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1.
Eur J Med Chem ; 186: 111883, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761385

RESUMO

As part of a continuing study, we designed and synthesized four series of 1-phenylimidazole-4-carboxylic acid derivatives as xanthine oxidoreductase (XOR) inhibitors, evaluated their in vitro inhibitory potencies against XOR and hypouricemic effects in mice, and determined their structure-activity relationships (SARs). Most of the compounds exhibited in vitro XOR inhibition at the nanomolar level. In comparison to febuxostat (half-maximal inhibitory concentration [IC50] value of 7.0 nM), compounds Ie and IVa exhibited the most promising XOR inhibitory effects with IC50 values of 8.0 and 7.2 nM, respectively. In the potassium oxonate/hypoxanthine-induced acute and long-term hyperuricemia mouse models, compounds Ie and IVa displayed significant hypouricemic potencies (P < 0.05), that were slightly weaker than and similar to febuxostat, respectively. More interestingly, both compounds showed a capacity to improve kidney damage by decreasing creatinine and urea nitrogen levels compared to the long-term hyperuricemia mouse group (P < 0.05), while febuxostat showed no significant effect.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Xantina Desidrogenase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantina Desidrogenase/metabolismo
2.
Eur J Med Chem ; 186: 111891, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759730

RESUMO

In 10-15% of cancers, telomere maintenance is provided by a telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making telomerase inhibitors ineffective on these cancers. Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or disrupt the T-loop structure, which would be promising therapeutic agents for ALT cancers. Notably, the 3'-terminal overhang of telomeric DNA might fold into multimeric G4 containing consecutive G4 subunits, which offers an attractive target for selective ligands considering large numbers of G4s widespread in the genome. In this study, a dimeric aryl-substituted imidazole (DIZ-3) was developed as a selective multimeric G4 ligand based on a G4-ligand-dimerizing strategy. Biophysical experiments revealed that DIZ-3 intercalated into the G4-G4 interface, stabilizing the higher-order structure. Furthermore, this ligand was demonstrated to induce cell cycle arrest and apoptosis, and thus inhibited cell proliferation in an ALT cancer cell line. Cancer cells were more sensitive to DIZ-3, relative to normal cells. Notably, DIZ-3 had little effect on the transcription of several G4-dependent oncogenes. This study provides a nice example for discovering dimeric agents to potentially treat ALT cancers via targeting telomeric multimeric G4.


Assuntos
Antineoplásicos/farmacologia , Quadruplex G/efeitos dos fármacos , Imidazóis/farmacologia , Telômero/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , 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 , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Relação Estrutura-Atividade
3.
Anal Chim Acta ; 1094: 47-56, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761047

RESUMO

A new planar sorptive phase based on the simple immobilization of polymeric ionic liquids on paper is proposed. The sorptive phase can develop hydrophobic or mixed-mode (combining hydrophobic and ion exchange) interactions with the target analytes. The polymer is prepared by the Radziszewski reaction, which takes place in aqueous media, and it has been thoroughly characterized by different techniques including infrared spectroscopy, matrix-assisted laser desorption/ionization coupled to high-resolution mass spectrometry and proton nuclear magnetic resonance. Three different strategies aimed to immobilize the polymeric ionic liquid on paper have been evaluated. Among them, simple thermal curing at 120 °C was selected. The as-prepared paper has been evaluated for the extraction of several non-steroidal anti-inflammatory drugs from urine, the analytes being finally determined by liquid chromatography with tandem mass spectrometry. The method detection limits were 3.8, 7.2, 6.8, 9.4, 15.7, and 5.1 µg/L for indomethacin, diclofenac, tolmetin, ketoprofen, naproxen, and ibuprofen, respectively. Calibration models were linear (R2 > 0.9949) up to 1000 µg/L. The intra-day precision, expressed as relative standard deviation and calculated at three different concentrations levels (limit of quantification, 250 µg/L, and 1000 µg/L), varied between 1.1 and 13%. The accuracy, calculated as relative recovery, was in the range from 72 to 95%, thus being considered appropriate. The easiness of polymeric ionic liquid paper synthesis and the multi-sample extraction protocol designed allows the processing of a high number of samples at the same time.


Assuntos
Anti-Inflamatórios não Esteroides/urina , Imidazóis/química , Líquidos Iônicos/química , Papel , Polímeros/química , Adsorção , Cromatografia Líquida , Humanos , Imidazóis/síntese química , Líquidos Iônicos/síntese química , Limite de Detecção , Polímeros/síntese química , Microextração em Fase Sólida/instrumentação , Microextração em Fase Sólida/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem
4.
Chemosphere ; 239: 124735, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31499306

RESUMO

A key challenge in adsorption process of toxic organic and inorganic species is the design and development of adsorbent materials bearing an abundance of accessible adsorption sites with high affinity to achieve both fast adsorption kinetics and elevated adsorption capacity for toxic contaminants. Herein, a novel anion-exchange adsorbent based on fibrous silica nanospheres KCC-1 was synthesized by a facile hydrothermal-assisted post-grafting modification of KCC-1 with 1-methyl-3- (triethoxysilylpropyl)imidazolium chloride for the first time. Silica fibers with micro-mesoporous structure display the proper combination of features to serve as a potential scaffold for decorating adsorption sites to create desired ion-exchange adsorbent. The obtained N-methylimidazolium-functionalized KCC-1 (MI-Cl-KCC-1) with fibrous nanosphere morphology showed a high surface area (∼241 m2 g-1) and high pore volume (0.81 m2 g-1). The adsorption behaviors of toxic hexavalent chromium from aqueous media by the MI-Cl-KCC-1 were systematically studied using the batch method. The adsorption rate was relatively fast, and MI-Cl-KCC-1 possesses a high capacity for the adsorption of Cr(VI). The maximum Cr(VI) adsorption was obtained at pH 3.0-4.0. Different non-linear isotherm equations were tested for choosing an appropriate adorption isotherm behavior, and the adsorption data for MI-Cl-KCC-1 were consistent with the Langmuir model with a maximum adsorption capacity of 428 ±â€¯8 mg g-1.


Assuntos
Cromo/isolamento & purificação , Imidazóis/química , Nanoestruturas/química , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Ânions , Cromo/química , Imidazóis/síntese química , Troca Iônica , Cinética , Micro-Ondas , Dióxido de Silício/química , Poluentes Químicos da Água/química , Purificação da Água/métodos
5.
Eur J Med Chem ; 185: 111832, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718944

RESUMO

Imidazolium salts have shown great promise as anticancer materials. A new imidazolium salt (TPP1), with a triphenylphosphonium substituent, has been synthesized and evaluated for in vitro and in vivo cytotoxicity against bladder cancer. TPP1 was determined to have a GI50 ranging from 200 to 250 µM over a period of 1 h and the ability to effectively inhibit bladder cancer. TPP1 induces apoptosis, and it appears to act as a direct mitochondrial toxin. TPP1 was applied intravesically to a bladder cancer mouse model based on the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Cancer selectivity of TPP1 was demonstrated, as BBN-induced tumors exhibited apoptosis but normal adjacent urothelium did not. These results suggest that TPP1 may be a promising intravesical agent for the treatment of bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Compostos Organofosforados/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Imidazóis/síntese química , Imidazóis/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Relação Estrutura-Atividade , Neoplasias da Bexiga Urinária/patologia
6.
Eur J Med Chem ; 184: 111732, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610372

RESUMO

A series of novel 1-substituted-2-aryl imidazoles (SAI) were designed and synthesized based on our previously reported ABI (2-Aryl-4-Benzoyl Imidazole) analogs and on the structure of combretastatin A-4 (CA-4). These compounds showed potent antiproliferative activities against six human cancer cell lines with IC50 values in nano molar range. Among them, compound 3X exhibited the best anticancer activity with an average IC50 value of ∼100 nM. The compound maintains the mechanism of action by inhibiting tubulin polymerization, thus causing cell arrest at G2/M phase and apoptosis. In vivo efficacy studies indicated that 3X was highly effective in suppressing tumor growth in a MDA-MB-468 xenograft model of nude mouse with a TGI (Tumor Growth Suppression) of 77% at 60 mg/kg without causing significant toxicity. In addition, 3X displayed significantly better water solubility (36.70 µg/mL) than CA-4 (2.83 µg/mL). Molecular modeling study indicated that 3X binds well to the colchicine binding site in tubulin. Our results suggest that the novel SAI analogs deserve further investigation as potential anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Suínos , Células Tumorais Cultivadas
7.
Chem Pharm Bull (Tokyo) ; 67(10): 1116-1122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582631

RESUMO

In recent studies, combinations of histone deacetylases (HDACs) inhibitor with kinase inhibitor showed additive and synergistic effects. BRafV600E as an attractive target in many diseases treatments has been studied extensively. Herein, we present a novel design approach though incorporating the pharmacophores of BRafV600E inhibitor and HDACs inhibitor in one molecule. Several synthesized compounds exhibited distinct BRafV600E and HDAC1 inhibitory activities. The representative dual Raf/HDAC inhibitor, 7a, showed better antiproliferative activities against A549 and SK-Mel-2 in cellular assay than SAHA and sorafenib, with IC50 values of 9.11 µM and 5.40 µM, respectively. This work may lay the foundation for the further development of dual Raf/HDAC inhibitors as potential anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Molecules ; 24(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640206

RESUMO

A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS2 in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained ensures post-modifications in view of N-bridgeheaded heterobicyclic structures.


Assuntos
Imidazóis/síntese química , Tionas/síntese química , Técnicas de Química Sintética , Reação de Cicloadição , Imidazóis/química , Estrutura Molecular , Tionas/química
9.
Eur J Med Chem ; 182: 111568, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419778

RESUMO

The human protozoan parasites Leishmania donovani and L. infantum are the causative agents of visceral leishmaniasis, as such, responsible for approximately 30,000 deaths annually. The available chemotherapeutic treatments are reduced to a few drugs whose effectiveness is limited by rising drug resistance/therapeutic failure, and noxious side-effects. Therefore, new therapeutic hits are needed. Compounds displaying the imidazo[2,1-a]isoindole skeleton have shown antichagasic, anti-HIV, antimalarial and anorectic activities. Here, we report the leishmanicidal activity of thirty one imidazo[2,1-a]isoindol-5-ol derivatives on promastigotes and intracellular amastigotes of L. donovani. Eight out of thirty one assayed compounds showed EC50 values ranging between 1 and 2 µM with selectivity indexes from 29 to 69 on infected THP-1 cells. Six compounds were selected for further elucidation of their leishmanicidal mechanism. In this regard, compound 29, the imidazoisoindolol with the highest activity on intracellular amastigotes, induced an early decrease of intracellular ATP levels, as well as mitochondrial depolarization, together with a partial plasma membrane destructuration, as assessed by transmission electron microscopy. Consequently, the inhibition of the energy metabolism of Leishmania plays an important role in the leishmanicidal mechanism of this compound, even when other additional targets cannot be ruled out. In all, the results supported the inclusion of the imidazoisoindole scaffold for the development of new leishmanicidal drugs.


Assuntos
Antiprotozoários/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , Leishmania donovani/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Imidazóis/síntese química , Imidazóis/química , Indóis/síntese química , Indóis/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
10.
Carbohydr Polym ; 223: 115071, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31427015

RESUMO

Methylimidazolium side groups were grafted via ether linkage to dextran and the self-assembly of these polymers with 4-sulfonato-calix[n]arenes (SCXn) was studied in aqueous solutions. Dynamic light scattering and zeta potential measurements revealed the mixing ratio ranges of the constituents where stable nanoparticles could be created. The macrocycle size of SCXn and the molecular mass of the polymer barely affected the nanoparticle diameter, but the lowering of the imidazolium degree of substitution substantially diminished the stability of the associates. The pH change from neutral to acidic also unfavourably influenced the self-organization owing mainly to the decrease of the SCXn charge. Cryogenic transmission electron microscopy images proved the spherical morphology of the nanoproducts in which the stoichiometry of the constituents was always close to the one corresponding to charge compensation. The flexible and positively charged dextran-chains are compacted by the polyanionic SCXn. Coralyne, a pharmacologically important alkaloid was efficiently embedded by self-assembly in the produced nanoparticles reaching 99% association efficiency.


Assuntos
Benzenossulfonatos/química , Calixarenos/química , Dextranos/química , Portadores de Fármacos/química , Imidazóis/química , Nanopartículas/química , Alcaloides de Berberina/química , Dextranos/síntese química , Concentração de Íons de Hidrogênio , Imidazóis/síntese química
11.
Anal Chim Acta ; 1077: 243-248, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31307715

RESUMO

A novel imidazo[1,2-a]pyridine-rhodamine ratiometric fluorescent probe IP-Hg for Hg2+ based on a fluorescence resonance energy transfer mechanism has been developed. The probe has been proved to show high sensitivity and high selectivity toward Hg2+. Furthermore, it could be used for imaging Hg2+ in cells and in polluted water.


Assuntos
Corantes Fluorescentes/química , Imidazóis/química , Mercúrio/análise , Piridinas/química , Rodaminas/química , Poluentes Químicos da Água/análise , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Imidazóis/síntese química , Imidazóis/toxicidade , Lagos/análise , Limite de Detecção , Piridinas/síntese química , Piridinas/toxicidade , Rodaminas/síntese química , Rodaminas/toxicidade , Células Tumorais Cultivadas
12.
Chem Commun (Camb) ; 55(65): 9590-9605, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31334709

RESUMO

The study of artificial receptor molecules with the intention to mimic enzyme-substrate binding processes and catalysis in nature has always been a traditional area of research in supramolecular chemistry. Along this line, our group has developed a family of porphyrin cage compounds based on glycoluril and employed these in host-guest binding studies, as components of allosterically controlled self-assembled processes, in which structural changes in the cage upon complexation of a guest or a ligand change binding equilibria, and as enzyme mimics in supramolecular catalysis. In a recently started research program aimed at developing a new molecular approach to long-term data storage, porphyrin cage compounds are studied as molecular machines to encode information into synthetic polymer chains. In this Feature Article we will give an overview of the above aspects of our porphyrin cage compounds and place them in the context of related systems reported in the literature.


Assuntos
Alquinos/química , Materiais Biomiméticos/química , Imidazóis/química , Porfirinas/química , Receptores Artificiais/química , Materiais Biomiméticos/síntese química , Catálise , Imidazóis/síntese química , Ligantes , Metaloporfirinas/síntese química , Metaloporfirinas/química , Nanotecnologia/métodos , Porfirinas/síntese química , Receptores Artificiais/síntese química , Estereoisomerismo , Termodinâmica
13.
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
14.
J Chromatogr A ; 1606: 460376, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31345620

RESUMO

In this work, a polymeric imidazolium-embedded octadecyl ionic liquid (poly(1-vinyl-3-octadecylimidazolium naphthalene sulfonate))-grafted silica (poly(C18VIm+NapSO3-)@SiO2) sorbent was prepared and applied as a solid-phase extraction (SPE) sorbent in extraction of flavonoids. The synthesized poly(C18VIm+NapSO3-)@SiO2 sorbent was characterized by X-ray photoelectron spectrogram (XPS) and fourier transform infrared spectroscopy (FT-IR). The thermodynamic and kinetic adsorption models of the prepared poly(C18VIm+NapSO3-)@SiO2 sorbent towards flavonoids were discussed by nonlinear fitting adsorption curve and the results indicated the thermodynamic adsorption model in this work was tended to be Freundlich model rather than Langmuir one and the pseudo-second order model could be used to describe the dynamic adsorption process. In addition, the adsorption amounts indicated the sorbent has satisfactory extraction capabities towards flavonoids. For investigating the influence of independent variables and their interactions on the extraction efficiency, a Box-Behnken design was used for optimizing three greatly influential parameters after performing single-factor experiments. The interaction energies between flavonoids and two ionic liquids were calculated to understand the adsorption mechanism. Under the optimal conditions, a method used for determining flavonoids was developed by combining SPE technique with high performance liquid chromatography (HPLC), and the developed method exhibited low limits of detection (0.25-0.4 µg L-1), good linearities with correlation coefficients (R2) in the range of 0.9951-0.9996 and satisfactory recoveries ranging from 83.6% to 114.1%, which confirmed the proposed method could be successfully used to determine trace flavonoids in real samples.


Assuntos
Flavonoides/isolamento & purificação , Imidazóis/síntese química , Líquidos Iônicos/química , Polímeros/síntese química , Dióxido de Silício/química , Adsorção , Flavonoides/análise , Mel/análise , Cinética , Limite de Detecção , Espectroscopia Fotoeletrônica , Espectroscopia de Infravermelho com Transformada de Fourier
15.
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
16.
Carbohydr Polym ; 218: 154-162, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31221316

RESUMO

In this work, a novel poly(ionic liquid) with 1-vinyl-3-aminopropyl imidazolium cations was designed and used to modify cellulose aerogels via Schiff base reaction. The poly(ionic liquid) modified cellulose aerogels (PIL-CA) exhibited a well-interconnected porous structure and a high porosity of 86.2%. A zeta potential study showed the PIL-CA had a strong positive potential of more than 65 mV when its pH was below 6. Furthermore, after 350 min of adsorption experiments, the PIL-CA showed a superior adsorption capacity of 918 ± 8 mg g-1 towards bovine serum albumin (BSA) at pH 6 when its concentration was 1.5 mg m L-1. Finally, the PIL-CA was employed for the selective separation of target protein from a real serum sample, obtaining the BSA with high purity of over 98%.


Assuntos
Celulose/análogos & derivados , Géis/química , Imidazóis/química , Líquidos Iônicos/química , Polivinil/química , Soroalbumina Bovina/química , Adsorção , Animais , Bovinos , Celulose/síntese química , Géis/síntese química , Concentração de Íons de Hidrogênio , Imidazóis/síntese química , Líquidos Iônicos/síntese química , Polivinil/síntese química , Porosidade
17.
Molecules ; 24(12)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226827

RESUMO

Isomers provide more possibilities for the structure of organic compounds. Molecular structures determine their corresponding properties, therefore the intrinsic relationship between structure and properties of isomers is of great research value. Isomers with a stable structure and excellent performance possess more potential for development and application. In this paper, we design and synthesize structural isomers with different molecular symmetries based on the asymmetric structure of imidazole and the symmetrical structure of pyrene. Isomers with stable molecular structures can be obtained by a simple and efficient "one-pot" reaction, involving axisymmetric configuration and centrosymmetric configuration. Using this "click-like" reaction, the structure of target molecules is controllable and adjustable. Furthermore, the effect of molecular configurations on molecular stacking of crystal is studied. The variation of the optical and thermal properties, the optimized structures, and orbital distributions of isomers depends on different molecular geometry with different symmetry, which are revealed by crystallographic analysis. This present strategy provides an efficient synthetic method for the design and synthesis of structural isomers based on pyrene-imidazole.


Assuntos
Imidazóis/química , Isomerismo , Pirenos/química , Cristalografia , Imidazóis/síntese química , Estrutura Molecular , Pirenos/síntese química
18.
ACS Appl Mater Interfaces ; 11(26): 22925-22931, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31252492

RESUMO

Covalently self-assembled polymer nanocapsules (NCs) based on cucurbit[6]uril have been previously prepared and their applications in payload delivery and bioimaging have been demonstrated, showing significant potentials. However, the preparation of these NCs often requires laborious and tedious multistep reactions, including a low-yield conversion of perhydroxycucurbit[6]uril to perallyloxycucurbit[6]uril, subsequent photopolymerization of perallyloxycucurbit[6]uril with dithiol linkers, and two additional steps of treatment to remove disulfide loops and create cationic sulfoniums. Herein, we report a novel, facile approach leading to cucurbit[6]uril-based polymer NCs via direct alkylation of perhydroxycucurbit[6]uril with a ditopic linker, thereby saving significant time and efforts, which may lead to significant expansion in investigations of these unique materials in various applications, particularly biomedical sciences. As a proof of concept, we have further demonstrated that a photosensitive therapeutic payload, such as chlorin e6, may get encapsulated inside the NCs for improved, targeted photodynamic therapy against cancer cells.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Imidazóis/síntese química , Nanocápsulas/química , Neoplasias/terapia , Fotoquimioterapia , Alquilação/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Nanocápsulas/uso terapêutico , Polímeros/química , Polímeros/farmacologia , Porfirinas/química
19.
Eur J Med Chem ; 178: 177-194, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185410

RESUMO

Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of ß-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Katanina/antagonistas & inibidores , Piridinas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Carcinoma Endometrioide/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Katanina/metabolismo , Ligantes , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Med Chem ; 179: 109-122, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247373

RESUMO

Toll-like receptors (TLRs) are promising targets for treatment of viral infections, autoimmune diseases, and cancers. Here, two new series of selective small-molecule TLR7 agonists with novel scaffolds and good selectivity over TLR8 are described, some with potencies in the low micromolar range. 8-Hydroxy-1-isobutylchromeno[3,4-d]imidazol-4(1H)-one (26) from the first series was designed and synthesized on the basis of previously described TLR7 antagonist 2, and is shown to be a selective TLR7 agonist (EC50, 1.8 µM). The second series was based on 2-(trifluoromethyl)quinolin-4-amine and 2-(trifluoromethyl)quinazolin-4-amine scaffolds, which were defined according to our in-house ligand-based virtual screening protocol. Further synthesis of a focused library of analogs, biological evaluation, and docking studies provided systematic exploration of the structure-activity relationships, which indicate that a secondary or tertiary amine with smaller flexible alkyl substituents up to three carbon atoms in length, or bulkier rigid aliphatic rings is required at position 4 on 2-(trifluoromethyl)quinoline/quinazoline scaffold for potent TLR7 agonist activity. The influence of selected TLR7 agonists on cytokine production is also reported showing that N-cyclopropyl-2-(trifluoromethyl)quinazolin-4-amine (46) is able to induce increased levels of IL-6 and IL-8. These data demonstrate successful in-silico definition of novel TLR7 versus TLR8-selective compounds as promising chemical probes for further development of potent small-molecule immunomodulators.


Assuntos
Imidazóis/farmacologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Citocinas/análise , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismo
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