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PubMed2005

Functionalization of pyrimidine and purine nucleosides at C4 and C6: C-nucleophilic substitution of their C4- and C6-(1,2,4-triazol-1-yl) derivatives.

A study of C-nucleophilic substitution at the C4-position on pyrimidine and C6-position on 2'-deoxyguanosine to produce novel nucleosides is presented with the spectroscopic properties of their respective substitution products. C4-(1,2,4-triazol-1-yl) pyrimidine nucleosides 1 were treated with nitroalkanes, malononitrile, acetylacetone, ethyl nitroacetate, acetoacetate and cyanoacetate at 100 degrees C in dioxane in the presence of DBU resulting in the production of novel nucleosides 2-11. To explore the application of this methodology to purine chemistry, this approach was used to produce novel analogs from 2'-deoxyguanosine. We found that the triazolo derivative 12 undergoes C-nucleophilic substitution with nitromethane, malononitrile, acetylacetone, ethyl nitroacetate and cyanoacetate in the presence of potassium carbonate (K2CO3) in DMF at 100 degrees C to give novel nucleosides 13-17.

Acetates↗
PubMed1999

Synthesis of pharmacologically active indoles.

Formylation of 6-methoxy-1-methyl and 5-methyl,2,3-diphenyl-1H-indole (Ib and IX) gave the 5- and 6- carboxaldehyde derivatives (II and X) respectively, which were treated with ethyl cyanoacetate to form the corresponding 2-cyano-3-substituted acrylic acid ethyl ester (III and XI). The latter compounds reacted with hydrazine hydrate, urea and thiourea to form the corresponding 5-amino-4-substituted 2,4,dihydropyrazol-3- one (IV), 6-indolyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile s (V and XII) and 6-indolyl-4-oxo-2-thixo-1,2,3,4-tetrahydropyrimidine-5-ca rbonitriles (VI and XIII). Reaction of the 5- and 6-carboxaldehyde derivatives with malononitrile afforded the 2-substituted malononitrile derivatives (VII and XIV). VII and XIV reacted readilly with aromatic ketones to give the 2-amino4,6-disubstituted nicotinonitriles (VIII a,b and XVa,b). The biological activity of compounds Ia, Ib, II, III, IX and X was tested for antiinflammatory, ulcerogenic and antispasmodic activities.

Animals↗
PubMed1999

Anisylidine pyruvic acid in heterocyclic synthesis

A series of substituted pyran, pyridine, thiin (3), (4), (5) and (6) were prepared from anisylidine pyruvic acid (1a). The indenopyran (7) was also prepared from (1a) via Michael addition reaction. Compound (1a) condensed with o-phenylenediamine and o-aminophenol to give (8) and (9). Reaction of (1a) with thiosemicarbazide afforded (10) which cyclized to give the triazine (11). Compound (1b) was subjected to react with o-phenylenediamine, o-aminophenol and diamino-arylazopyrazole derivatives to yield the Schiff bases (12, 13) and (14) respectively. Addition of malononitrile (1 mole) to (1b) gave (15) while addition of (2 moles) of malononitrile gave (16). Reaction of (1b) with urea yielded the pyrrolopyrimidine (17). The structures of the products were confirmed by their correct analytical data.

Journal Article↗
PubMedDate not supplied

Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease.

The authors used 2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ([18F]FDDNP), a hydrophobic radiofluorinated derivative of 2-(1-[6-(dimethylamino)-2-naphthyl]ethylidene)malononitrile (DDNP), in conjunction with positron emission tomography to determine the localization and load of neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. Previous work illustrated the in vitro binding characteristics of [18F]FDDNP to synthetic beta-amyloid(1-40) fibrils and to NFTs and APs in human AD brain specimens. In the present study, greater accumulation and slower clearance was observed in AP- and NFT-dense brain areas and correlated with lower memory performance scores. The relative residence time of the probe in brain regions affected by AD was significantly greater in patients with AD (n=9) than in control subjects (n=7; p=0.0007). This noninvasive technique for monitoring AP and NFT development is expected to facilitate diagnostic assessment of patients with AD and assist in response-monitoring during experimental treatments.

Aged↗
PubMed2004

Synthesis of novel dihydropyridine, dihydropyrimidine, dithioacetal and chalcone derivatives from formylchromones.

Condensation of 6-Formylfurochromone (4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1]benzopyran-6-carbaldehyde) 5a and malononitrile without solvent afforded (2E)-2-cyano-3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]benzopyran-6-yl) acrylamide 8 at hydrolysis with dilute HCL. 2,6-Diamino-4-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]benzopyran-6-yl)-1,4-dihydropyridine-3,5-dicarbonitrile 9 and 6-(2,6-diacetyl-3,5-dimethylcyclohexa-2,5-dien-1-yl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5-one 10a,b were synthesized by one-pot cyclocondensation reaction of formyl 5a, malononitrile and ammonium acetate/or ammonium hydroxide/or aniline. The reaction of formyl 5a, malononitrile/acetylacetone (Thio) urea/guanidine HCL to give 6-amino-4-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1]benzopyran-6-yl)-2-methylene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile compounds 11a,b, 6-(2-amino-5,6-dimethyl-1,4-dihydropyrimidin-4-yl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5-one 12a,b. Condensation of formylfurochromone 5a with thiol compounds afforded 6-isopropyl-4-methoxy-9-(methoxy Ia or methyl Ib)-5H-furo[3,2-g][1]benzopyran-5-one 13a-f; 6-(1,3-dithiolan-2-yl)-4-methoxy-5H-furo[3,2-g]chromen-5-one 14a,b; 7-hydroxy-6-isopropyl-5-methoxy-2-methyl-4H-benzopyran-4-one 5a-c; 6 hydroxy-7-[mercapto(methylthio)methyl-8-methoxy-3-methylnaphthalen-1(4H)-one 16, respectively. Formylfurochromones 5a-c were reacted with different substituted of acetyl compounds (khellinone, 2-acetyl pyrrol, 3-acetyl coumarin, methyl-2-thienyl ketone and p-aminoacetophenone respectively) to proceed 4-methoxy-9-(methoxy Ia or methyl Ib)-6-(1E)-3-oxobut-1-enyl]-5H-furo[3,2-g][1]benzopyran-5-one 17, 5-methoxy-2-methyl-6[(1E)-3-oxobut-1-enyl]-4a,5,8,8a-tetrahydro-4H-benzopyran-4-one 18a-d, 4,9-dimethoxy-6-[(1E)-3-methoxyprop-1-enyl]-5H-furo[3,2-g][1]benzopyran-5-one-N-methylene-N-phenylamine-6-(iminomethyl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5-one 19.

Acetals↗
PubMed2000

Disruption of microtubules in living cells by tyrphostin AG-1714.

Tyrphostin AG-1714 and several related molecules with the general structure of nitro-benzene malononitrile (BMN) disrupt microtubules in a large variety of cultured cells. This process can be inhibited by the stabilization of microtubules with taxol or by pretreatment of the cells with pervanadate, which inhibits tyrosine phosphatases and increases the overall levels of phosphotyrosine in cells. Unlike other microtubule-disrupting drugs such as nocodazole or colchicine, tyrphostin AG-1714 does not interfere with microtubule polymerization or stability in vitro, suggesting that the effect of this tyrphostin on microtubules is indirect. These results imply an involvement of protein tyrosine phosphorylation in the regulation of overall microtubule dynamics. Tyrphostins of AG-1714 type could thus be powerful tools for the identification of such microtubule regulatory pathways.

Animals↗
PubMed2002

Engineering a remarkably low HOMO-LUMO gap by covalent linkage of a strong pi-donor and a pi-acceptor--tetrathiafulvalene-sigma-polynitrofluorene diads: their amphoteric redox behavior, electron transfer and spectroscopic properties.

Novel R3TTF-sigma-A compounds 14, 16 and 19 (R3TTF = trial-kyletrathiafulvalene, sigma = saturated spacer, A = polynitrofluoren-9-dicyano-methylene acceptor) incorporating very strong donor and acceptor moieties have been synthesized by condensation of the corresponding R3TTF-sigma-fluoren-9-one diads with malononitrile. Reversible five-step amphoteric redox behavior has been observed with an extremely low HOMO-LUMO gap (approximately 0.3 eV). For compound 14 a strong EPR signal is observed in the solid state, ascribed to intermolecular complexation: a less intense signal is seen in solution, corresponding to ca. 2% of the molecules existing in a radical form at room temperature. Intramolecular charge transfer in diads 14 and 16 is manifested in strong absorption bands in the near-IR region of their electronic spectra. Spectroelectrochemical data reveal marked electrochromic behavior in the visible and near-IR region of both compounds. The first X-ray crystal structure of a fluorene radical-anion salt is reported, namely the copper salt of 2,4,5,7-tetranitro-9- dicyanomethylenefluorene (1:1 stoichiometry).

Journal Article↗
PubMed2002

Pyrido[2, 3-d]pyrimidines and pyrimido[5',4':5, 6]pyrido[2, 3-d]pyrimidines as new antiviral agents: synthesis and biological activity.

A series of 7-amino- and 7-oxo-5-aryl-6-cyanopyrido[2, 3-d]pyrimidines, 4 and 11, respectively, and pyrimido [5', 4':5, 6]pyrido[2, 3-d]pyrimidine derivatives 6 and 7 was synthesized and investigated as antiviral agents. Different synthetic strategies for the preparation of the target compounds were explored. A synthetic procedure for 4 and 11 starting with 6-amino-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidine, proper aldehyde, and malononitrile or ethyl cyanoacetate, respectively, in a one-pot reaction proved to be the method of choice for preparation of compounds of such type. Construction of another pyrimidine ring on the pyridine nucleus of compound 4 was achieved either by reaction with phenyl iso(thio)cyanate or with formic acid to yield 6 and 7, respectively. The structure of the prepared compounds was confirmed through elemental analysis and spectral investigation. Most of the newly synthesized compounds were subjected to antiviral activity testing against herpes simplex virus (HSV) where some of them show good activities.

3T3 Cells↗
PubMed1988

Microbial hydrolysis of organic nitriles and amides.

Nitrile-hydrating enzymes produced by bacteria and fungi catalyse the conversion of a large number of chemically diverse nitriles, including many economically important compounds used industrially for chemical synthesis of amides and acids. This paper presents data on two new, highly different nitrile-hydrolysing enzymes which were isolated in connection with our studies on enzymic nitrile transformations. Particular attention was paid to the enzymes' substrate specificities and sensitivity to substrate/product inhibition. One of our microbial isolates was a Rhodococcus sp. (strain CH5). This strain produces a constitutive hydratase that has a broad substrate spectrum, including aliphatic and aromatic nitriles, mononitriles and dinitriles, hydroxynitriles and amino-nitriles. It also produces a constitutive amidase of equally low substrate specificity. The hydratase/amidase system catalysed the hydrolysis of D,L-aminonitriles into racemic mixtures of amino acids. Strain CH5 is able to produce high concentrations of malonic acid monoamide from malononitrile and malonamide. The other isolate, Alcaligenes sp. (strain I4), can convert high concentrations of cyanoacetate into malonic acid, presumably by means of an aliphatic nitrilase that is specific for cyanoacetate. Enzyme kinetic experiments have shown that this enzyme is very resistant to both substrate and product inhibition.

Alcaligenes↗
PubMed1978

The roles of mediators, irritants and allergens in causing mucin secretion from the trachea.

Two species, the cat and the goose, have been investigated to determine whether a variety of pharmacological mediators, irritants and allergens change the rate at which mucins (mucus glycoproteins) are secreted into the trachea. Mucins were labelled by the administration of radioactive precursors which the mucous cells took up and incorporated into glycoproteins. These were periodically washed out of a segment of trachea with physiological saline solution. Changes in the amount of mucin secreted were estimated from measurements of the amount of bound radioactivity in tracheal washings. Histamine increased mucin secretion but the effects were stronger and more consistent in the goose than in the cat. A variety of prostaglandins increased the secretion in both species. 5-Hydroxytryptamine failed to stimulate mucin output in the cat. Ammonia and cigarette smoke both increased mucin secretion in the cat and preliminary results suggest that this was by a combination of local and reflex mechanisms. O-Chlorobenzilidine malononitrile increased secretion from the goose trachea entirely by a local mechanism. Preliminary experiments in which sensitized cats were challenged by various routes have equivocal results on whether anaphylaxis increases airway mucin secretion. It is concluded that irritants cause mucin secretion both by reflexes and local mechanisms. The mechanisms for the latter may well include release of pharmacological mediators.

Allergens↗
PubMed2004

Synthesis and biological testing of novel analogues of sydnone as potential antibacterial agents.

Several series of 3-phenylsydnone derivatives conjugated to well-known moieties with antibacterial activity were synthesized via several routes. These derivatives include 3-cyano-2-oxopyridine, 2-amino-3-cyanopyridine, 2-arylidene-1-ethylidenehydrazine and 2-aroyl-1-ethylidenehydrazine moieties. Thus, the key intermediate 3-(4-acetylphenyl)sydnone (3) was allowed to react with the appropriate aldehyde, ethyl cyanoacetate or malononitrile in presence of excess ammonium acetate in two steps (method 1) or through a one-pot reaction technique (methods 2 and 3) to give the corresponding sydnone derivatives 5 and 6, respectively. Moreover, condensation of compound 3 with hydrazine hydrate followed by the reaction with the appropriate aldehyde, mono- and dicarboxylic acid hydrazide yielded the corresponding sydnone derivatives 8, 9 and 10, respectively. Most of the synthesized compounds were screened for their in vitro antibacterial activity against various pathogenic organisms of both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentrations (MICs) were determined using agar dilution method.

Anti-Infective Agents↗
PubMed2004

Synthesis and antimicrobial evaluation of some novel cholestane heterocyclic derivatives.

This study was performed to investigate the reactivity of 5alpha-cholestan-3-one (1) towards various chemical reagents to produce new steroidal heterocyclic derivatives. The aminothieno[2, 3:2, 3]cholestane derivative 2 was synthesized according to Gewald's conditions. The diazonium salt of compound 2 coupled with malononitrile to afford dicyanomethylenhydrazinothieno[2', 3':2, 3]cholestane derivative 5. The behavior of compound 5 towards nitrogen nucleophiles and several active methylene reagents was investigated. Additionally, a variety of steroidal heterocyclic derivatives like compounds 15a, b-22a, b were synthesized starting with 5alpha-cholestan-3-one (1). The structures of the compounds were established based on the analytical and spectral data. The in vitro antimicrobial activity of some newly synthesized compounds against bacteria and fungi was studied.

Ampicillin↗
PubMed2005

A novel synthesis and molluscicidal activity of some functionally substituted pyridine, pyrido[3,2-c]pyridazine, and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives.

Ethyl benzoylacetate reacts with the malononitrile dimer to afford 4-amino-5-benzoyl-2-dicyano methyl-6-hydroxypyridine, which undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives. These azo derivatives could be cyclized into pyrido[3,2-c]pyridazine and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives upon reflux in ethanolic NaOH, presumably via their hydrazo tautomers. The molluscicidal activity of these compounds was evaluated.

Animals↗
PubMed2006

Nitrile hydrolysis activity of Rhodococcus erythropolis NCIMB 11540 whole cells.

The nitrile hydrolyzing properties of the bacterium strain Rhodococcus erythropolis NCIMB 11540 have been investigated. Using whole cells of the microorganism, a wide variety of aromatic and aliphatic cyanide-containing substrates was successfully hydrolyzed to the corresponding amide or acid. In the case of dicyanides, selective monohydrolysis took place, which was further explored in the desymmetrization of malononitriles resulting in the corresponding cyano amides in enantiomeric excesses of up to 98%.

Hydrolysis↗
PubMed2004

Highly efficient and mild copper-catalyzed N- and C-arylations with aryl bromides and iodides.

Mild, efficient, copper-catalyzed N-arylation procedures for nitrogen heterocycles, amides, carbamates, and C-arylation procedures for malonic acid derivatives have been developed that afford high yields of arylated products with excellent selectivity. The N-arylation of imidazole with aryl bromides or iodides was found to be greatly accelerated by inexpensive, air-stable catalyst systems, combining catalytic copper salts or oxides with a set of structurally simple chelating ligands. The reaction was shown to be compatible with a broad range of aryl halides, encompassing sterically hindered, electron-poor, and electron-rich ones, providing the arylated products under particularly mild conditions (50-82 degrees C). The lower limit in ligand and catalyst loading and the scope of Ullmann-type condensations catalyzed by complexes bearing those ligands with respect to the nucleophile class have also been investigated. Chelating Schiff base Chxn-Py-Al (1c) generates a remarkably general copper catalyst for N-arylation of pyrrole, indole, 1,2,4-triazole, amides, and carbamates; and C-arylation of diethyl malonate, ethyl cyanoacetate, and malononitrile with aryl iodides under mild conditions (50-82 degrees C). The new method reported here is the most successful to date with regard to Ullmann-type arylation of some of these nucleophiles.

Journal Article↗
PubMed2000

New pyrazolo[3,4-b]pyrazines: synthesis and biological activity.

Some new pyrazolo[3,4-b]pyrazines and related heterocycles were synthesized and evaluated for their antifungal and antiparasitic activities. The key intermediate, 6-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carbonitrile (3) was obtained in a one-pot synthesis via the reaction of 5-amino-3-methyl-4-nitroso-1-phenylpyrazole 2 with malononitrile.

Animals↗
PubMedDate not supplied

Riot control agents: pharmacology, toxicology, biochemistry and chemistry.

The desired effect of all riot control agents is the temporary disablement of individuals by way of intense irritation of the mucous membranes and skin. Generally, riot control agents can produce acute site-specific toxicity where sensory irritation occurs. Early riot control agents, namely, chloroacetophenone (CN) and chlorodihydrophenarsazine (DM), have been replaced with 'safer' agents such as o-chlorobenzylidene malononitrile (CS) and oleoresin of capsicum (OC). Riot control agents are safe when used as intended: however, the widespread use of riot control agents raises questions and concerns regarding their health effects and safety. A large margin exists between dosages that produce harassment and dosages likely to cause adverse health effects for modern riot control agents such as CS and dibenz[b,f]1 : 4-oxazepine (CR). Yet, despite the low toxicity of modern riot control agents, these compounds are not entirely without risk. The risk of toxicity increases with higher exposure levels and prolonged exposure durations. Ocular, pulmonary and dermal injury may occur on exposure to high levels of these substances, and exposure to riot control agents in enclosed spaces may produce significant toxic effects. Reported deaths are few involving riot control agents, and then only under conditions of prolonged exposure and high concentrations. Recently, concern has focused on the deaths resulting from law enforcement use of OC, a riot control agent generally regarded as safe because it is a natural product. As with other xenobiotics, not enough is known concerning the long-term/chronic effects of riot control agents. Clearly, there is considerable need for additional research to define and delineate the biological and toxicological actions of riot control agents and to illuminate the full health consequences of these compounds as riot control agents.

Administration, Inhalation↗
PubMed2005

Characterization of some synthetic Ru and Ir complexes by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) was applied to the analysis of Ru(OCOCF(3))(2)(CO)(PPh(3))(2), Ru(OCOC(3)F(7))(2)(CO)(PPh(3))(2), Ir(tBuppy)(3) and Ir(ppy)(2)(acac) complexes. A troublesome problem in the MALDI-TOFMS characterization of these metal complexes is the possible replacement of complex ligands by matrix. In this contribution, 10 matrices, ranging from acidic to basic, were investigated: alpha-cyano-4-hydroxycinnamic acid (CHCA), 2,5-dihydroxybenzoic acid (DHB), sinapinic acid (SA), dithranol, 2,4,6-trihydroxyactophenone (THAP), 6-azo-2-thiothymine (ATT), norharman, 2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile (DCTB), 4-nitroaniline (NA) and 2-amino-5-nitrophyridine (ANP). With most of the matrices, including the neutral and basic ones, matrix substitution of ligand could clearly be detected. Based on the experimental results, possible mechanisms of matrix substitution were discussed. It was demonstrated that the ligand exchange process might also occur through the gas-phase reactions initiated by laser shots. Among the matrices tested, DCTB was found to be the best one for the complexes that are prone to ligand exchange by matrix.

Journal Article↗