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PubMed2005

Orientation change of adsorbed pyrazine on roughened rhodium electrodes as probed by surface-enhanced Raman spectroscopy.

A surface-enhanced Raman spectroscopic (SERS) study of pyrazine adsorbed on roughened Rh electrodes was performed. Potential and concentration effects on the adsorption behavior of pyrazine were investigated. The SER spectra display four pairs of overlapping bands with the relative intensity of each pair being highly potential dependent, which has not been observed on other metals. The orientation change of the adsorbed pyrazine from the end-on to N/pi bonded edge-on configuration is proposed to account for this potential-dependent relative intensity change. This hypothesis is further supported by the SERS results obtained at different pyrazine concentrations. In conjunction with the orientation effect, the interaction of Rh with hydrogen and oxygen generated at different potentials has a great influence on the adsorption configuration of pyrazine.

Journal Article↗
PubMed1991

Hydrophobicity parameter of diazines. II: Analysis and prediction of partition coefficients of disubstituted pyrazines.

The partition coefficient in a 1-octanol-water system (log P) of a number of disubstituted pyrazines was measured. The increment produced by introduction of two substituents [pi(disubst)PR] was analyzed in terms of the pi value of substituents in monosubstituted pyrazine (pi 2PR) and other physicochemical substituent parameters, considering electronic and steric interactions operating bidirectionally between individual partners of substituents and aza-functions. When the substituents were nonamphiprotic and their steric interaction was not significant, the pi (disubst)PR value was approximately predicted by the summation of the pi 2PR values of corresponding substituents. For amphiprotic substituents, a correction for electronic interactions between the two substituents was needed but it was less important than that required in disubstituted benzenes. The results suggest that the difference in the pi values between disubstituted pyrazine and benzene systems was mostly governed by that between monosubstituted pyrazine and benzene systems with component substituents. In 2,6- and 2,3-disubstituted derivatives, bulky substituents had steric effects in such a way that the log P value was lowered.

Benzene↗
PubMed1995

Comparative studies of antiplatelet activity of nonsteroidal antiinflammatory drugs and new pyrazine CH- and NH-acids.

Nine known nonsteroidal antiinflammatory drugs (NSAID) and three new pyrazine derivatives possessing an active methylene moiety (pyrazine CH/NH-acids) were tested with regards to their in vitro and in vivo antiplatelet activity. Concentrations of the agents were determined which caused 25% and 50% inhibition of aggregation of human blood platelets induced by fixed concentrations of ADP, collagen and epinephrine. The in vivo test consisted in determination of percent protection of mice from pulmonary microembolism caused by injection of a mixture of collagen and epinephrine. The in vitro antiaggregatory activity of the agents studied was rather low, excepting the inhibition of the collagen-induced aggregation by ketoprofen. Several NSAID and two new pyrazine CH/NH-acids appeared highly potent antithrombotic agents in vivo. Activity of NSAID expressed as percent protection against lung thromboembolism in the mouse was demonstrated to depend quantitatively on acid properties of the agents. The new chemical class of pharmacologically active agents, pyrazine CH/NH-acids, offers an original pharmacophore which is distinctive from the carboxylic or enolic functionalities typical for the established NSAID, and as such, may be devoid of some disadvantages of known antiplatelet drugs.

Adenosine Diphosphate↗
PubMed1993

Pyrazine derivatives affect membrane fluidity of vascular smooth muscle microsomes in relation to their biological activity.

We have previously demonstrated that several structurally similar pyrazine derivatives, tetramethylpyrazine (TMP), triethylpyrazine (3EP) and tetraethylpyrazine (TEP) consistently inhibited a wide spectrum of plasmalemma-associated biological activities of vascular smooth muscles in contractility and radioligand binding studies in the following order of increasing potency, TMP < 3EP < TEP. We speculated that these pyrazine derivatives elicit multiple effects in the above order of potency by affecting, at least in part, the bulk physical properties of the lipid bilayers in the cell membrane. This hypothesis was tested in the current study using plasmalemma-enriched microsomes isolated from dog aortic smooth muscle using two different biophysical techniques: fluorescence polarization and electron spin resonance. The calculated membrane fluidity values obtained as a function of temperature by both methods are consistent with the above order of potency. The amount of incorporation of these pyrazine derivatives into the vascular smooth muscle membranes also increased with the increasing hydrophobicity of these drugs, i.e., TMP < 3EP < TEP. Our results are consistent with the contention that these pyrazine derivatives not only interact with receptor protein molecules in the biological membranes, but also modulate these receptor properties via their interaction with the lipid bilayer altering the membrane microviscosity.

Animals↗
PubMed2006

Novel 5,7-disubstituted 6-amino-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitriles, the promising protein kinase inhibitors with antiproliferative activity.

New derivatives of pyrrolo[2,3-b]pyrazine were synthesized and tested on a panel of cultured human tumor cell lines. It was found that 6-amino-5-(3-chlorophenylamino)-7-(1-methyl-1H-benzo[d]imidazol-2-yl)-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitrile (4j) exhibited a significant antiproliferative activity: GI50 for cell lines RXF 393 (renal cancer) and BT-549 (breast cancer) were 14 and 82 nM, respectively. To identify possible molecular targets, docking of the most active compounds into the active sites of cyclin-dependent kinases was performed. Molecular modeling of the inhibitor-enzyme complexes showed the differences in the binding poses of new pyrrolo[2,3-b]pyrazine derivatives in the kinase ATP-binding site compared with known pyrrolo[2,3-b]pyrazine inhibitors called aloisines. The patterns of drug kinase interactions correlated well with antiproliferative activities of novel derivatives. Key interactions and binding mode of docked compounds are discussed.

Antineoplastic Agents↗
PubMed2002

Synthesis and biological activity of 5-alkyl-6-(alkylsulfanyl)- or 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides and corresponding thioamides.

Nucleophilic substitution of chlorine in 5-alkyl-6-chloropyrazine-2-carboxamides with various alkyl and arylthiolates afforded 20 5-alkyl-6-(alkylsulfanyl)- and 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides. The reaction of the amides with Lawesson's reagent yielded the corresponding thioamides. The assessment of in vitro antimycobacterial and antifungal activity of the compounds was carried out. In both series, the antimycobacterial activity increases with increasing molecular weight of the alkylsulfanyl group in position 6 of the pyrazine ring. Thioamides exhibited higher activity than the corresponding amides. 5-Butyl-6-(phenylsulfanyl)pyrazine-2-carbothioamide (2j) possessed the highest activity (91% inhibition) against Mycobacterium tuberculosis and also the highest lipophilicity (log P = 4.95). Only a poor in vitro antifungal effect was noted in 5-butyl-6-(butylsulfanyl)pyrazine-2-carboxamide (1i) and 6-(ethylsulfanyl)-5-isobutylpyrazine-2-carbothioamide (2q) against Trichophyton mentagrophytes and Absidia corymbifera.

Anti-Infective Agents↗
PubMed1999

Antiproliferative, differentiating and apoptotic effects elicited by imidazo[1,2-a]pyrazine derivatives.

1. The activity of two series of imidazo[1,2-a]pyrazine derivatives on cell proliferation and differentiation and on apoptosis was examined in relation to their effects on phosphodiesterase (PDE) activity and on purinoceptors. 2. In the first series SC-18 and SC-51 inhibited mitogen-induced 3H-thymidine incorporation in human lymphocytes. 3. The compounds of the new series PAB13, PAB23 and SCA40 inhibited the proliferation of the HEL cell line. 4. Nine imidazo[1,2-a]pyrazine derivatives of the new series have been studied on the Dami cell proliferation. SCA41 and SCA44 inhibited cell growth, SCA40 and PAB40 were moderately effective, whereas PAB12 and PAB30 were devoid of effect. The antiproliferative effects of these six non-cytotoxic compounds could not be related to their action on PDE or on purinoceptors, but rather to their lipophilicity. Conversely, for PAB13, PAB15, and PAB23, the decrease in cell number was related to their cytotoxic and apoptotic effects through their cAMP-increasing and PDE-inhibitory potency, but unrelated to an effect on purinoceptors. 5. Imidazo[1,2-a]pyrazine derivatives decreased the expression of Glycoprotein (GP)Ib in Dami cells while some of them enhanced that of GPIIb/IIIa. These effects appeared to involve inhibition of both cAMP- and cGMP-PDE. 6. These studies demonstrate the potential interest of imidazo[1,2-a]pyrazine derivatives in the query of novel anticancer drugs.

Animals↗
PubMed2003

Novel pyrazine metabolites found in polymyxin biosynthesis by Paenibacillus polymyxa.

A complex mixture of methyl-branched alkyl-substituted pyrazines was found in the growth medium of the polymyxin-producing bacterium Paenibacillus polymyxa, and of these, seven are new natural compounds. A total of 19 pyrazine metabolites were identified. The dominant metabolite was 2,5-diisopropylpyrazine as identified using a combination of high-resolution mass spectrometry, (1)H- and (13)C-nuclear magnetic resonance, gas chromatography-mass spectrometry as well as co-elution with an authentic standard. Its biosynthesis was correlated with growth and production was strongly stimulated by valine supplementation. The other pyrazine metabolites, all related pyrazines with either one, two or three alkyl substituents, were identified by means of their mass spectral data and/or co-elution with authentic standards.

Bacillaceae↗
PubMed1992

Molecular recognition of amiloride analogs: a molecular electrostatic potential analysis. 1. Pyrazine ring modifications.

Ab initio molecular electrostatic potential (MEP) patterns are used to determine the electrostatic requirements for the formation of a stable blocking complex between amiloride analogs and the epithelial sodium channel of Rana ridibunda. MEP maps calculated in the 3-21G(*) and STO-3G basis sets for amiloride and analogs with pyrazine ring modifications are used to interpret differences in the microscopic rate constants for analog-channel binding determined by Li et al. MEP maps of the protonated analogs are correlated to differences in the value of kon, the microscopic association constant. Those analogs with kon values similar to amiloride are found to have a MEP maximum that is localized over the side chain, as well as strong, distinguishing minima in the MEP pattern off the carbonyl oxygen and positions 3, 4, and 5 of the pyrazine ring. MEP maps of a model-encounter complex (protonated analog and formic acid anion) are correlated to differences in koff, the microscopic dissociation constant. The major conclusions of this work are that (1) a stable blocking complex is formed with analogs which have a deep, localized minimum off the 6 position of the pyrazine ring, (2) the stability of the blocking complex is directly related to the depth of that minimum, (3) substitution at position 5 affects not only the depth but also the location and size of the minimum off position 6, and (4) steric factors may influence the optimal binding of the 6-position ligand to the ion channel. The MEP analysis also suggests that the distance between the proton donors of the chelating guanidinium moiety and the deep, localized minimum off position 6 of the pyrazine ring may define an important spatial requirement for all those analogs which form a stable blocking complex with the channel.

Amiloride↗
PubMed2001

Prediction of the aroma quality and the threshold values of some pyrazines using artificial neural networks.

An artificial neural network is used to predict both the classification of aroma compounds and their flavor impression threshold values for a series of pyrazines. The classification set consists of 98 compounds (32 green, 43 bell-pepper, and 23 nutty smelling pyrazines), and the regression sets consist of 24 green and 37 bell-pepper odorous pyrazines. The best classification of the three aroma impressions (93.7%) is obtained by using a multilayer perceptron network architecture. To predict the threshold values of bell-pepper fragrance, a standard Pearson R correlation coefficient of 0.936 for the training set, 0.912 for the verification set, and 0.926 for the test set is received with two hidden layers consisting of two and one neurons. The network for the threshold prediction of the class of green-smelling pyrazines with one hidden layer containing three neurons turns out to be the best with a standard Pearson R correlation coefficient of 0.859 for the training, 0.918 for the verification, and 0.948 for the test set. These good correlations show that artificial neural networks are versatile tools for the classification of aroma compounds.

Flavoring Agents↗
PubMed1983

Piperazinylimidazo[1,2-a]pyrazines with selective affinity for in vitro alpha-adrenergic receptor subtypes.

Regioselective syntheses of alkyl- and halogen-substituted piperazinylimidazo[1,2-a]pyrazines by novel oxidation-dehydration of [(beta-hydroxyalkyl)amino]pyrazines are described. Lanthanide shift reagent studies allowed correction of literature assignments of NMR chemical shifts and coupling constants for the imidazo[1,2-a]pyrazine ring system (e.g., J5,8 greater than J6,8). Equilibrium constants for displacement of specifically bound [3H]clonidine and [3H]prazosin from calf cerebral cortex homogenates in vitro are tabulated for reference and title compounds, and structure-affinity relationships for alpha 2- vs. alpha 1-adrenergic receptors are considered. Compound 2a, 8-(1-piperazinyl)imidazo[1,2-a]pyrazine, is equipotent with mianserin on the clonidine receptor (alpha 2) but ca. 70 times as selective as mianserin for this alpha 2-adrenergic receptor. Reduction of the imidazo ring (2,3-dihydro) lowers affinity for the alpha 2 receptor without affecting alpha 1-receptor affinity. Computer-assisted molecular modeling techniques are applied to the estimation of conformational energies of 2a and its 5-position isomer in relation to the semirigid molecule mianserin.

Animals↗
PubMed1984

Synthesis of imidazo[1,2-a]pyrazine derivatives with uterine-relaxing, antibronchospastic, and cardiac-stimulating properties.

A series of imidazo[1,2-alpha]pyrazine derivatives was synthesized by condensation of alpha-halogenocarbonyl compounds and aminopyrazines. Various compounds resulted from competitive reactions or reagent isomerization and demonstrated in vitro uterine-relaxing and in vivo antibronchospastic activities. On isolated atria, 5-bromoimidazo-[1,2-alpha]pyrazine showed positive chronotropic and inotropic properties; the latter was associated with an increase in the cyclic AMP tissue concentration. Potentiation of the isoproterenol positive inotropic effect of 5-bromoimidazo[1,2-alpha]pyrazine and the lack of blockade of the 5-bromoimidazo[1,2-alpha]pyrazine positive inotropic effect by propranolol suggested phosphodiesterase-inhibiting properties.

Animals↗
PubMed1984

Tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines: vascular smooth muscle relaxants and antihypertensive agents.

A series of tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines were synthesized and tested for their ability to relax K+-depolarized aortic smooth muscle and antihypertensive activity. It was shown that compounds producing the most relaxation of aortic smooth muscle (5-[2,6-dimethoxyphenyl)methyl]-1,2,3,3a-tetrahydropyrrolo[1,2-a] quinoxalin-4(5H)-one and 5-[(2,6-dimethoxyphenyl)methyl]-5,6,6a,7,8,9-hexahydropyrrolo[1,2- a] pyrazine, 10 and 19, respectively) demonstrated the least hypotensive activity. Those compounds that were the most effective hypotensive agents (6a,7,8,9-tetrahydro-5-(phenylmethyl)pyrido[3,2-a]pyrrolo[1,2-a]++ +pyrazin- 6(5H)-one and 6a,7,8,9-tetrahydro-5-(4-pyridinylmethyl)pyrido[3,2-e]pyrrolo [1,2-a]pyrazin-6(5H)-one, 12 and 13, respectively) displayed little vascular smooth muscle relaxant activity.

Animals↗
PubMed2004

Pyrrolodiazines. 6. Palladium-catalyzed arylation, heteroarylation, and amination of 3,4-dihydropyrrolo[1,2-a]pyrazines.

The palladium-catalyzed Suzuki cross-coupling reaction of arylboronic acids and 6-bromo- and 6,8-dibromo-3,4-dihydropyrrolo[1,2-a]pyrazines afforded 6-substituted and 6,8-disubstituted 3,4-dihydropyrrolo[1,2-a]pyrazines in good yields. Stille and Negishi coupling reactions have been used to prepare 6-heteroaryl-substituted derivatives in moderate yields by employing heteroaryl halides and 6-metalated 3,4-dihydropyrrolo[1,2-a]pyrazines as reaction partners. A variety of cyclic secondary amines have also been incorporated at position C-6 of 6-bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine in the presence of the palladium catalyst Pd(2)(dba)(3) in conjunction with BINAP as ligand. This amination reaction is one of the few reported examples of such a palladium-catalyzed transformation on a pyrrole ring, although the reaction could not be extended to less nucleophilic amines.

Alkylation↗
PubMed2001

Pyrazine odour makes visually conspicuous prey aversive.

Unpalatable insects frequently adopt multimodal signals to ward off predators, incorporating sounds and odours into their colourful displays. Pyrazine is an odour commonly used in insect warning displays, and has previously been shown to elicit unlearned biases against common warning colours, e.g. yellow and red in naive predators. We designed two experiments to test for similar effects of pyrazine on the conspicuousness of prey, perhaps the most ubiquitous aspect of aposematic coloration. In the first experiment, we offered predators (Gallus gallus domesticus) a choice between conspicuous crumbs and cryptic crumbs in the presence or absence of pyrazine. In the second experiment, we manipulated the birds' experience of conspicuous prey during an initial training phase. Only in the presence of pyrazine did birds show a bias against conspicuously coloured food, and this occurred whether or not they had previously experienced food that contrasted with the background. This emergent behaviour relied upon the visual and odorous signal components being presented together. These unlearned, yet hidden, responses against conspicuousness demonstrate that there are initial benefits to prey being conspicuous when the multimodal nature of warning signals is accounted for.

Animals↗
PubMed1990

Studies on antiallergic agents. I. Synthesis and antiallergic activity of novel pyrazine derivatives.

Various pyrazine derivatives were synthesized and their antiallergic activity was examined. The inhibitory activity on allergic histamine release of the compounds bearing a 5-tetrazolyl group was more potent than that of the corresponding carboxyl derivatives. The introduction of -CONH- or -NHCO- between the pyrazine ring and the 5-tetrazolyl group as a spacer greatly enhanced the activity. N-(1H-Tetrazol-5-yl)-2-pyrazinecarboxamide (I-3) was estimated to exhibit nearly the same potency as disodium cromoglycate (DSCG). The structure-activity relationship among various derivatives modified by introducing some substituents onto the 3-, 5- or 6-position of the pyrazine ring of I-3 was investigated. The activity remained unchanged or was reduced when such substituents as methyl, chloro, methoxy, methylamino and dimethylamino were introduced at the 3- or 5-position. In contrast, 6-substitution with various alkylamino groups more or less increased the activity. Among them, the 6-dimethylamino (I-17c) and 6-(1-pyrrolidinyl) (I-34) derivative were proved to be most potent. The IC50 values (concentration which produces 50% inhibition of the allergic histamine release) of I-17c and I-34 were determined to be 4.7 x 10(-10) and 4.6 x 10(-10) M, respectively. These two compounds produced a potent inhibitory activity on passive cutaneous anaphylaxis (PCA) in rat, not only by the intravenous route (ED50 = 0.0096 mg/kg for both compounds) but also by the oral route (ED50 = 0.19 and 0.18 mg/kg, respectively). On the other hand, when the pyrazine ring of some representative compounds was replaced with a pyridine ring, the inhibitory activity on histamine release was significantly reduced.

Animals↗
PubMed1997

[Synthesis and antibacterial properties of pyrido[2,3-b]pyrazine derivatives].

Novel pyrido[2,3-b]pyrazine 1,4-dioxide and pyrido [2,3-b]pyrazine 1-oxide derivatives were synthesized from furazano [4,5-b]pyridine 3-oxide and the enolic form of 1,3-diketones or beta-ketoesters catalyzed by silica gel or molecular sieves. Their antibacterial activities were evaluated. As the results of anti-bacterial screening tests in vitro, pyrido[2,3-b]pyrazine 1,4-dioxide derivatives revealed strong activities, but pyrido[2,3-b]pyrazine 1-oxide derivatives revealed no activities.

Anti-Bacterial Agents↗
PubMed1989

Influence of pyrazine derivatives on the day of vaginal opening in juvenile female rats.

Effects of pyrazine derivatives on the day of the first opening of the vagina in juvenile female rats were studied. Tetraethyl and 2,5-dimethyl pyrazine caused a significant delay in the first vaginal opening day of juvenile female rats, but no delay was noted in the case of 2,5-diethyl or triethyl pyrazine. These results suggest that tetraethyl and 2,5-dimethyl pyrazine cause delays in the onset of puberty in juvenile female rats.

Animals↗