RESUMO
We recently discovered new nucleotides (4-pyridone-3-carboxamide-1-beta -D-ribonucleoside phosphates) in human erythrocytes. To establish the precursor compound and pathways of nucleotide derivative formation and breakdown, human erythrocytes were incubated for 3 hours with 0.3 mM 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside (4PYR) and erythrocyte concentrations of 4PYR and adenine nucleotides were followed. 4PYR triphosphate increased from 16.1 +/- 0.6 micro M to 74.9 +/- 9.17 and 4PYR monophosphate increased from 5 micro M to 254.7 +/- 13.9 micro M. Conversely, incubation with 0.3 mM 4-pyridone-3-carboxamide (4PY) did not lead to additional 4PYR nucleotide formation. 4PYR nucleotides were catabolized to 4PYR. We conclude that 4PYR nucleotides are formed in erythrocytes by nucleoside kinase-mediated 4PYR phosphorylation and catabolized by 5'nucleotidase-mediated dephosphorylation.
Assuntos
Eritrócitos/metabolismo , Nucleosídeos/sangue , Nucleosídeos/metabolismo , Nucleotídeos/sangue , Nucleotídeos/metabolismo , Humanos , Incubadoras , Nucleosídeos/química , Fatores de TempoRESUMO
Because mutation of AMP deaminase 1 gene leading to reduced AMP deaminase activity may result in protection of cardiac function in patients with heart disease, inhibitors of AMP deaminase (AMPD) may have therapeutic applications. This study evaluated the effect of a specific inhibitor of AMP deaminase 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo [4,5-d][1,3]diazepin-8-ol (AMPDI) on the isolated human enzyme and on nucleotide catabolism in rat cardiomyocytes. AMPDI effectively inhibited isolated human AMPD with an IC(50) = 0.5 micro M. AMPDI was much less effective with isolated cardiomyocytes (IC(50) = 0.5 mM). AMPDI is a very effective inhibitor of AMPD that despite lower efficiency in the cell system examined could be useful for in vivo studies.
Assuntos
AMP Desaminase/antagonistas & inibidores , Azepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Adenosina/metabolismo , Animais , Azepinas/síntese química , Inibidores Enzimáticos/síntese química , Humanos , Imidazóis/síntese química , Inosina Monofosfato/metabolismo , Miócitos Cardíacos/metabolismo , RatosRESUMO
The alpha-oxo ketene dithioacetalic derivatives (2a-e) were obtained by the reaction of 2-acetylpyrazine (1) with CS2 and appropriate mono- or dihalogeno-compound. An action of the primary amines and diamines upon 3,3-di(methylsulphanyl)-1-(2-pyrazinyl)-2-propen-1-one (2a) yielded 3-(alkylamino)-3-(methylsulphanyl)-1-(2-pyrazinyl)-2-propen-1-on e (3a-g), 1-(2-pyrazinyl)-2-tetrahydro-1H-2-imidazolyliden-1-ethanone (3h) and the 2-hexahydro-2-pyrimidinyliden-1-(2-pyrazinyl)-1-ethanone derivatives (3i-j), respectively. Tuberculostatic activity of the studied compounds was found to be low except the compound 2b (MIC 192-62 micrograms/cm3; MIC 210-31 micrograms/cm3).
Assuntos
Antituberculosos/síntese química , Pirazinas/síntese química , Antituberculosos/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/farmacologia , Espectrofotometria Infravermelho , Sulfetos/síntese química , Sulfetos/farmacologiaRESUMO
Hydrogenation of 4-N-substituted thiosemicarbazonic acid acetylpyrazine derivatives with NaBH4 in dry ethanol led to seventeen new compounds. The in vitro tuberculostatic activity investigations of the 15 synthesized compound were carried out. MIC few of i.v. compounds were lower than 32 micrograms/cm3.
Assuntos
Antituberculosos/síntese química , Pirazinas/síntese química , Tiossemicarbazonas/síntese química , Animais , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Micobactérias não Tuberculosas/efeitos dos fármacosRESUMO
A series of quinoxalylamino-1,3-diazacycloalkanes was obtained by the reaction of the corresponding substituted aminoquinoxalines with alcohols and amines. The effect of selected compounds on the blood pressure of anaesthesized normotensive rats was studied.
Assuntos
Fármacos Cardiovasculares/síntese química , Quinoxalinas/síntese química , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Masculino , Quinoxalinas/farmacologia , Ratos , Ratos WistarRESUMO
The action of acetylsalicylic acid, ticlopidine and a new pyrazine derivative HF90 selected in preliminary screenings (11, 18, 19) was studied by using the mouse antithrombotic assay according to DiMinno and Silver (22) and in vitro blood platelet aggregation method according to Born (23). Acute pulmonary thromboembolism was induced by injection of a mixture of collagen and epinephrine into the mouse tail vein. The effect of HF90, an acidic pyrazine derivative possessing active methylene moiety, administered at doses of 50 and 100 mg/kg, was compared to the action of the well established antithrombotic agents: ticlopidine (100 mg/kg) and acetylsalicylic acid (20 mg/kg). The compounds were administered i.p. in single doses 1 h and 24 h before the thrombotic challenge or once a day per three consecutive days before the thrombotic challenge. Ticlopidine appeared to provide the better protection against microembolism than acetylsalicylic acid although its effect has not manifested itself immediately after administration. The pyrazine derivative examined has a lower but significant antithrombotic activity. The chemical class of pyrazine derivatives with active methylene moiety (the so called pyrazine CH/NH-acids) (16) provides a new original antiinflammatory pharmacophore and HF90 may serve as the "lead compound" in the search for new agents of pharmacological interest.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Fibrinolíticos/farmacologia , Nitrilas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirazinas/farmacologia , Ticlopidina/farmacologia , Animais , Humanos , Técnicas In Vitro , Masculino , Camundongos , Tromboembolia/prevenção & controleRESUMO
Syntheses of 4-N-substituted thiosemicarbazoic acetylpyrazine derivatives have been described. The in vitro microbiological investigations of the 25 synthesized compound were carried out.
Assuntos
Antituberculosos/síntese química , Pirazinas/síntese química , Tiossemicarbazonas/síntese química , Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/farmacologia , Tiossemicarbazonas/farmacologiaRESUMO
A series of pyrazinylamino-1,3-diazacycloalkanes was obtained by reaction of the corresponding substituted aminopyrazines with aliphatic amines. Selected compounds were studied with respect to their potential circulatory activity. The effect on the blood pressure, isolated rat tail artery and heart atria, and an influence on the human blood platelet aggregation were investigated.
Assuntos
Aminas/síntese química , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Artérias/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Pirazinas/síntese química , Aminas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Clonidina/análogos & derivados , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Inibidores da Agregação Plaquetária/farmacologia , Pirazinas/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Cauda/irrigação sanguíneaAssuntos
Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Animais , Artérias/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa/efeitos dos fármacosRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Fibrinolíticos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirazinas/farmacologia , Difosfato de Adenosina/farmacologia , Animais , Colágeno/farmacologia , Epinefrina/farmacologia , Humanos , Indometacina/farmacologia , Cetorolaco , Masculino , Camundongos , Embolia Pulmonar/tratamento farmacológico , Tolmetino/análogos & derivados , Tolmetino/farmacologiaRESUMO
1. A series of newly synthesized pyrazine CH- and NH-acids was subjected to analytical and pharmacological studies. 2. The compounds were chromatographed in HPLC systems employing three reversed-phase columns and methanol-buffer solvents of various composition at acidic, neutral and alkaline pH. 3. Chemometrical analysis by the principal component method allowed for ordering of the compounds on a plane determined by the first two principal component axes. 4. Pharmacological tests were done for representatives of the series of compounds. 5. An in vivo antithrombotic assay on mice proved diversified bioactivity within the group of agents. 6. Attempts were undertaken to relate chromatographic behaviour to antithrombotic activity. 7. Based on the results obtained, an approach was proposed to reduce the number of pharmacological tests in selecting the most promising agents.
Assuntos
Amidas/síntese química , Fibrinolíticos/síntese química , Nitrilas/síntese química , Pirazinas/síntese química , Difosfato de Adenosina/farmacologia , Amidas/análise , Amidas/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Colágeno/farmacologia , Fibrinolíticos/análise , Fibrinolíticos/farmacologia , Técnicas In Vitro , Camundongos , Nitrilas/análise , Nitrilas/farmacologia , Pirazinas/análise , Pirazinas/farmacologia , Análise de RegressãoRESUMO
A group of condensed triazole-thiazine derivatives (2a-i, 3b, 3j) was obtained in reaction of the corresponding 5-substituted 1,2,4-triazole-3-thiones (1a-j) with epichlorohydrin in alkaline medium. The structure of the compounds synthesized was confirmed by spectral and roentgenographic methods. Tuberculostatic and circulatory activities of the compounds were also studied.
Assuntos
Antituberculosos/síntese química , Fármacos Cardiovasculares/síntese química , Tiazinas/síntese química , Triazóis/síntese química , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Cardiotônicos/farmacologia , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia , Triazóis/química , Triazóis/farmacologiaRESUMO
It was found that reaction of sodium alcoholates and cyanopyrazine yields alkoxypyrazine-nitriles. In heterogenic reaction both 2-alkylimidesters-6-chloropyrazine or 2-alkylimidoesters-6-alkoxypyrazine can be obtained dependent. This is dependent on quantity of alcohol used for reaction. Final products, alkoxypyrazinethioamides were tested for tuberculostatic activity (MIC within 31-500 mcg/cm3).
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Química Farmacêutica , Testes de Sensibilidade MicrobianaRESUMO
The synthesis of pyrazine derivatives, e.g. 1,3,4-thiodiazole (I, III-V, XII), 1,2,4-triazole (II) and N-substituted amidrazones is reported.
Assuntos
Compostos Azo/química , Pirazinas/síntese química , Tiadiazóis/síntese química , Triazóis/síntese química , Química Farmacêutica , Pirazinamida/síntese química , Pirazinas/químicaRESUMO
Two subgroups of 5-substituted triazoles were synthesized: derivatives of 3(3-substituted-amino-2-hydroxypropylthio)-5-substituted-4H-1,2,4- triazole and derivatives of N-substituted amides of 5-substituted-s-(1,2,4-triazole-3)thioglycolic acid. Selected members of the two subseries were tested pharmacologically. The blood pressure lowering effect in anaesthetized normotensive rats was weak to moderate. More pronounced was the inhibitory effect against adrenaline induced human blood platelet aggregation. In experiments on isolated rat heart atria and on isolated rat tail artery the activity of the agents was much weaker than in the case of known beta or alpha adrenoceptor antagonists. Generally, the chance to find a potential antihypertensive agent within the group studied seems to be low. Antiaggregatory activity of the compounds deserves further studies.
Assuntos
Fármacos Cardiovasculares/síntese química , Tioglicolatos/síntese química , Triazóis/síntese química , Animais , Anti-Hipertensivos/síntese química , Pressão Sanguínea/efeitos dos fármacos , Epinefrina/farmacologia , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Ratos , Ratos Endogâmicos , Sulfetos/síntese química , Sulfetos/farmacologia , Tioglicolatos/farmacologia , Triazóis/farmacologiaRESUMO
The effect of a series of ten newly synthesized diazacycloalkanes as well as four standard imidazoline drugs on blood pressure of anesthetized normotensive rats was measured. The hypotensive activity of the agents studied, expressed as logit of the maximum effect, logit E(%), was quantitatively related to the changes in their chemical structure. Highly significant relationship between the hydrophobicity parameter, sigma f, and logit E(%) value has been found.
Assuntos
Anti-Hipertensivos/farmacologia , Imidazóis/farmacologia , Pirazinas/farmacologia , Animais , Fenômenos Químicos , Físico-Química , Cromatografia em Camada Fina , Técnicas In Vitro , Masculino , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
2-Amino-3-chloropyrazine and 2-amino-6-chloropyrazine were reacted with appropriate sodium alkoxides to give 2-aminopyrazine derivatives with the methoxy, benzyloxy, chlorobenzyloxy, dichlorobenzyloxy, bromobenzyloxy or dibromobenzyloxy group at positions 3 and 6 (I-XIV). The obtained compounds were converted into N-pyrazinyl-N'-benzoylthioureas (XV-XXXI) by reacting with benzoyl isothiocyanate. Their hydrolysis yielded N-pyrazinylthioureas XXXII-XLVII. Analogical reactions of alkoxyaminopyrazines with p-chlorophenyl isothiocyanate or 2,6-dichlorophenyl isothiocyanate afforded corresponding N-pyrazinyl-N'-(p-chlorophenyl)thioureas and N-pyrazinyl-N'- (2,6-dichlorophenyl)thioureas (XLVIII-LVIII). The obtained compounds were found to display tuberculostatic in vitro activity with MIC values from 8 meg/cm3 to 1000 mu meg/cm3.