMS by ozonation were proposed. The NDMA enhancement mechanism by the combined effect of O3 and ∙OH can be attributed to greater amounts of intermediates with higher NDMA yield (such as unsymmetrical dimethylhydrazine (UDMH)) produced. These findings provide new understanding of NDMA formation upon ozonation of typical amine-based compounds.

Preliminary Pharmacological Screening of Some Thiosemicarbazide, s-triazole, and Thiadiazole Derivatives.

Two thiosemicarbazide derivatives 1 and 2, three 2-amino-1,3,4-thiadiazole derivatives 3-5, and three N1- substituted-4-methyl-1,2,4-triazole-5-thione derivatives 6-8 were synthesized and evaluated for their central nervous system effects using rodent behavioral models. With the exception of 6, all compounds were devoid of neurotoxicity and they did not affect the body temperature of mice. New lead structures 1-4 with potential analgesic activity were identified.

Ethyl thiosemicarbazide intercalated organophilic calcined hydrotalcite as a potential sorbent for the removal of uranium(VI) and thorium(IV) ions from aqueous solutions.

This work was conducted to determine the practicability of using a new adsorbent 4-ethyl thiosemicarbazide intercalated, organophilic calcined hydrotalcite (ETSC-OHTC) for the removal of uranium (U(VI)), and thorium (Th(IV)) from water and wastewater. The FTIR analysis helped in realizing the involvement of nitrogen and sulphur atoms of ETSC in binding the metal ions through complex formation. Parameters like adsorbent dosage, solution pH, initial metal ions concentration, contact time and ionic strength, that influence adsorption phenomenon, were studied. The optimum pH for maximum adsorption of U(VI) and Th(IV) was found to be in the range 4.0-6.0. The contact time required for reaching equilibrium was 4 hr. The pseudo second-order kinetic model was the best fit to represent the kinetic data. Analysis of the equilibrium adsorption data using Langmuir, Freundlich and Sips models showed that the Freundlich model was well suited to describe the metal ions adsorption. The K(F) values were 25.43 and 29.11 mg/g for U(VI) and Th(IV), respectively, at 30 degrees C. The adsorbent can be regenerated effectively from U(VI) and Th(IV) loaded ones using 0.01 mol/L HCl. The new adsorbent was quite stable for many cycles, without much reduction in its adsorption capacity towards the metals.

Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors.

A novel series of N(1)-(3-fluoro-4-(6,7-disubstituted-quinolin-4-yloxy)phenyl)-N(4)-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50=1.4nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.

Design, synthesis, in vitro MAO-B inhibitory evaluation, and computational studies of some 6-nitrobenzothiazole-derived semicarbazones.

Monoamine oxidase B (MAO-B) is an important drug target for the treatment of neurological disorders. A series of 6-nitrobenzothiazole-derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO-B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO-B, with IC(50) values in the nanomolar to micromolar range. Molecular docking studies were performed with AutoDock 4.2 to deduce the affinity and binding mode of these inhibitors toward the MAO-B active site. The free energies of binding (ΔG) and inhibition constants (K(i)) of the docked compounds were calculated by the Lamarckian genetic algorithm (LGA) of AutoDock 4.2. Good correlations between the calculated and experimental results were obtained. 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as the lead MAO-B inhibitor, with top ranking in both the experimental MAO-B assay (IC(50): 0.004±0.001 µM) and in computational docking studies (K(i): 1.08 µM). Binding mode analysis of potent inhibitors suggests that these compounds are well accommodated by the MAO-B active site through stable hydrophobic and hydrogen bonding interactions. Interestingly, the 6-nitrobenzothiazole moiety is stabilized in the substrate cavity with the aryl or diaryl residues extending up into the entrance cavity of the active site. According to our results, docking experiments could be an interesting approach for predicting the activity and binding interactions of this class of semicarbazones against MAO-B. Thus, a binding site model consisting of three essential pharmacophoric features is proposed, and this can be used for the design of future MAO-B inhibitors.

Novel 1-acyl-4-substituted semicarbazide derivatives of primaquine - synthesis, cytostatic, antiviral and antioxidative studies.

A series of novel 1,4-substituted semicarbazides 5a-g with a primaquine moiety bridged by a carbonyl group at position 1 and a cycloalkyl, aryl, benzyloxy or hydroxy substituent at position 4 were prepared and biologically evaluated. The synthetic pathways applied for preparation of the title compounds involved benzotriazole as synthetic auxiliary. Primaquine semicarbazides 5a-g and their synthetic precursors benzotriazolecarbonyl semicarbazides 4 were evaluated for cytostatic, antiviral and antioxidative activities. All compounds of the series 5 showed high selectivity towards MCF-7 cells (breast carcinoma) with IC(50) values in the low micromolar range and the most active was benzyl derivative 5c (IC(50) 1 ± 0.2 µM). The benzhydryl derivative 5e showed significant cytostatic activities towards all the tested cell lines (IC(50) 4-18 µM). The same compound was the strongest lipoxygenase inhibitor as well (51%). The highest antioxidant activity was demonstrated for the hydroxy derivative 5g and benzotriazolecarbonyl semicarbazides 4b,c (61.2-68.5%). No antiviral activity was observed against a wide variety of DNA and RNA viruses.

Design, synthesis and pharmacological evaluation of novel azole derivatives of aryl acetic acid as anti-inflammatory and analgesic agents.

A series of substituted azole derivatives (3a-e, 4a-e and 5a-e) were synthesised by the cyclisation of N(1)(diphenylethanoyl)-N(4)-substituted phenyl thiosemicarbazides under various reaction conditions. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds 5-(diphenylmethyl)-N-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3b) and 5-(diphenylmethyl)-N-(3-chloro-4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3c) emerged as the most active compounds of the series, and were moderately more potent than the standard drug, ibuprofen. (This abstract was published in Inflammation Research, Supplement 2, Volume 56, page A101, 2008.).

Synthesis, X-ray crystal structures, thermal and electrochemical properties of thiosemicarbazidatodioxouranium(VI) complexes.

The stable uranyl complexes, [UO(2)(L)C(9)H(19)OH], were obtained from 3,5-dichlorosalicyl-(L(I)) and salicyl-aldehyde-S-propyl-thiosemicarbazones (L(II)) with substituted-salicylaldehyde in nonyl alcohol. The structures of the complexes have been characterized by elemental analysis, IR, (1)H NMR, conductivity, magnetic moment measurements, cyclic voltammetry, thermal gravimetric analysis and single crystal X-ray diffraction technique. The U(VI) centre is seven-coordinated in a distorted pentagonal bipyramidal geometry. The relative orientations of the nonyl alcohol and S-propyl group in the title complexes are completely different due to different crystal packing. Electrochemical behaviors of the thiosemicarbazone ligands and the uranyl complexes were studied using cyclic voltammetry and square wave voltammetry. Redox processes of the compounds are significantly influenced by the central metal ions and the nature of substituents on the thiosemicarbazones, which are important factors in controlling the redox properties. In situ spectroelectrochemical studies were employed to determine the colors and spectra of electro-generated species of the complexes.

Quantitative assessment of the metabolic activation of alicyclic amines via aldehyde.

INTRODUCTION: Recently it has been reported that some drugs that produce reactive intermediates may cause clinical adverse effects following covalent binding to biomacromolecules. For example, Schiff base production mediated by aldehyde is a possible mechanism of drug-protein adducts. However, because thiols do not trap aliphatic aldehydes via hemiacetal or hemiaminal, the glutathione-trapping method cannot be used to determine the covalent bindings of the Schiff base. METHODS: We established a quantitative method to determine covalent binding mediated by aldehydes via hemiaminal or hemiacetal using non-radiolabeled compound and [(14)C]semicarbazide as a hard-trap agent with unique post-incubation. RESULTS: The trapped aldehyde obtained from the post-incubation was almost equivalent to the covalent binding of the radiolabeled tool compound. Our novel method showed its usefulness in quantitative detection of aldehyde's covalent binding ability by several reagents with alicyclic amine and launched drugs as control. DISCUSSION: The post-incubation method is useful for screening newly synthesized compounds to quantitatively assess the bioactivation of aldehydes descending from alicyclic amines.

Copper(II) and uranyl(II) complexes with acylthiosemicarbazide: synthesis, characterization, antibacterial activity and effects on the growth of promyelocytic leukemia cells HL-60.

New chelates of N(1)-[4-(4-X-phenylsulfonyl)benzoyl]-N(4)-butyl-thiosemicarbazide (X=H, Cl, Br) with Cu(2+) and UO(2)(2+) have been prepared and characterized by analytical and physico-chemical techniques such as magnetic susceptibility measurements, elemental and thermal analyses, electronic, ESR and IR spectral studies. Room temperature ESR spectra of Cu(II) complexes yield {g} values characteristic of distorted octahedral and pseudo-tetrahedral geometry. Infrared spectra indicate that complexes contain six-coordinate uranium atom with the ligand atoms arranged in an equatorial plane around the linear uranyl group. Effects of these complexes on the growth of human promyelocytic leukemia cells HL-60 and their antibacterial activity (against Staphylococcus epidermidis ATCC 14990, Bacillus subtilis ATCC 6633, Bacillus cereus ATCC 14579, Pseudomonas aeruginosa ATCC 9027 and Escherichia coli ATCC 11775 strains) were studied comparatively with that of free ligands.

Alumina physically loaded by thiosemicarbazide for selective preconcentration of mercury(II) ion from natural water samples.

The multifunctional ligand, thiosemicarbazide, was physically loaded on neutral alumina. The produced alumina-modified solid phase (SP) extractor named, alumina-modified thiosemicarbazide (AM-TSC), experienced high thermal and medium stability. This new phase was identified based on surface coverage determination by thermal desorption method to be 0.437+/-0.1 mmol g(-1). The selectivity of AM-TSC phase towards the uptake of different nine metal ions was checked using simple, fast and direct batch equilibration technique. AM-TSC was found to have the highest capacity in selective extraction of Hg(II) from aqueous solutions all over the range of pH used (1.0-7.0), compared to the other eight tested metal ions. So, Hg(II) uptake was 1.82 mmol g(-1) (distribution coefficient log K(d)=5.658) at pH 1.0 or 2.0 and 1.78, 1.73, 1.48, 1.28 and 1.28 mmol g(-1) (log K(d)=4.607, 4.265, 3.634, 3.372 and 3.372), at pH 3.0, 4.0, 5.0, 6.0 and 7.0, respectively. On the other hand, the metal ions Ca(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Pb(II) showed low uptake values in range 0.009-0.720 mmol g(-1) (log K(d)<3.0) at their optimum pH values. A mechanism was suggested to explain the unique uptake of Hg(II) ions based on their binding as neutral and chloroanionic species predominate at pH values < or =3.0 of a medium rich in chloride ions. Application of the new phase for the preconcentration of ultratrace amounts of Hg(II) ions spiked natural water samples: doubly distilled water (DDW), drinking tap water (DTW) and Nile river water (NRW) using cold vapor atomic absorption spectroscopy (CV-AAS) was studied. The high recovery values obtained using AM-TSC (98.5+/-0.5, 98.0+/-0.5 and 103.0+/-1.0) for DDW, DTW and NRW samples, respectively based on excellent enrichment factor 1000, along with a good precision (R.S.D.% 0.51-0.97%, n=3) demonstrate the accuracy and validity of the new modified alumina sorbent for preconcentrating ultratrace amounts of Hg(II) with no matrix interference.

N-Hydroxythiosemicarbazones: synthesis and in vitro antitubercular activity.

N-Hydroxythiosemicarbazide was prepared by two methods starting from 2,4-dimethoxy benzyl amine and hydroxylamine hydrochloride, which in turn was reacted with various aldehydes and ketones to obtain the titled compounds. Eighteen compounds were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv using the agar dilution method. Compound 10p was found to be the most potent compound (MIC: 0.28 microM) and was 2.5 times more active than standard isoniazid.

Co(II), Ce(III) and UO2VI) bis-salicylatothiosemicarbazide complexes: binary and ternary complexes, thermal studies and antimicrobial activity.

A series of new metal complexes of Co(II), Ce(III) and UO(2)(VI), with the Schiff base ligand, H2L, bis-salicylatothiosemicarbazide have been prepared in presence of different molar ratios of LiOH.H2O as a deprotonating agent. Also, the ternary complexes were prepared by using 2-aminopyridine (2-Ampy) or oxalic acid (Ox) as a secondary ligand. All synthesized compounds were identified and confirmed by elemental analyses, molar conductivities, spectral (UV-Vis, IR, 1H NMR, mass) and magnetic moment measurements as well as TG-DSC technique. The changes in the selected vibrational absorption bands in IR and NMR spectra of the Schiff base ligand upon coordination indicate that, the ligand behaves as a neutral, monoanionic and/or dianionic tetradentate manner with ONNO donor sites. Conductance measurements suggest the non-electrolytic and 1:1 electrolytic nature of the metal complexes. Thermal studies suggest a mechanism for degradation of the metal complexes as function of temperature supporting the chelation modes, moreover, show the possibility of obtaining new complexes pyrolytically in the solid state which cannot be synthesized from solution. Antimicrobial screening of the free ligand and its binary complexes showed that, the free ligand and some metal complexes possess antimicrobial activities towards four type of bacteria and five types of fungi and these results were compared with eleven type of known antibiotics.