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PubMed1986

Conductive polymers derived from iron, ruthenium, and osmium metalloporphyrins: The shish-kebab approach.

The synthesis and characterization of pyrazine-bridged polymers of iron(II/III), ruthenium(II/III), and osmium(II/III) octaethylporphyrin (dubbed "shish-kebab" polymers) are presented. Optical and dc conductivity measurements reveal that the ruthenium and osmium polymers, when partially oxidized, are highly conductive. Electrochemical and ESR results are presented that indicate the existence of an interesting metal-centered conduction pathway. Unlike most of the previously reported porphyrinic molecular metals in which the conduction electrons are macrocyclic-based, electron transport in these materials proceeds exclusively along the metal-pyrazine backbone.

Journal Article↗

PubMed2002

Odorants of different chemical classes interact with distinct odorant binding protein subtypes.

The ligand profile for three odorant binding proteins (OBPs) of the rat have been determined using a large number of odorous compounds from different chemical classes. To evaluate the binding spectra of distinct subtypes, all OBPs were produces in Escherichia coli as recombinant His-tagged fusion proteins. The individual binding properties of each OBP subtype were analysed using a large array of organic compounds, representing derivatives of aliphatic and aromatic compounds, as well as terpenes, pyrazines and thiazoles, in a competitive spectroscopic binding assay with various fluorescence chromophores as the specific interacting partner for the OBPs. Most of the compounds were identified to interact only with one OBP subtype. But interestingly, a small change, for example in the 2-methyl or 2-ethoxy side chain in the pyrazine and thiazole derivatives to a 2-isobutyl group, caused overlapping binding affinities to rat-OBP1 and rat-OBP3. However, the data strongly support the notion that each OBP subtype displays a characteristic ligand binding profile and interacts with a different subset of exogenous organic compounds in a micromolar range.

Animals↗

PubMed2001

Photoelectron imaging on time-dependent molecular alignment created by a femtosecond laser pulse.

Rotational wave packet revivals on an excited electronic state have been measured by femtosecond time-resolved photoelectron imaging for the first time. The first full revival at 82 ps of S1 (n,pi*) pyrazine was clearly observed in the time dependencies of the photoelectron intensity and the photoelectron angular distribution (PAD). The PAD, measured for laser aligned pyrazine, clearly reflects the different characters of pi* and 3s molecular orbitals.

Journal Article↗

PubMed2005

Formation of quinol co-crystals with hydrogen-bond acceptors.

The crystal structures of eight new co-crystals of quinol with pyrazine, piperazine, morpholine, pyridine, piperidine, 4,4'-bipyridine, N-methylmorpholine and N,N'-dimethylpiperazine are reported. Quinol forms 1:1 co-crystals with pyrazine, piperazine and N,N'-dimethylpiperazine, but 1:2 co-crystals with morpholine, 4,4'-bipyridine, N-methylmorpholine, pyridine and piperidine. This difference can be rationalized in most cases by the presence of, respectively, two or one strong hydrogen-bond acceptor(s) in the guest molecule. The exception to this generalization is 4,4'-bipyridine, which forms a 1:2 co-crystal, possibly to optimize crystal packing. All structures are dominated by hydrogen bonding between quinol and the guest molecules. A doubly bridging motif, which connects pairs of quinol and guest molecules via NH...O or CH...O interactions, is present in all but the sterically hindered N,N'-dimethylpiperazine and N-methylmorpholine co-crystals.

Crystallization↗

PubMed1981

Oxidation of meso-diaminosuccinic acid, a possible natural substrate for D-aspartate oxidase.

meso-Diaminosuccinic acid, a natural antagonist of aspartic acid, is a good substrate for beef kidney D-aspartate oxidase. The oxygen consumption and the ammonia production are in good agreement with the stoichiometry of a typical oxidative deamination. The deamination involves only one of the two amino groups of diaminosuccinate, and is followed by decarboxylation of the first reaction product, 2-amino-3-oxosuccinic acid. By condensation of the compounds thus originating from this latter, pyrazine 2,5-dicarboxylic acid and pyrazine 2,6-dicarboxylic acid are formed. DL-Diaminosuccinic acid is not oxidized by D-aspartate oxidase, nor does it inhibit the enzyme activity.

Amino Acid Oxidoreductases↗

PubMed2002

Detection of superoxide in vascular tissue.

During the past decade, it has become apparent that reactive oxygen species play a critical role in the genesis of many vascular diseases. The superoxide anion is among the most important of these, not only because of its rapid reaction with NO but also because it serves as a progenitor for many other reactive oxygen species. Although there are many approaches to detecting and quantifying superoxide in chemical systems, its detection in intact tissues is more difficult. The validity of the most popular and frequently used assay for this purpose, lucigenin-enhanced chemiluminescence, has been recently questioned. It has been suggested that lucigenin itself, especially at high concentrations (>50 micromol/L), may act as a source for superoxide via redox cycling. Lower lucigenin concentrations (5 micromol/L) do not participate in redox cycling to an important extent in intact tissues and, therefore, provide an accurate assessment of the rate of superoxide production in such samples. Other useful assays for superoxide include those using the fluorescent dye dihydroethidine, 2-methyl-6-phenyl-3,7-dihydroimidazo(1,2-alpha)pyrazin-3-one (CLA), and 2-(p-hydroxybenzyl)-6-(p-hydroxyphenyl) 8-benzylimidazo[1,2-alpha]pyrazin-3-one (coelenterazine). The chemiluminescent compound 5-amino-2,3-dihydroxy-1,4-phthalayineidone (luminol) may also be used to detect various reactive oxygen species and may be made specific for various oxidants, such as hydrogen peroxide, superoxide, and peroxynitrite, by altering the experimental conditions. Although each of these methods may be associated with potential artifacts, the use of > or =2 different techniques that yield similar results provides a reliable approach for the study of reactive oxygen species in intact vascular tissues.

Animals↗

PubMed2001

Synthesis and in-vitro antimicrobial activity of new 1,2,4-triazoles.

We have described the synthesis of new 1,2,4-triazoles and have evaluated their antimicrobial profile. Antitubercular activity was determined in triplicate using the Lowenstein-Jensen medium. A loopful of Mycobacterium tuberculosis suspension was inoculated on the surface of each Lowenstein-Jensen media containing the test compounds (100, 10 or 1 microg mL(-1)). To evaluate in-vitro antibacterial activity, compounds (50, 5 or 0.5 microg) were evaluated against B. subtilis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus typhi by the disc diffusion method. To evaluate antifungal activity Sabourauds Dextrose agar medium was used. Some of the compounds (5, 0.5 or 0.05 microg mL(-1)) were screened for activity against Aspergillus niger 88 and Aspergillus niger 90 and others were screened for activity against T. rubrum TR1, T. rubrum R6, T. rubrum R7 and T. mentagrophyte M1, using the cup plate method. Our results show that the triazoles with a pyrazine moiety at position 3 were more active as antitubercular and antifungal agents compared with the triazoles which had a pyrazine moiety at position 4 of the molecule.

Anti-Bacterial Agents↗

PubMed1975

Studies on the degradation of pterine and pterine-6-carboxylic acid by Pseudomonas fluorescens UK-1.

Pseudomonas fluorescens UK-1 has been incubated in basal mineral medium which was 0.5mM in pterine or pterine-6-carboxylic acid. During incubation the test organism splits the pteridine ring by liberating carbon dioxide from position 2. Glucose added to the medium greatly enhances both the growth of the organism and the carbon dioxide formation. Despite the structural similarities between pterine and pterine-6-carboxylic acid, only the degradation products derived from pterine are fluorescent in UV-light. Among the degradation products lumazine, pyrazine-2-carboxylic acid, and pyrazine-2-carboxamide have been identified. Also the activities of pterine deaminase and a carbon dioxide-liberating enzyme have been determined.

Aminohydrolases↗

PubMed2000

[Advances in the development of new antitubercular agents from a group of monocyclic 6-membered heterocyclic compounds with a greater number of nitrogen atoms].

Tuberculosis and other mycobacterial diseases are considered to be one of the major health problems at present. Since 1985, and in particular in the 1990s, a search for new structures of antimycobacterial substances has been one of the priorities of chemotherapeutic research. Pyrazine derivatives have always attracted the interest of research laboratories searching for new chemotherapeutic agents against tuberculosis. The present review paper, based on the journal Chemical Abstracts and original papers, surveys the attempts of the laboratories searching for new antituberculotic agents in the region of six-membered heterocyclic pyrimidine, pyrazine, and triazines compounds in recent fifteen years.

Antitubercular Agents↗

PubMed2006

[Inhibition of extracts from 17 Chinese herbs on periodontal pathogenic microbes].

PURPOSE: To evaluate the efficiency of 17 Chinese herbs on periodontal pathogenic microbes. METHODS: 17 efficient substances from Chinese herbs were purchased from Chinese Drug Identification Bureau, including magnesium lithospermate B, magnolol, tetramethyl pyrazine, matrine, dycyrrhizin, gentiopicrin, aloperin, baicalin, oleanolic acid, ginkgo seed, total glucosides of paeony capsules, anisldehyde, archin, cablin patchouli, hydrochloric acid Berberine, forsythin, and kakonein. Antimicrobial sensitivity tests of broth microdilution methods on 96-microwell plate were carried out for identification of the antimicrobial activity of extracts against six species of microorganisms: Actinobacillus actinomycete mitans(Aa) Y4, Actinomycetes viscosus(Av) 19246, Porphyromonas gingivalis(Pg) 33277, Fusobacterium necrophorum(Fn) 25286, Actinomyces naeslundii(An) wvl 45 and Prevotella nigrescens(Pn). RESULTS: It was found that magnesium lithospermate B and magnolol showed the most efficient inhibition on microorganism of Pn and Fn, with the MIC being 0.053 and 0.313 mg/ml for Pn and Fn, respectively. Tetramethyl pyrazine, matrine, dycyrrhizin, gentiopicrin, aloperin, baicalin, and oleanolic acid had better inhibition than total glucosides of paeony capsules, anisldehyde, archin, cablin patchouli, hydrochloric acid berberine, forsythin, and kakonein. CONCLUSION: The Chinese herbs, magnesium lithospermate B and magnolol are efficient agents for inhibition against periodontal pathogenic microbes.

Actinomyces↗

PubMed2006

[Characterization of two new pigmented mycobacteria isolates].

Two pigmented mycobacteria isolated from sputum specimens were described by biochemical tests, whole-cell fatty acid analyses by High Performance Liquid Chromatography (HPLC) and sequencing of 65-kDa heat shock protein gene and 16S rRNA gene. The hsp65 gene and 16S rRNA gene sequences of the Mycobacterium sp. G1368 and Mycobacterium sp. E498 were deposited in DDBJ/EMBL/GenBank under accession numbers AY553874, DQ324791 and AY379074, DQ324792, respectively. Mycobacterium sp. G1368 grew in about one week at 37 degrees C and 42 degrees C and produced smooth, yellow colonies. It reduced tellurite and hydrolyzed urea. Nitrate reduction, aryl sulfatase, pyrazin amidase, heat stable catalase and semiquantitative catalase tests were also positive, while Tween 80 hydrolysis was weakly positive. Mycobacterium sp. E498 grew in about 9 days at 37 degrees C and formed smooth, yellow colonies. It hydrolyzed Tween 80, possessed aryl sulfatase, pyrazin amidase and heat stable catalase, however, it did not possess urease and nitrate reductase. These data, in addition to their position in the phylogenetic tree, strongly support the status of novel species at least for Mycobacterium sp. G1368.

Bacterial Proteins↗

PubMed1994

Novel N-oxides as bioreductive drugs.

A series of imidazo [1,2-a] quinoxaline mono-N-oxides and their aza- analogues have been synthesized together with analogues substituted in the 8-position. These compounds have been evaluated as bioreductively activated cytotoxins in vitro and in vivo. These compounds had differential cytotoxicities in vitro of up to 20 for 8-amino derivatives such as RB90740 and 65 for 8-aminoalkoxy derivatives such as 1,2-dihydro-8-(1-(demethylamino)ethoxy)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide, but were disappointing in vivo with a maximum growth delay of 10 days compared with 30 days for SR4233 in the RIF-1 tumor model. RB90740 is only effective at killing V79 cells at extremely low levels of oxygen, in contrast to SR4233, and this oxygen dependence can explain the poor and often variable activity of the compound in vivo. 1,2-dihydro-8-(1-(demethylamino)ethoxy)-4-phenylmidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide, as the most effective drug in vitro, remains the lead structure for any further drug development.

Animals↗

PubMed1993

Stereoselective blockade of amphibian epithelial sodium channels by amiloride analogs.

The blockade of amphibian epithelial sodium channels by amiloride has been shown to not be a simple diffusion-limited encounter but rather a selective binding process with the rate of approach of the molecule for the channel site determined by the side chain at position 2 of the pyrazine ring and the stability of the blocking complex provided largely by the bond of the ligand at position 6. The presence of such a putative channel-associated receptor suggests that the sodium channel might have chiral recognition for its blockers. Using the short-circuit technique to measure the amiloride-sensitive sodium current through the apical membrane of the toad urinary bladder and frog skins, we evaluated the sodium channel-blocking potency of three enantiomeric pairs of amiloride analogs with chiral centers on the side chain. We demonstrated the stereoselectivity in sodium channel blockade of those analogs and confirmed the existence of a second attachment site on the channel for interacting with the lipophilic ligand on the side chain of the analog molecule to enhance its blocking activity. Depending on the separation between the chiral carbon and the pyrazine ring and the chemical groups on the chiral carbon, the eudismic ratio for the 50% inhibition constant of the enantiomers, i.e., the ratio of the sodium channel-blocking potency of the more active enantiomer to that of the less active enantiomer, was found to range from slightly more than 1 to more than 100.

Amiloride↗

PubMed1997

Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats.

The serotonin (5-HT)(2A/2c) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 microl/side and was inhibited by the 5-HT2A antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT(2C/2B) antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50 of 1.5 nmoles/0.5 microl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A receptors. Pretreatment of rats with the 5-HT1A agonist (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1A receptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A receptors.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1998

Xenobiotic-enhanced expression of cytochromes P450 2E1 and 2B in primary cultured rat hepatocytes.

Cytochrome P450 2E1 (CYP2E1) and 2B (CYP2B) mRNA and protein expression was examined in primary cultured rat hepatocytes under basal cell culture conditions and in response to three prototypic CYP2E1 inducers, i.e. ethanol, acetone, and pyrazine. Xenobiotic treatment for 24 hr, initiated after hepatocytes had been maintained in culture for 72 hr, resulted in 2-8-fold increases in CYP2E1 protein levels, relative to untreated cells. A >/=2-fold increase in CYP2E1 protein levels was detected at the lowest concentration (1 mM) of each of the xenobiotics examined. The increase in CYP2E1 protein expression was not accompanied by any significant increase in 2E1 mRNA expression. In contrast, CYP2B protein and mRNA levels were increased by acetone or pyrazine at concentrations greater than 1 mM. Ethanol (up to 100 mM) failed to significantly increase CYP2B protein or mRNA levels. The maximal increases measured for CYP2B protein and mRNA ( approximately 25-fold and approximately 90-fold, respectively) after treatment of hepatocytes with acetone were comparable to those measured in our laboratory, and reported by others, for phenobarbital treatment of primary cultured rat hepatocytes. The results of this study show that the pattern of expression of CYP2E1 and 2B in this primary cultured rat hepatocyte system and the magnitude of induction parallel those reported for rat liver in vivo in response to these xenobiotics. This primary hepatocyte culture system provides opportunities for studies of the role of CYP2E1 in the metabolism and bioactivation of drugs, chemicals, and putative carcinogens, as well as mechanistic studies on xenobiotic-mediated regulation of CYP2E1 expression.

Acetone↗

PubMed1990

Prolactin and cortisol responses to MK-212, a serotonin agonist, in obsessive-compulsive disorder.

To examine further the serotoninergic system in obsessive-compulsive disorder (OCD), the plasma concentrations of cortisol and prolactin and the behavioral responses after oral administration of MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine), a serotonin agonist, and placebo were studied in 17 patients with OCD and nine normal controls. The two groups did not differ significantly in basal plasma prolactin or cortisol levels. Nevertheless, both the prolactin and cortisol response to oral administration of MK-212 (20 mg) were significantly blunted in the patients with OCD compared with those of the normal controls. MK-212 did not affect the intensity of OCD symptoms. However, MK-212, as compared with placebo, produced slight but statistically significant increases in self-ratings of nausea, dizziness, anxiety, feeling strange, and mixed feelings of calmness and restlessness, as well as depression and feeling high. These behavioral ratings were not significantly different in patients and normal controls. These findings are consistent with previous reports of diminished serotoninergic responsivity in OCD and raise the possibility of subsensitivity of at least some serotonin receptors in this disorder.

Administration, Oral↗

PubMed2000

Hydrophobicity parameter of diazines IV: a new hydrogen-accepting parameter of monosubstituted (di)azines for the relationship of partition coefficients in different solvent systems.

We recently proposed a new hydrogen-accepting scale, S(HA), for each member of the substituted (di)azine series on the basis of the heat of formation calculated under various dielectric environments by the COSMO method. In this paper, the S(HA) scale was used to examine relationships between log P(CL) (P(CL): CHCl(3)/H(2)O partition coefficient) and log P(oct) (P(oct): 1-octanol/H(2)O partition coefficient) for each of the 2-substituted pyridine (I), monosubstituted pyrazine (II), and pyrimidine (III) series. This S(HA) parameter worked nicely, representing the hydrogen-accepting effect of the solute molecule. A correlation equation with excellent quality, such as log P(CL) = a log P(oct) + sS(HA) + constant, was obtained for each series. We further defined the parameter S(HA/PY), derived from S(HA) values for the heterocyclic series by shifting the reference points to unsubstituted pyridine, to unify separately derived correlation equations. Thus, the correlation between log P(CL) and log P(oct) for all combined data of three series was derived by using a single equation as log P(CL) = a log P(oct) + sS(HA/PY) + constant. The S(HA) parameters were reasonably considered as being free-energy related, and the rationale for the hydrogen-bond-acceptor scale was presented.

Azides↗

PubMed1995

Pyridazines, LXXII: On the synthesis of azinium and diazinium compounds structurally related to pyridazomycin.

Preparation of series of pyridine-, pyridazine-, and pyrazine-derived carboxamides bearing at the ring N-atom an alkyl side-chain with a terminal carboxylic group (7-11) or with a terminal acetylamino malonic ester moiety (13-17, 19-23) is described. Two desaza-pyridazomycin derivatives (24, 26) and homologs thereof (25, 27) were synthesised. The novel compounds which are structurally related to the antifungal antibiotic pyridazomycin were screened for antifungal activity: preliminary in vitro tests showed no activity.

Antifungal Agents↗