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1.
Bioorg Med Chem Lett ; 30(20): 127472, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781216

RESUMO

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N4-(3-Chloro-4-fluorophenyl)-N6-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC50 = 0.157 µM, SI = 25) with no cytotoxicity and moderate in vivo PK properties.


Assuntos
Compostos de Anilina/farmacologia , Antivirais/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Quinazolinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Compostos de Anilina/toxicidade , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular , Chlorocebus aethiops , Cricetulus , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinazolinas/toxicidade , Ratos , Relação Estrutura-Atividade
2.
Nature ; 584(7819): 75-81, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760044

RESUMO

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.


Assuntos
Compostos de Anilina/síntese química , Hidrogênio/química , Processos Fotoquímicos , Aminação , Aminas/química , Compostos de Anilina/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise/efeitos da radiação , Cicloexanonas/química , Oxirredução/efeitos da radiação , Processos Fotoquímicos/efeitos da radiação , Esteroides/síntese química , Esteroides/química , Terpenos/síntese química , Terpenos/química
3.
Org Biomol Chem ; 18(4): 666-670, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31894805

RESUMO

A metal-free K2S2O8-HFIP synergistically promoted double Friedel-Crafts alkylation between a glycine derivative and N-substituted aniline was developed to efficiently synthesize diarylmethane derivatives with high para-selectivity. The reaction proceeded smoothly in the absence of any metal and ligand, and exhibited a good tolerance of functional groups.


Assuntos
Ésteres/química , Glicina/análogos & derivados , Compostos de Potássio/química , Propanóis/química , Sulfatos/química , Alquilação , Compostos de Anilina/síntese química , Compostos Benzidrílicos/síntese química , Modelos Químicos , Estrutura Molecular , Oxirredução
4.
Mater Sci Eng C Mater Biol Appl ; 108: 110456, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924021

RESUMO

Under different pathological conditions, high levels of reactive oxygen species (ROS) cause substantial damage to multiple organs. To counter these ROS levels in multiple organs, we have engineered highly potent novel terpolymers. We found that combination of FDA-approved polyethylene glycol, fumaric acid moieties and electroactive tetra(aniline) by varying the content of tetra(aniline) results into a novel drug composition with biologically active and tunable intrinsic antioxidant properties. To test the intrinsic antioxidative properties of these novel terpolymers, we used alloxan to induce diabetes in rats where ROS generation is known to be higher. The systemic administration of terpolymers to the diabetic rats showed strong electroactive antioxidant behavior which not only normalized ROS levels, but also improved the levels of enzymatic antioxidants including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). As a proof-of-principle, we here show TANI based novel drug composition of terpolymers with tunable intrinsic antioxidant properties in multiple organs.


Assuntos
Compostos de Anilina , Antioxidantes , Diabetes Mellitus Experimental/tratamento farmacológico , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Catalase/sangue , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Glutationa/sangue , Humanos , Masculino , Ratos , Espécies Reativas de Oxigênio , Superóxido Dismutase/sangue
5.
Chemosphere ; 238: 124636, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31470308

RESUMO

Electrochemical reduction process is a promising method for wastewater treatment, and its performance is determined by cathode material. Nitrogen doped carbon is a kind of favorable cathode material for electrochemical reduction, but deep understanding for the effect of nitrogen concentration and reduction pathway is still needed. In this paper, nitrogen doped porous carbon (NPC) with different nitrogen concentration were fabricated by directly carbonization of ZIF-8 under various temperatures. The electrochemical reduction performance of NPCs was evaluated by reducing nitrobenzene (NB), and the effects of nitrogen concentration were discussed. NPC with 22.7% nitrogen concentration exhibited the best NB reduction performance with the NB removal constant about 1.0 h-1 under optimal conditions; the NB removal rate and aniline (AN) production on this NPC are 4.2 and 8.5 times higher than graphite electrode. Further H* quenching experiment indicates the NPC electrochemical reduction process mainly following an indirect hydrogenation reduction pathway. These results offer some insights into the electrochemical reduction process on nitrogen doped carbon, which may facilitate the design of efficient metal free carbon based catalyst for wastewater electrochemical pretreatment.


Assuntos
Carbono , Técnicas Eletroquímicas/métodos , Nitrobenzenos/química , Nitrogênio , Substâncias Redutoras/química , Compostos de Anilina/síntese química , Catálise , Eletrodos , Porosidade , Águas Residuárias/química , Purificação da Água/métodos
6.
Chemosphere ; 239: 124806, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726521

RESUMO

Nitrobenzene (NB) is recalcitrant to microbial biodegradation due to the electron-deficient character of the nitro group (NO2-). Prior work has found that the reductant could enhance NB biodegradation by providing excess electron donors. However, the existing theory couldn't explain the increase-and-decrease pattern of the NB biodegradation rate with an increase in a reductant concentration. Our results suggest that the reductant affects NB biodegradation by two mechanisms: the available electron donors and the stimulation or inhibition of biomass growth, which are linked by a pseudo-first-order reaction kinetics. In addition, the results showed that directly inoculating the plain soil into the aquatic system and then allowing the synergistic effect of the organic reductant (ascorbic acid) and the substrate (peptone) enhance NB biodegradation. Employing the new method, 200 mg L-1 NB was transformed in 72 h. GC-MS analysis detected two novel intermediate metabolites, indicating that NB was degraded into aniline and further transformed into acetanilide and 9-octadecenamide before its mineralization. This study sheds light on how to exploit the synergistic effects of the availability of excess electron donors and biomass growth by controlling the reductant and a substrate in the right concentration range (e.g., ascorbic acid < 0.8 mgL-1 + peptone).


Assuntos
Ácido Ascórbico/química , Biodegradação Ambiental , Nitrobenzenos/metabolismo , Peptonas/química , Poluentes do Solo/análise , Solo/química , Acetanilidas/síntese química , Compostos de Anilina/síntese química , Estudos de Viabilidade , Cinética , Ácidos Oleicos/síntese química
7.
Eur J Med Chem ; 185: 111809, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683104

RESUMO

Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 µM, 0.104 µM and 0.916 µM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2 = 0.965) and CoMSIA (q [2] = 0.875, r2 = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Relação Quantitativa Estrutura-Atividade , Células A549 , Acrilamidas/síntese química , Acrilamidas/química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células Tumorais Cultivadas
8.
Eur J Med Chem ; 187: 111937, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841727

RESUMO

Prodrugs for targeted tumor therapies have been extensively studied in recent years due to not only maximising therapeutic effects on tumor cells but also reducing or eliminating serious side effects on healthy cells. This strategy uses prodrugs which are safe for normal cells and form toxic metabolites (drugs) after selective reduction by enzymes in tumor tissues. In this study, prodrug candidates (1-36) containing nitro were designed, synthesized and characterized within the scope of chemical experiments. Drug-likeness properties of prodrug candidates were analyzed using DS 2018 to investigate undesired toxicity effects. In vitro cytotoxic effects of prodrug canditates were performed with MTT assay for human hepatoma cells (Hep3B) and prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) as healthy control. Non-toxic compounds (3, 5, 7, 10, 12, 15, 17, 19 and 21-23), and also compounds (1, 2, 5, 6, 9, 11, 14, 16, 20 and 24) which had low toxic effects, were selected to examine their suitability as prodrug canditates. The reduction profiles and kinetic studies of prodrug/Ssap-NtrB combinations were performed with biochemical analyses. Then, selected prodrug/Ssap-NtrB combinations were applied to prostate cancer cells to determine toxicity. The results of theoretical, in vitro cytotoxic and biochemical studies suggest 14/Ssap-NtrB, 22/Ssap-NtrB and 24/Ssap-NtrB may be potential prodrug/enzyme combinations for nitroreductase (Ntr)-based prostate cancer therapy.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Nitrorredutases/antagonistas & inibidores , Pró-Fármacos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Terapia Genética , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Nitrorredutases/genética , Nitrorredutases/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade
9.
Drug Des Devel Ther ; 13: 3079-3089, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695326

RESUMO

Purpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia. Methods: A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound. Results: The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC50 value of 0.12 µM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC50 values of 1.59 and 1.09 µM against A549 cells, 2.46 and 1.35 µM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results. Conclusion: This study provides insights for developing hypoxia-activated kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Células A549 , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Hipóxia Celular , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Células HT29 , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nitroimidazóis/síntese química , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
10.
Macromol Rapid Commun ; 40(24): e1900455, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31709638

RESUMO

Nitrogen-rich conjugated microporous polymers (CMPs) with tunable porosities and reversible redox properties have received increasing interest as electrode materials for supercapacitors. Herein, pyridyl building blocks with different substitutions are selected to synthesize four amine-linked conjugated microporous polytriphenylamine (PTPA) networks via Buchwald-Hartwig cross-coupling reaction engineering the redox activity of PTPAs. The structures, porosities, and redox activities of these four PTPAs are investigated. The electrochemical characterization results show that PTPA obtained using 2,5-diaminopyridine dihydrochloride (i.e., PTPA-25) displays the highest specific capacitances up to 335 F g-1 in 1.0 m H2 SO4 at a current density of 0.5 A g-1 . Upon 5000 cycles, PTPA-25 maintains good initial capacitances up to 65%, nearly 100% Coulombic efficiencies at a current density of 2 A g-1 , and high rate properties (remained a high capacitance of 250 F g-1 at 10 A g-1 ). The influence of different substitutions of pyridyl on the redox activities of the synthesized PTPA electrodes is further proposed, which would give insight into engineering the performance of CMPs-based supercapacitors.


Assuntos
Compostos de Anilina/química , Polímeros/química , Compostos de Anilina/síntese química , Técnicas Eletroquímicas , Eletrodos , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Estrutura Molecular , Oxirredução , Tamanho da Partícula , Polímeros/síntese química , Porosidade , Propriedades de Superfície
11.
Analyst ; 144(22): 6570-6577, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31591613

RESUMO

A fluorescent probe based on a triphenylamine benzopyridine platform for hydrogen sulfide (H2S) assaying has been designed and synthesized. As a result of the H2S-triggered cleavage reaction, the disappearance of the quenching effect of dinitrophenyl and the increased hydrophobicity in a poor solvent lead to the aggregation-induced emission (AIE) effect; consequently an obvious 'turn-on' fluorescence signal can be observed in this process. The probe TPANF features high selectivity towards H2S, low detection limit (0.17 µM), and good photostability and biocompatibility. Moreover, it has been successfully utilized to monitor H2S in food samples to distinguish the extent of food deterioration and to identify the H2S concentration variation in living cells. In addition, endogenous H2S in HCT-116 xenograft tumor tissues was imaged by using this probe. The approach could provide useful insight for the development of other activatable AIE-based probes that are potentially helpful for specific assaying in food chemistry and biological systems.


Assuntos
Compostos de Anilina/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Compostos de Quinolínio/química , Compostos de Anilina/síntese química , Compostos de Anilina/toxicidade , Animais , Galinhas , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Contaminação de Alimentos/análise , Células HCT116 , Humanos , Limite de Detecção , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia de Fluorescência/métodos , Carne de Porco/análise , Produtos Avícolas/análise , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/toxicidade , Suínos
12.
Kaku Igaku ; 56(1): 127-134, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31554771

RESUMO

OBJECTIVE: Obtaining the information on safety and effectiveness of radiopharmaceutical synthesizer NEPTIS plug - 01 and florbetapir (18F) injection solution synthesized by NEPTIS plug - 01 from the post marketing surveillance study. METHODS: Regarding the safety evaluation, failure of device and adverse events were recorded. Regarding the effectiveness evaluation, we assessed the quality of PET images and the impact on the clinical diagnosis. RESULT: During the study period, 12 patients were enrolled. No adverse event was reported from those 12 patients. Two events in 2 patients were reported as a failure of device (In a subsequent investigation, those failures were thought to be caused by inadequacy of procedure manual, which has been revised now). For the quality of PET images, all 12 cases were "good" or "excellent", regardless of the positive or negative of amyloid plaque. The attending physician's diagnosis was changed in 9 patients following the PET imaging. CONCLUSION: NEPTIS plug-01 and florbetapir (18F) were safe and has a favorable effectiveness profile in 12 patients under daily clinical setting.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/síntese química , Composição de Medicamentos/instrumentação , Etilenoglicóis/síntese química , Vigilância de Produtos Comercializados , Compostos Radiofarmacêuticos/síntese química , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Etilenoglicóis/administração & dosagem , Etilenoglicóis/efeitos adversos , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Placa Amiloide , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/efeitos adversos , Segurança
13.
Biomater Sci ; 7(11): 4730-4737, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497814

RESUMO

Electrical stimulation (ES) exhibits a positive role in promoting the cell activity of osteoblasts. Conducting polymers have the advantages of biocompatibility, good environmental stability and easy synthesis, which have been widely used as charge carriers for electrical stimulation; moreover, considering clinical applications, biomaterial-related infection is an important issue that needs to be solved. Thus, conducting polymers with both antibacterial and osteogenic properties are highly demanded for effect repair. However, it remains a challenge to combine these two characteristics efficiently in a simple way. Herein, an Ag-loaded poly(amide-amine) dendrimer was prepared by a simple chemical reduction procedure, which acted as a dopant for the polymerization of polyaniline (PANI) on biomedical titanium (Ti) sheets. The obtained PANI coating showed outstanding antibacterial properties against Gram-negative (E. coli) and Gram-positive (S. aureus) microbes with a 1000-fold increase when compared with that of pure Ti. In addition, note that the polymer coating together with ES facilitated the proliferation and differentiation of MC3T3. The alkaline phosphatase (ALP) activity and intracellular calcium content of the cells showed a 19.09% and 24.02% increase, respectively, when compared with the case of electrically stimulated Ti after 12 days. Moreover, the existence of PAMAM facilitated mineralization. The strategy developed herein is simple and can be easily manipulated, which shows potential applications in the coating of implants for hard tissue repair.


Assuntos
Compostos de Anilina/farmacologia , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Escherichia coli/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Células 3T3 , Compostos de Anilina/síntese química , Compostos de Anilina/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/química , Relação Dose-Resposta a Droga , Estimulação Elétrica , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Propriedades de Superfície , Titânio/química
14.
Int J Biol Macromol ; 140: 255-264, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421175

RESUMO

Dextran with good biocompatibility and degradability shows great potentials for drug delivery and tissue engineering applications. Electro-responsive drug delivery system can provide on-demand and localized drug release. However, dextran-based conductive hydrogel with electrical stimuli responsiveness as drug delivery system has not been reported. Herein, we designed and fabricated a kind of biocompatible biodegradable conductive hydrogel system with the property of electro-responsiveness as a new smart drug delivery system for localized drug release. These series of hydrogels were synthesized by mixing dextran and electroactive aniline trimer with hexamethylene diisocyanate as crosslinker to form hydrogel network. These series of hydrogels exhibited stable rheological property and controllable swelling ratio. These hydrogels showed good conductivity and desirable electric stimuli ability to control drug release. Furthermore, this kind of hydrogel was controlled by external electrical stimuli to generate a kind of "on-off" precise drug release system. When extra voltage was applied, they released more drug intelligently and less drug molecule without external stimuli. The hydrogel showed good cytocompatibility and in vivo biocompatibility by using H&E staining and Toluidine blue staining. All together, these results indicated that these series of biocompatible conductive dextran-based hydrogels were promising candidates as smart drug delivery systems in future biomedical field.


Assuntos
Compostos de Anilina/síntese química , Materiais Biocompatíveis/síntese química , Dextranos/síntese química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Hidrogéis/síntese química , Compostos de Anilina/uso terapêutico , Materiais Biocompatíveis/uso terapêutico , Dextranos/uso terapêutico , Desenho de Fármacos , Condutividade Elétrica , Estimulação Elétrica , Hidrogéis/uso terapêutico , Engenharia Tecidual
15.
Eur J Med Chem ; 181: 111594, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419741

RESUMO

A series of novel acetamine phenyl pleuromutilin derivatives incorporating 2-aminothiophenol moieties into the C14 side chain were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against three Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213 and AD 3) and two Escherichia coli (ATCC 25922 and 9-1) were evaluated by the broth dilution method. Most of the synthesized derivatives displayed potent activities. Compound 27 was found to be the most active antibacterial derivative against MRSA (minimal inhibitory concentration = 0.015 µg/mL) which may lead to a promising antibacterial drug. Furthermore, compound 27 displayed more rapid bactericidal kinetic than tiamulin in in vitro time-kill studies and possessed a longer PAE than tiamulin against MRSA. The PK properties of compound 27 were then measured. The half life (t1/2), clearance rate (Cl) and the area under the plasma concentration-time curve (AUC0→∞) of compound 27 were 6.88 h, 21.64 L/h/kg and 0.48 µg h/mL, respectively. The in vivo antibacterial activities of compound 27 against MRSA were further evaluated using thigh infection model and systemic infection model. Compound 27 possessed superior antibacterial efficacy to tiamulin against MRSA infection in both model.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/uso terapêutico , Diterpenos/síntese química , Diterpenos/uso terapêutico , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Feminino , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos Endogâmicos ICR , Compostos Policíclicos/síntese química , Compostos Policíclicos/uso terapêutico , Infecções Estafilocócicas/microbiologia
16.
Eur J Med Chem ; 181: 111552, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387063

RESUMO

Tyrosine kinase inhibitors (TKIs) have achieved substantial clinical effects for cancer treatment while causing a number of adverse effects. Since hypoxia is an intrinsic difference between solid tumor and healthy tissues, one strategy to overcome the adverse effects of TKIs is to enhance the specificity of anti-tumor activity by selectively targeting hypoxic region of tumors. Herein, we designed and synthesized a series of novel 4-anilinoquinazoline derivatives by introducing 3-nitro-1,2,4-triazole group to the side chain of vandetanib with modification of aniline moiety. Lead compounds, 10a and 10g, exhibited potent inhibitory activity against EGFR and VEGFR-2 kinase. Moreover, these two compounds were shown to enhance anti-proliferative activities on A549 and H446 cells under hypoxic conditions compared to vandetanib and dramatically down-regulate VEGF gene expression. In vivo studies confirmed that 10a and 10g not only inhibited tumor growth in A549 xenografts of BALB/c-nu mice but also significantly reduce toxicity associated with weight loss compared to vandetanib. These results suggest that EGFR/VEGFR-2 dual inhibitors, 10a and 10g, emerged as potential hypoxia-selective anti-tumor drugs with less toxicity for inhibiting in vitro and in vivo models of non-small cell lung cancer cells.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Compostos de Anilina/síntese química , Compostos de Anilina/química , 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 , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Talanta ; 204: 592-601, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357339

RESUMO

Development of conjugated polymers with fluorescence sensing characteristics has received close attention from researchers in fields of environmental protection, biosensing and toxins detection on food. In this paper, novel polyaniline derivatives of poly(9-methyl-9H-carbazol-3-amine) and poly(9,9-dihexyl-9H-fluoren-2-amine) are prepared by facile chemical polymerization. Then they are characterized with NMR (Nuclear Magnetic Resonance), GPC (Gel Permeation Chromatography), XRD (X-Ray Diffraction), FT-IR (Fourier Transform Infrared spectroscopy), FL (Fluorescence spectrometry) and UV-vis (Ultraviolet-visible spectroscopy) characterizations and further applied to the fluorescence detection of different acids and amines. Moreover, the obtained poly(9-methyl-9H-carbazol-3-amine) displays excellent fluorescence properties in the detection for both acids and amines. Besides, this poly(9-methyl-9H-carbazol-3-amine) can not only be used for fluorescence detection in solution, but also can be prepared into solid state and applied in the gas phase fluorescence detection. This work has greatly expanded the scope of application to these polyaniline derivatives materials, opening a new path for the researches on multi-functional chemosensor.


Assuntos
Compostos de Anilina/química , Carbazóis/química , Fluorenos/química , Corantes Fluorescentes/química , Compostos de Anilina/síntese química , Carbazóis/síntese química , Etilenodiaminas/análise , Etilenodiaminas/química , Fluorenos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Ácido Clorídrico/análise , Ácido Clorídrico/química , Ligação de Hidrogênio , Limite de Detecção , Metilaminas/análise , Metilaminas/química , Ácido Nítrico/análise , Ácido Nítrico/química , Reprodutibilidade dos Testes , Espectrometria de Fluorescência/métodos
18.
Chem Commun (Camb) ; 55(58): 8494-8497, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31268095

RESUMO

A rational strategy was reported to construct boranil complexes (DPFB derivatives) with unique aggregation-induced emission effects by installing phenyl rings in the anil ligand as the intramolecular rotors. In view of the good biocompatibility and suitable lipophilicity, DPFB derivatives can serve as excellent fluorescent probes for specific imaging of lipid droplets in living cells and yolk lipids in zebrafish.


Assuntos
Compostos de Anilina/química , Compostos de Boro/química , Complexos de Coordenação/química , Corantes Fluorescentes/química , Gotículas Lipídicas/metabolismo , Compostos de Anilina/síntese química , Animais , Compostos de Boro/síntese química , Complexos de Coordenação/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Ligantes , Microscopia Confocal/métodos , Estrutura Molecular , Peixe-Zebra
19.
Molecules ; 24(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261881

RESUMO

Herein a novel series of histone deacetylases (HDACs) and epidermal growth factor receptor (EGFR) dual inhibitors were designed and synthesized based on the structure of the approved EGFR inhibitor osimertinib (AZD9291). Among them, four compounds 5D, 5E, 9D and 9E exhibited more potent total HDAC inhibition than the approved HDAC inhibitor SAHA. However, these compounds only showed moderate to low inhibitory potency towards EGFR with compounds 5E and 9E possessing IC50 values against EGFRWT and EGFRT790M in the micromolar range. 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay revealed the potent antiproliferative activities of compounds 5D, 5E, 9D and 9E, among which 9E was even more potent against HeLa, MDA-MB-231, MDA-MB-468, HT-29 and KG-1 cell lines than SAHA and AZD9291. Further selectivity profile of 9E showed that this compound was not active against other 13 cancer-related kinases and two epigenetic targets lysine specific demethylase 1 (LSD1) and bromodomain-containing protein 4 (BRD4). These results support further structural modification of 9E to improve its EGFR inhibitory activity, which will lead to more potent and balanced HDAC and EGFR dual inhibitors as anticancer agents.


Assuntos
Acrilamidas/química , Compostos de Anilina/síntese química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Proteínas Quinases/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Células HT29 , Células HeLa , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
20.
Eur J Med Chem ; 178: 214-231, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185412

RESUMO

Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model. Inhibitory activity against the NusB-NusE binding, circular dichroism of compound treated NusB, antimicrobial activity, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells were measured. Structure-activity relationship and quantitative structure-activity relationship were also concluded and discussed. Some of the derivatives demonstrated improved antimicrobial activity than the hit compound against a panel of clinically important pathogens, lowering the minimum inhibition concentration to 1-2 µg/mL against Staphylococcus aureus, including clinical strains of methicillin-resistant Staphylococcus aureus at a level comparable to some of the marketed antibiotics. Given the improved antimicrobial activity, specific inhibition of target protein-protein interaction and promising pharmacokinetic properties without significant cytotoxicity, this series of diaryl compounds have high potentials and deserve for further studies towards a new class of antimicrobial agents in the future.


Assuntos
Compostos de Anilina/farmacologia , Antibacterianos/farmacologia , Benzilaminas/farmacologia , Ligação Proteica/efeitos dos fármacos , Bases de Schiff/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/toxicidade , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Proteínas de Bactérias/metabolismo , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/toxicidade , Células CACO-2 , Desenho de Fármacos , Eritrócitos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/toxicidade , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
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