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In this study some new beta-[(2-benzimidazolyl)thio]-beta-benzoyl styrene derivatives have been synthesized by reacting 2-(phenacetylthio)benzimidazole and substituted benzaldehydes in piperidine/dry benzene. Structures were verified by microanalysis, IR and NMR spectral analysis. Antimicrobial activities of the compounds were investigated by the microdilution susceptibility test; Muller-Hinton Broth and Sabouraud Dextrose Broth were used for the determination of antibacterial and antifungal activity. Test organisms: Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as Gram (+) bacteria, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATTC 27853 as Gram (-) bacteria, and Candida albicans, Candida pseudotropicalis, Candida parapsilosis and Candida stellatoidea as yeast-like fungi. All the compounds showed good antimicrobial effect, especially against gram (+) bacteria. Among the compounds tested beta-[(2-benzimidazolyl)thio]-beta-benzoyl-4-chloro styrene (compound 9), beta-[(2-benzimidazolyl)thio]-beta-benzoyl-4-nitro styrene (compound 10) and beta-[(2-benzimidazolyl)thio]-beta-benzoyl-4-acetylamino styrene (compound 11) showed the most favorable activity.
GOALS, SCOPE AND BACKGROUND: From 2005, deposition of organic waste will be banned in Sweden. Likewise, in Germany and Austria, similar bans are being planned, and further countries will probably follow. Thus, there is a need to develop new methods and to refine established techniques for sludge management in the whole of the European Union. For this end, there is also an urgent need for appropriate ecotoxicological approaches to elucidate and assess the hazard potential of sewage sludge. Therefore, the present study was designed to assess the capacity of various established sludge treatment methods using different oxygen regimes to degrade recalcitrant nitro-substituted organic compounds and reduce their toxicity. Sewage sludge samples from a wastewater treatment plant in Sweden (Cambrex Karlskoga AB, industrial area Björkborn) receiving wastewater from industries manufacturing pharmaceutical substances, chemical intermediates and explosives were processed with different sludge treatment methods. Among other treatment methods, bioreactors (for anaerobic and aerobic sludge treatment) were used. In the present investigation, a battery of in vitro bioassays was employed to compare the cytotoxic and genotoxic potentials of different fractions of sludge samples in order to elucidate whether the treatments were suitable to reduce the toxicity of the sludge. METHODS: In order to investigate the cytotoxicity of the extracts of treated and untreated sludge samples, the acute cytotoxicity test with the permanent cell line RTL-W1 was used. Genotoxicity was tested by means of the comet assay (single cell gel electrophoresis) with RTL-W1 cells, and mutagenicity was assessed with the Ames test using the Salmonella typhimurium strains TA98, TA98NR and TA100. Sludge toxicity was tested in different fractions of organic extracts produced by acetone and hexane extractions. The subsequent clean-up procedure (silica gel chromatography and elution with hexane and dichloromethane) resulted in two fractions, a lipophilic hexane-fraction and a semi-lipophilic dichloromethane-fraction. For the genotoxicity and mutagenicity tests, these fractions were reunited at equal ratios. RESULTS AND DISCUSSION: The acute cytotoxicity test with RTL-W1 cells revealed a high cytotoxic potential for the semi-lipophilic DM-fractions of all sludge samples with NR50 values (= effective concentration for 50% cell death in the neutral red test) from 8.9 up to 20 mg sludge d.w./ml medium. A low cytotoxic potential for the hexane fractions of the untreated sludge samples (NR50 400 to > 400 mg sludge d.w./ml medium) was observed, whereas the hexane fractions of the treated sludge samples showed elevated cytotoxicity increasing further with treatment in the bioreactors. The comet assay indicated that three out of eight of the reunited fractions had a significant genotoxic potential. Whereas the genotoxic potential of one sample treated anaerobically was very high with an induction factor of 11.6, a similar sample (taken from the same anaerobic reactor four months later) and one untreated sample showed lower potentials. The samples treated in another anaerobic bioreactor as well as the samples treated aerobically showed no genotoxic potential. Results indicate that aerobic treatment was basically adequate for reducing the genotoxicity of the sludge, whereas anaerobic treatment was only partly useful for reduction of genotoxicity. The Ames test revealed a very high mutagenic potential for the reunited fractions of the untreated sludge samples with strain TA98 (maximum induction factors (IFmax) up to 45) and a relatively high potential for one of the samples treated aerobically (S2, IFmax = 18 (TA98, S9-)), thus documenting the suitability of both anaerobic and aerobic treatments to reduce the mutagenicity of the samples, however, with the aerobic treatment being less effective. CONCLUSIONS: Overall, none of the microbiological treatments for wastewater sludge in bioreactors was found to be ideal for general toxicity reduction of the sludge samples. Whereas cytotoxicity of the sludge increased or levelled off in most cases following either treatment, genotoxicity both increased or decreased after anaerobic treatment, depending on the specific sample. However, mutagenicity could generally be reduced by anaerobic treatment and, to a lesser degree, by aerobic treatment. RECOMMENDATIONS AND PERSPECTIVES: The complex modification of the diverse damage potentials of sludge sample extracts by use of an in vitro biotest battery following treatment for toxicity reduction in bioreactors showed that considerations of different toxicological endpoints is essential for an adequate hazard assessment. Whereas in the case of cytotoxicity reduction, the reactors proved ineffective, mutagenicity could be reduced significantly at least in some cases in this case study.
Lung cancer caused by polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental agents is a major problem in industrialized nations. The high case-fatality rate of the disease, even with the best supportive treatment, underscores the importance of primary lung cancer prevention. Development of biomarkers of exposure and effects to PAHs and related compounds is now underway and includes measurement of urinary metabolites of specific PAHs as well as detection of protein and DNA adducts as indicators of effective dose. Validation of these markers in terms of total environmental dose requires that concurrent measures of air levels and potential dermal exposure be made. In addition, the interrelationships between PAH biomarkers must be determined, particularly when levels of the marker in surrogate molecules (e.g., protein) or markers from surrogate tissues (e.g., lymphocyte DNA) are used to assess the risk to the target organ, the lung. Two approaches to biomarker studies will be reviewed in this article: the progress made using blood lymphocytes as surrogates for lung tissues and the progress made developing noninvasive markers of carcinogen-DNA adduct levels in lung-derived cells available in bronchial-alveolar lavage and in sputum. Data are presented from studies in which exfoliated urothelial cells were used as a surrogate tissue to assess exposure to human urinary bladder carcinogens in occupational groups.
alpha-[5-(5-Nitro-2-furyl)-1,3,4-oxadiazol-2-ylthio]aceth ydrazide, alpha-[5-(5-nitro-2-furyl)-1,3,4-oxadiazol-2-ylthio]acetamid e, delta-allyl-1-[( 5-(5-nitro-2-furyl)-1,3,4-oxadiazol-2-ylthio]acety) thiosemicarbazide, and other related compounds have been synthesised for testing against Mycobacterium tuberculosis.
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Glutathione S-transferase (GST) expression was examined in hepatic cytosol from rats and rabbits treated with 4-picoline, pyrrole, pyridine, pyrazine, imidazole, or piperidine using enzymatic activity, SDS-PAGE, and immunoblot analyses and the results were compared to those obtained with phenobarbital and 3-methylcholanthrene. SDS-PAGE and immunoblot analyses of hepatic cytosol prepared from rats treated with pyrazine revealed the induction of class alpha (Ya and Yc) and mu (Yb) bands with a corresponding 2.4-fold increase in metabolic activity using 1-chloro-2,4-dinitrobenzene as substrate. A new class alpha band migrating in the region of the Yc band was observed in the SDS-PAGE and detected in the immunoblot of cytosol from pyrrole-treated rats, whereas treatment with 4-picoline, imidazole, or piperidine failed to alter the expression of the major classes of GST isozymes in this species. SDS-PAGE and immunoblot analyses of rabbit hepatic cytosol revealed a unique species-dependent difference in the expression of GSTs. While phenobarbital and 3-methylcholanthrene induce class alpha and mu GST expression in rat hepatic cytosol, one of the most interesting observations was that neither of these agents stimulated GST expression in the rabbit. Immunoblot analysis of cytosol isolated from 4-picoline-treated rabbits using GST class alpha-specific IgG showed the appearance of a novel class alpha 28-kDa GST band and the concomitant disappearance of a class alpha 29-kDa GST band. In addition, SDS-PAGE and immunoblot analyses showed that treatment of rabbits with pyrrole, pyrazine, imidazole, or piperidine resulted in the disappearance of this class alpha 29-kDa GST band with no detectable expression of the class alpha 28-kDa GST band; the level of the class alpha 29-kDa band was unaffected by pyridine treatment. In contrast, immunoblot analyses of hepatic cytosol revealed that a 25.5-kDa class mu GST band disappeared following treatment with pyridine, but was unaffected by treatment with other nitrogen heterocycles. The Vmax of glutathione conjugation to the substrate 1-chloro-2,4-dinitrobenzene decreased by 52, 36, 59, 41, 37, and 32% in hepatic cytosol isolated from 4-picoline-, pyrrole-, pyridine-, pyrazine-, imidazole-, and piperidine-treated rabbits, respectively. The results suggest that nitrogen heterocycles differ in their ability to modulate glutathione S-transferase isozyme expression in rat and rabbit hepatic tissue and that rabbit hepatic GSTs are refractory to induction by agents such as pyrazine, phenobarbital, or 3-methylcholanthrene and hence these xenobiotics do not appear to be bifunctional inducers in this species.
A novel approach to density prediction by elemental composition is developed for various important classes of explosives. Some correlations based on two different models are introduced for 82 different energetic compounds whose molecules contain functional groups common to C(a)H(b)N(c)O(d) explosives. These include acyclic and cyclic nitramines, nitrate esters and nitroaliphatic compounds. Of the 69 well-known and recently new synthesized organic explosives for which direct comparison could be made with Tarver group additivity method, root mean square (rms) of deviation for 19 acyclic and cyclic nitramines is 2.839 and 3.412 while for 50 nitrate esters and nitroaliphatic explosives is 1.936 and 1.752 for new and Tarver's method, respectively. This method is the simplest procedure for calculating density of energetic compounds which gives good results as compared to well-developed group additivity method for estimation density of organic explosives.
Complete separation of the 14 nitroaromatic and nitramine analytes targeted in EPA Method 8330 was achieved using a 30 x 4.6 mm Bondesil CN guard column in series with a 250 x 4.6 mm Bondesil C18 column (5 microns particles). Consistent with Method 8330 specifications, the mobile phase in the separation was 1:1 methanol:water and the flow-rate was 1.5 ml min-1. The success of this two-phase system proved to be largely a consequence of the unique resolution afforded by the Bondesil C18 column: complete separation of the 14 explosives could not be achieved using other CN/C18 column combinations. Additionally, while Method 8330 calls for a 100-microliter injection loop, separation on the Bondesil CN/C18 system was possible only using a 20-microliter injection loop. The loss of resolution with larger injection volume appears to be a result of the injection solvent, methanol, modifying the composition of the mobile phase both in the CN guard column and in the initial portion of the C18 column. The current method nevertheless represents an improvement over Method 8330, which calls for both a screening and confirming analysis. By separating the 14 Method 8330 analytes in a single run, the two-phase approach can increase sample throughput by decreasing analysis times.
Nitroheterocycles have been shown to inhibit the incorporation of 3H-TdR by cultured L-929 cells, and the degree of inhibition is related to their electron-affinity. On the basis of their chemical reactivity and potential clinical utility, nitrofurazone, misonidazole and metronidazole were selected for more detailed studies of the mechanism of inhibition of DNA synthesis. Double-isotope labelling in conjunction with hydroxyapatite chromatography allowed the evaluation of drug effects on initiation of DNA replicons, DNA chain elongation and DNA damage (single-strand breaks), and their correlation with eventual cell viability. Partial inhibition of initiation of DNA synthesis generally preceded other measurable effects, and was not reversed by incubation in the absence of drug. In the absence of DNA strand breaks (at low drug doses or after a repair interval) the rate of elongation was similar in both treated and untreated cell populations. Measurable DNA damage (strand breaks) was predictive for cytotoxicity. At lower drug doses, or under aerobic conditions, DNA synthesis was not always associated with a decrease in plating efficiency (cytotoxicity) but was reflected in decreased colony size (growth rate) of the cells. Thus the aerobic "toxicity" previously reported for chronic exposure to these agents may be better described as a "cytostatic" effect. Under anaerobic conditions (where cell killing is much greater) inhibition of initiation plays a less important role, and the nitroheterocycles are metabolically reduced to intermediates which are truly cytotoxic.
Law enforcement agencies use ion mobility spectrometers for the detection of explosives, drugs of abuse, and chemical warfare agents. Ion mobility spectrometry (IMS) has the advantages of short analysis times, detections in the parts per billion concentrations, and high sensitivity. On-site environmental analysis of explosives or explosive residues in water is possible with ion mobility spectrometers. Unfortunately, the direct analysis of low levels of explosives in water is difficult. Extraction provides a method for pre-concentrating the analytes and removing interferents. Coupling solid-phase extraction (SPE) with IMS is useful for the identification of trace amounts of explosives in water. Commercially available SPE disks were used. After extraction, the sample disk is inserted into the ion mobility spectrometer, where the analytes are thermally desorbed from the disk. Concentrations as low as one part per trillion were detected with a Barringer Ionscan 350. An external computer and acquisition software (LabVIEW, National Instruments) were used to collect data. SIMPLISMA (SIMPLe-to-use-Interactive Self-modeling Mixture Analysis) was applied to the data to resolve features that vary with respect to time.
The pyridone 1a reacts with POCl3/DMF to yield the title compound 2a. After irradiation of 2a the enolether 3 is isolated, as shown by an X-ray structure determination. The pyridine 4 obtained by dehydrogenation of 2a leads under reductive conditions to the benzo[c][2,7]naphthyridines 5-7. The reaction of 4 with o-phenylenediamine gives the benzimidazole 8, while using 2-aminophenol or 2-aminothiophene respectively the pyrido[2,3-b[1,5]benzoxazepine 11 and the corresponding benzothiazepine 12 are obtained.
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Glucocorticoids (GC) are widely used in therapy for their many pharmacological properties including antiinflammatory and immunosuppressive actions. However, their use over long periods is hampered by a number of severe side effects. Given the biological properties of nitric oxide (NO) and previous experience with nonsteroidal antiinflammatory agents, we synthesized new chemical entities combining both NO and GC properties. Here we report the synthesis of nitro esters of prednisolone obtained through the esterification, with different linkers, on the hydroxy group at C-21 position of the corticosteroid structure. The alkyl chain, as of the nitrooxy derivative (2), or aromatic linkers, as of o-, m-, and p-nitrooxymethylbenzoate derivatives (3-5), respectively, furnish stable compounds that release NO and inhibit the GC receptors in biological assays. To improve solubility we introduced a more water-soluble linker such as the nitrooxyalkylpiperidine or -piperazine group (6-9). Also these compounds retained properties of both NO and prednisolone. Compound 5 (NCX 1015) was selected for its better profile: enhanced antiinflammatory properties and reduced side effects compared with prednisolone. NCX 1015 is currently under preclinical development.