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1.
J Chromatogr Sci ; 57(9): 784-789, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31504275

RESUMO

Various pyrazines have been synthesized via reaction of selected cellulosic-derived sugars, ammonium hydroxide and amino acids at 110°C for 2 hours. Different methods of sample cleanup such as liquid-liquid extraction (LLE), liquid-solid extraction, column chromatography and distillation were employed to isolate pyrazines from the reaction mixture. Effective LLE of pyrazines from aqueous solution using either hexane, methyl-t-butyl ether (MTBE) or ethyl acetate required multiple extraction steps with fresh solvent each time. When hexane was used as the extraction solvent, no imidazole derivatives were extracted with the pyrazines. However, when MTBE or ethyl acetate was employed, 4-methyl imidazole was co-extracted and further cleanup was required. Passing the organic solvent extracts through a column of silica revealed that the silica retained the undesirable imidazoles, such as 4-methyl imidazole. A mixture of 90/10 hexane/ethyl acetate as eluting solvent provided the desirable pyrazines, but it also provided a desirable separation of pyrazines as a function of total alkyl substituent content. Distillation of the aqueous reaction mixture was also used to isolate the pyrazines, leaving the undesirable imidazoles in the undistilled portion of the reaction. Additional chromatographic methods were used to isolate pyrazines from the aqueous distillate including a column packed with C18-bonded silica.


Assuntos
Aminoácidos/química , Hidróxido de Amônia/química , Pirazinas/análise , Pirazinas/isolamento & purificação , Açúcares/química , Celulose/química , Cromatografia Gasosa-Espectrometria de Massas , Imidazóis , Pirazinas/síntese química , Pirazinas/química , Dióxido de Silício/química
2.
Eur J Med Chem ; 180: 546-561, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31344614

RESUMO

A novel series of 6-substituted-8-(1-cyclohexyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine and 6-substituted-8-(1-benzyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine is first time synthesized and screen in vitro biological activity for 60 human cancer cell lines representing nine different cancer types. Derivatives 10 and 36 show antitumor activity for all tested cell lines, display comparable full panel mean-graph midpoint growth inhibition (MG_MID GI50) values of 2.10 and 2.23 µM, respectively. Furthermore, these derivatives show strong binding interactions with DNA and bovine serum albumin (BSA), studied through absorption, emission, and circular dichroism techniques. These spectroscopic studies reveal that imidazo[1,2-a]pyrazine-benzimidazoles 10 and 36, intercalate with ct-DNA as a leading interaction for fundamental biologically significant effects, with monobenzimidazole show better activity than bisbenzimidazole. These experiments have confirmed that the imidazo[1,2-a]pyrazine and benzimidazole moieties are efficient pharmacophores to trigger binding to DNA. These compounds have also interacted with bovine serum albumin protein that demonstrating high values of binding constant.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Imidazóis/farmacologia , Pirazinas/farmacologia , Animais , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 179: 470-482, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271959

RESUMO

A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Receptor trkB/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Glicoproteínas de Membrana/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Receptor trkB/metabolismo , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
4.
Chem Pharm Bull (Tokyo) ; 67(6): 556-565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155561

RESUMO

Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).


Assuntos
Aldeído Redutase/metabolismo , Inibidores Enzimáticos/síntese química , Pirazinas/química , Aldeído Redutase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Ligações de Hidrogênio , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Pirazinas/síntese química , Pirazinas/metabolismo
5.
Sensors (Basel) ; 19(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052519

RESUMO

A small extent of endogenous labile zinc is involved in many vital physiological roles in living systems. However, its detailed functions have not been fully elucidated. In this study, we developed a novel biheteroaryl-based low molecular weight fluorescent sensor, 3-(phenylsulfonyl)-pyrazine-pyridone (5b), and applied it for the detection of endogenous labile zinc ions from lung cancer cells during apoptosis. The electron-withdrawing property of the sulfonyl group between the phenyl ring as an electron donor and the pyridone ring as a fluorophore inhibited the intramolecular charge transfer state, and the background fluorescence of the sensor was decreased in aqueous media. From the structure-fluorescence relationship analysis of the substituent effects with/without Zn2+, compound 5b acting as a sensor possessed favorable properties, including a longer emission wavelength, a large Stokes shift (over 100 nm), a large fluorescence enhancement in response to Zn2+ under physical conditions, and good cell membrane permeability in living cells. Fluorescence imaging studies of human lung adenocarcinoma cells (A549) undergoing apoptosis revealed that compound 5b could detect endogenous labile zinc ions. These experiments suggested that the low molecular weight compound 5b is a potential fluorescence sensor for Zn2+ toward understanding its functions in living systems.


Assuntos
Técnicas Biossensoriais , Íons/isolamento & purificação , Neoplasias Pulmonares/química , Zinco/isolamento & purificação , Humanos , Íons/química , Neoplasias Pulmonares/diagnóstico , Imagem Óptica , Pirazinas/síntese química , Pirazinas/química , Piridonas/síntese química , Piridonas/química , Água/química , Zinco/química
6.
Molecules ; 24(10)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117306

RESUMO

A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.


Assuntos
Cianetos/química , Imidazóis/síntese química , Nitrogênio/química , Pirazinas/síntese química , Aldeídos/química , Imidazóis/química , Estrutura Molecular , Pirazinas/química
7.
Talanta ; 199: 89-96, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952321

RESUMO

A new highly green luminescent binuclear palladium 2-pyrazinecarboxamide-bipyridine complex [Pd(pyc)(bpy)] was prepared and characterized. The binuclear Pd(pyc)(bpy) complex doped in sol-gel matrix has a strong luminescence intensity at 547 nm with λex = 330 nm in water The method depends on the quenching of the luminescence intensity of the binuclear Pd(pyc)(bpy) complex at 547 nm by different concentrations of uric acid. The remarkable quenching of the luminescence intensity of the binuclear Pd(pyc)(bpy) complex, doped in a sol-gel matrix, by uric acid was successfully used for the determination of uric acid in serum samples of patients with hypouricemia disease. The calibration plot was achieved over the concentration 3.9 × 10-9 to 1.2 × 10-4 mol L-1uric acid with a correlation coefficient of 0.9 and a detection limit of 1.8 × 10-10 mol L-1. The method was used satisfactorily for the assessment of the uric acid in a number of serum samples collected from various patients with Hypouricemia disease.


Assuntos
2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/química , Complexos de Coordenação/química , Dispositivos Ópticos , Paládio/química , Pirazinas/química , Ácido Úrico/sangue , 2,2'-Dipiridil/síntese química , Carcinoma Hepatocelular/sangue , Doenças Cardiovasculares/sangue , Complexos de Coordenação/síntese química , Géis , Humanos , Neoplasias Hepáticas/sangue , Imagem Óptica , Pirazinas/síntese química
8.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925695

RESUMO

We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 µg/mL, 46 µM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Antibacterianos/química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Fungos/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirazinas/química
9.
Org Biomol Chem ; 17(15): 3709-3713, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30882838

RESUMO

An original gram-scale synthesis of O-acetylated forms of coelenterazine, furimazine or hydroxy-bearing analogues of luciferins is described. The comparison over two hours of their bioluminescence, using the nanoKAZ/NanoLuc luciferase, provides remarkable insights useful for the selection of a substrate adapted for a given application.


Assuntos
Luciferina de Vaga-Lumes/síntese química , Imidazóis/síntese química , Pirazinas/síntese química , Acetilação , Animais , Vaga-Lumes , Luciferina de Vaga-Lumes/análogos & derivados , Luciferina de Vaga-Lumes/química , Imidazóis/química , Luciferases de Vaga-Lume/metabolismo , Medições Luminescentes , Estrutura Molecular , Pirazinas/química
10.
Biosci Biotechnol Biochem ; 83(6): 1124-1135, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30782084

RESUMO

(R)-2-amino-2-ethoxycarbonylsuccinimide (ASI-2) is a key intermediate used in the pharmaceutical industry and is valuable for the industrial synthesis of ranirestat, which is a potent aldose reductase inhibitor. ASI-2 was synthesized in a process combining chemical synthesis and bioconversion. Bioconversion in this study is a key reaction, since optically active carboxylic acid derivative ((R)-1-ethyl hydrogen 3-benzyloxycarbonylamino-3-ethoxycarbonylsuccinate, Z-MME-AE) is synthesized from a prochiral ester, diethyl 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinate, Z-MDE-AE, at a theoretical yield of 100%. Upon screening for microorganisms that asymmetrically hydrolyze Z-MDE-AE, Bacillus thuringiensis NBRC13866 was found. A novel esterase EstBT that produces Z-MME-AE was purified from Bacillus thuringiensis NBRC13866 and was stably produced in Escherichia coli JM109 cells. Using EstBT rather than porcine liver esterase (PLE), ASI-2 was synthesized with a 17% higher total yield by a novel method, suggesting that the esterase EstBT is a PLE substitute enzyme and therefore, may be of interest for future industrial applications.


Assuntos
Inibidores Enzimáticos/síntese química , Esterases/metabolismo , Fígado/enzimologia , Pirazinas/síntese química , Compostos de Espiro/síntese química , Sequência de Aminoácidos , Animais , Bacillus thuringiensis/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sequência de Bases , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/química , Escherichia coli/genética , Hidrólise , Pirazinas/química , Proteínas Recombinantes/genética , Compostos de Espiro/química , Suínos
11.
Molecules ; 24(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669461

RESUMO

A novel deep-blue fluorescent emitter was designed and synthesized. The external quantum efficiency (ηEQE) of the blue-emitting, doped, organic light-emitting diode (OLED) was as high as 4.34%. The device also exhibited an excellent color purity with Commission Internationale de l'Eclairage (CIE) coordinates of x = 0.15 and y = 0.05. In addition, the triplet energy had a value of 2.7 eV, which is rare for an emitter with deep-blue emission, which makes it a preferred choice for high-performance white OLEDs. By optimizing the device architectures, the color of hybrid-white OLEDs could be tunable from warm white to cool white using the aforementioned material as a bifunctional material. That is, the ηEQE of the hybrid warm-white OLED is 20.1% with a CIE x and y of 0.46 and 0.48 and the ηEQE of the hybrid cool-white OLED is 9% with a CIE x and y of 0.34 and 0.33.


Assuntos
Carbazóis/síntese química , Corantes Fluorescentes/síntese química , Pirazinas/síntese química , Cor , Técnicas Eletroquímicas , Fluorescência , Estrutura Molecular , Transição de Fase , Processos Fotoquímicos , Relação Estrutura-Atividade , Termodinâmica
12.
Bioorg Med Chem ; 27(5): 748-759, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683552

RESUMO

To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a-8c with similar EC50 values (0.20-0.22 µM) comparative to that of sofosbuvir (EC50 = 0.18 µM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50 = 7.3 µM) and S-29b (EC50 = 19.5 µM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pirazinas/farmacologia , Sofosbuvir/análogos & derivados , Sofosbuvir/farmacologia , Antivirais/síntese química , Sangue/metabolismo , Linhagem Celular Tumoral , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pirazinas/síntese química , Sofosbuvir/síntese química
13.
Bioorg Med Chem Lett ; 29(6): 836-838, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685094

RESUMO

Starting from the recently launched FLT3/AXL multi-targeted inhibitor Gilteritinib (5), we conducted a side-chain ring closure medicinal chemistry approach leading to the identification of compound 15c as a highly potent AXL inhibitor in the biochemical and cellular anti-proliferative assays, with IC50 values of 1.2 and 0.3 nM, respectively. Compared with the reference compound 5, our new discovered AXL inhibitor 15c is more potent in both assays.


Assuntos
Benzazepinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzazepinas/síntese química , Benzazepinas/farmacocinética , Linhagem Celular Tumoral , Descoberta de Drogas , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/síntese química , Pirazinas/química , Pirazinas/farmacocinética , Ratos Sprague-Dawley
14.
Eur J Med Chem ; 164: 241-251, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30597325

RESUMO

A library-friendly approach to generate new scaffolds is decisive for the development of molecular probes, drug like molecules and preclinical entities. Here, we present the design and synthesis of novel heterocycles with spiro-2,6-dioxopiperazine and spiro-2,6-pyrazine scaffolds through a three-component reaction using various amino acids, ketones, and isocyanides. Screening of select compounds over fifty CNS receptors including G-protein coupled receptors (GPCRs), ion channels, transporters, and enzymes through the NIMH psychoactive drug screening program indicated that a novel spiro-2,6-dioxopyrazine scaffold, UVM147, displays high binding affinity at sigma-1 (σ1) receptor in the nanomolar range. In addition, molecular docking of UVM147 at the human σ1 receptor have shown that it resides in the same binding site that was occupied by the ligand 4-IBP used to obtain a crystal structure of the human sigma-1 (σ1) receptor.


Assuntos
Perazina/metabolismo , Pirazinas/metabolismo , Receptores sigma/metabolismo , Aminoácidos/química , Sítios de Ligação , Cristalografia por Raios X , Ligantes , Simulação de Acoplamento Molecular , Perazina/síntese química , Ligação Proteica , Pirazinas/síntese química , Compostos de Espiro/síntese química
15.
Eur J Med Chem ; 163: 660-670, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576901

RESUMO

Transforming growth factor-ß activated kinase-1 (TAK1) is a potential therapeutic target for cancers and inflammatory diseases. We synthesized a series of novel imidazopyrazine derivatives, which were found to exhibit potent inhibitory effect against TAK1. Compound 22a, which possesses a good pharmacokinetic profile, showed excellent in vitro kinase activity and significant in vivo efficacy in mice xenografted with SW620, a KRAS-dependent colon cancer cell line.


Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirazinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Xenoenxertos , Humanos , Inflamação/tratamento farmacológico , Camundongos , Neoplasias/tratamento farmacológico , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologia
16.
ChemMedChem ; 14(1): 132-146, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30430749

RESUMO

Inflammation is widely reported as a main factor for the development of chronic diseases such as cancer, diabetes, and even metabolic syndrome. Thus, the search for novel anti-inflammatory compounds is required. Herein we describe the synthesis of a collection of peptidic pyrazinones by a convenient approach involving a multicomponent isocyanide-based reaction followed by a tandem deprotection/oxidative cyclization step. This series of compounds were tested for their potential anti-inflammatory capacity in an in vivo murine model, and four compounds were identified to inhibit tetradecanoylphorbol acetate (TPA)-induced edema by more than 75 %. The two most active compounds, N-benzyl-2-(4-hydroxy-3,5-dimethoxyphenyl)-2-[2-oxopyrazin-1(2H)-yl]acetamide (10 o) and N-cyclohexyl-2-[2-oxopyrazin-1(2H)-yl]-2-[4-(trifluoromethyl)phenyl]acetamide (10 x), with methyl and trifluoromethyl groups, were also able to decrease myeloperoxidase activity and leukocyte infiltration. Moreover, 10 x decreased the thickness of TPA-treated mouse ears, as observed in histological analysis of the tissues.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/tratamento farmacológico , Pirazinas/síntese química , Pirazinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Células COS , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Orelha , Edema/tratamento farmacológico , Masculino , Camundongos , Estrutura Molecular , Pirazinas/química , Relação Estrutura-Atividade
17.
Mol Divers ; 23(3): 585-592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30465252

RESUMO

This research describes a simple and efficient one-pot synthetic approach for the preparation of tetrahydrodiazepine and dihydropyrazine (or dihydroquinoxaline) derivatives in high yields in the presence of a substoichiometric amount of ammonium chloride as a green accelerator on water at 50 °C within 1-3 h.


Assuntos
Cloreto de Amônio/química , Azepinas/química , Azepinas/síntese química , Pirazinas/química , Pirazinas/síntese química , Catálise , Técnicas de Química Sintética , Química Verde , Água/química
18.
Mol Divers ; 23(1): 137-145, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30073609

RESUMO

A facile and efficient route to synthesize quinoxalinone and benzimidazopyrazinone was developed via two paths of a post-Ugi cascade reaction. By simply alternating the order of nucleophilic substitution reactions, both heterocycles could be accessed selectively from the same Ugi adduct. Microwave-assisted synthesis protocol provided these compounds with one purification procedure for three steps. These two scaffolds with more possible spaces for further modifications provide great benefit toward combinatorial and medicinal chemistry campaigns.


Assuntos
Pirazinas/síntese química , Quinoxalinas/síntese química , Técnicas de Química Combinatória , Micro-Ondas
19.
Bioorg Med Chem Lett ; 29(3): 406-412, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30587449

RESUMO

Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.


Assuntos
Compostos Heterocíclicos com 2 Anéis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pirazinas/farmacologia , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Pirazinas/síntese química , Pirazinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
20.
Arch Pharm (Weinheim) ; 352(2): e1800265, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30561073

RESUMO

A new class of pyrazino[1,2-a]benzimidazole derivatives possessing the SO2 Me pharmacophore at the para position of the C-3 phenyl ring was designed, synthesized, and tested for their cyclooxygenase-2 (COX-2) inhibitory, anti-cancer and anti-platelet aggregation activities. In vitro COX-1/COX-2 inhibition studies showed that 2-(4-methylphenyl)-1-methylene-3-(4-(methylsulfonyl)phenyl)-1,2-dihydropyrazino-[1,2-a]benzimidazole (5g) was the most potent COX-2 inhibitor (IC50 = 0.08 µM) and 2-(3,4,5-trimethoxyphenyl)-1-methylene-3-(4-(methylsulfonyl)phenyl)-1,2-dihydropyrazino-[1,2-a]benzimidazole (5m) had the highest selectivity index (SI > 909). Cytotoxicity of the synthesized compounds was also determined against the MCF-7 cell line. Most compounds were cytotoxic against MCF-7 cells and our results showed that compound 5m exhibited the highest anti-proliferative activity compared to the reference compound, cisplatin. Our data also indicated that compound 5k was the most potent platelet aggregation inhibitor according to aggregometry test results.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Pirazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Feminino , Humanos , Células MCF-7 , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-Atividade
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