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1.
Food Chem ; 339: 128085, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152876

RESUMO

Due to the excessive use of fungicides, pesticide residues have become a growing concern in recent years. Herein, we demonstrated an easy-prepared and low-cost surface enhanced Raman Scattering (SERS) chip composed of 3D silver microspheres (AgMSs) pattern for the quantitative testing of carbendazim in Chinese tea. Compared with the common monolayer SERS substrate, the 3D patterns formed by self-assembly AgMSs with fine nanostructure can offer much more aggregation-induced hotspots and generate strong 3D synergetic effects. Furthermore, when the thickness of the 3D pattern exceeded 6 µm, we replaced the conductive supporting coatings using the glass slides to reduce the cost without any impact on SERS properties. The prepared 3D chips achieved the determination of carbendazim within the linear range of 0.1-10 mg/L and the detection limit of 0.01 mg/L. It is simple and sensitive enough for the detection of most pesticide residues or other harmful organic molecules in our food or environment.


Assuntos
Benzimidazóis/análise , Carbamatos/análise , Contaminação de Alimentos/análise , Microesferas , Resíduos de Praguicidas/análise , Prata/química , Análise Espectral Raman , Chá/química , Benzimidazóis/química , Carbamatos/química , Cor , Humanos , Limite de Detecção , Resíduos de Praguicidas/química , Fatores de Tempo
2.
ACS Sens ; 5(9): 2747-2752, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32820626

RESUMO

With the current intense need for rapid and accurate detection of viruses due to COVID-19, we report on a platform technology that is well suited for this purpose, using intact measles virus for a demonstration. Cases of infection due to the measles virus are rapidly increasing, yet current diagnostic tools used to monitor for the virus rely on slow (>1 h) technologies. Here, we demonstrate the first biosensor capable of detecting the measles virus in minutes with no preprocessing steps. The key sensing element is an electrode coated with a self-assembled monolayer containing the measles antibody, immobilized through an N-heterocyclic carbene (NHC). The intact virus is detected by changes in resistance, giving a linear response to 10-100 µg/mL of the intact measles virus without the need to label or process the sample. The limit of detection is 6 µg/mL, which is at the lower limit of concentrations that can cause infections in primates. The NHC-based biosensors are shown to be superior to thiol-based systems, producing an approximately 10× larger response and significantly greater stability toward repeated measurements and long-term storage. This NHC-based biosensor thus represents an important development for both the rapid detection of the measles virus and as a platform technology for the detection of other biological targets of interest.


Assuntos
Anticorpos Imobilizados/imunologia , Benzimidazóis/química , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Vírus do Sarampo/isolamento & purificação , Anticorpos Imobilizados/química , Técnicas Eletroquímicas/instrumentação , Eletrodos , Ouro/química , Limite de Detecção , Vírus do Sarampo/imunologia
3.
Chemosphere ; 255: 127013, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32679631

RESUMO

In order to obtain higher agricultural yields, the use of chemical substances has been increased to prevent the proliferation of pests, as well as ensuring durability in the storage of the food produced. Such substances are known as pesticides that may well present risks to human health and the environment. In the presence of metal ions, these substances can interact forming new species with different characteristics. Carbendazim (MBC) is an example of a harmful pesticide, which has atoms of nitrogen and oxygen in its structure that can form complexes with metal ions. Thus, in this work has studied the interaction between the copper (II) metal ion and carbendazim and its formation in natural water. The Cu-MBC complex showed a reduction peak of 0.007 V and an oxidation peak of 0.500 V, with characteristics of a quasi-reversible process under a glassy carbon electrode. By anodic stripping voltammetry, a different behavior was observed in the interaction of copper and carbendazim in ultrapure water and Billings dam water; however, it was possible to observe the complex in both samples. Carbendazim in the presence of the metal shows lower oxidation potential value, indicating the influence of the metal on the electrochemical response of the pesticide.


Assuntos
Benzimidazóis/química , Carbamatos/química , Cobre/química , Poluentes Químicos da Água/química , Carbono/química , Técnicas Eletroquímicas/métodos , Eletrodos , Oxirredução
4.
Nucleic Acids Res ; 48(14): 7973-7980, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32597964

RESUMO

Coordinating multiple activities of complex enzymes is critical for life, including transcribing, replicating and repairing DNA. Bacterial RecBCD helicase-nuclease must coordinate DNA unwinding and cutting to repair broken DNA. Starting at a DNA end, RecBCD unwinds DNA with its fast RecD helicase on the 5'-ended strand and its slower RecB helicase on the 3'-ended strand. At Chi hotspots (5' GCTGGTGG 3'), RecB's nuclease cuts the 3'-ended strand and loads RecA strand-exchange protein onto it. We report that a small molecule NSAC1003, a sulfanyltriazolobenzimidazole, mimics Chi sites by sensitizing RecBCD to cut DNA at a Chi-independent position a certain percent of the DNA substrate's length. This percent decreases with increasing NSAC1003 concentration. Our data indicate that NSAC1003 slows RecB relative to RecD and sensitizes it to cut DNA when the leading helicase RecD stops at the DNA end. Two previously described RecBCD mutants altered in the RecB ATP-binding site also have this property, but uninhibited wild-type RecBCD lacks it. ATP and NSAC1003 are competitive; computation docks NSAC1003 into RecB's ATP-binding site, suggesting NSAC1003 acts directly on RecB. NSAC1003 will help elucidate molecular mechanisms of RecBCD-Chi regulation and DNA repair. Similar studies could help elucidate other DNA enzymes with activities coordinated at chromosomal sites.


Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Exodesoxirribonuclease V/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Benzimidazóis/química , Sítios de Ligação , Inibidores Enzimáticos/química , Exodesoxirribonuclease V/química , Exodesoxirribonuclease V/genética , Exodesoxirribonuclease V/metabolismo , Mutação
5.
Proc Natl Acad Sci U S A ; 117(24): 13261-13266, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482866

RESUMO

Modern organic reaction discovery and development relies on the rapid assessment of large arrays of hypothesis-driven experiments. The time-intensive nature of reaction analysis presents the greatest practical barrier for the execution of this iterative process that underpins the development of new bioactive agents. Toward addressing this critical bottleneck, we report herein a high-throughput analysis (HTA) method of reaction mixtures by photocapture on a 384-spot diazirine-terminated self-assembled monolayer, and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) analysis. This analytical platform has been applied to the identification of a single-electron-promoted reductive coupling of acyl azolium species.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Benzimidazóis/síntese química , Benzimidazóis/química , Diazometano/química , Oxirredução , Raios Ultravioleta
6.
Nat Commun ; 11(1): 2706, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483217

RESUMO

Aldehyde is one of most synthetically versatile functional groups and can participate in numerous chemical transformations. While a variety of simple aromatic aldehydes are commercially available, those with a more complex substitution pattern are often difficult to obtain. Benzylic oxygenation of methylarenes is a highly attractive method for aldehyde synthesis as the starting materials are easy to obtain and handle. However, regioselective oxidation of functionalized methylarenes, especially those that contain heterocyclic moieties, to aromatic aldehydes remains a significant challenge. Here we show an efficient electrochemical method that achieves site-selective electrooxidation of methyl benzoheterocycles to aromatic acetals without using chemical oxidants or transition-metal catalysts. The acetals can be converted to the corresponding aldehydes through hydrolysis in one-pot or in a separate step. The synthetic utility of our method is highlighted by its application to the efficient preparation of the antihypertensive drug telmisartan.


Assuntos
Acetais/química , Aldeídos/química , Técnicas Eletroquímicas/métodos , Hidrocarbonetos Aromáticos/química , Modelos Químicos , Acetais/síntese química , Aldeídos/síntese química , Amidinas/química , Benzimidazóis/química , Catálise , Hidrocarbonetos Aromáticos/síntese química , Hidrólise , Estrutura Molecular , Oxidantes/química , Oxirredução
7.
Dalton Trans ; 49(17): 5445-5453, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32266905

RESUMO

A completely water-soluble, high quantum yield blue-fluorescent benzimidazole derivative (AQ), containing a rigid benzimidazole-thiophene structure, was synthesized. Among 21 metal ions, the fluorescence of AQ was selectively turned off by Cu2+ to form an AQ-Cu2+ ensemble. Thereafter, the fluorescence of the AQ-Cu2+ ensemble was turned on by sulfide (S2-) with high selectivity and sensitivity in pure water solution. In comparison with AQ-Ag+ and AQ-Hg2+ ensembles, AQ-Cu2+ was the only ensemble that was capable of detecting a sulfide anion. Also, the fluorescence intensity of AQ was linearly proportional to the concentration of Cu2+ and S2-. Both Cu2+ and S2- were detected within a minute in vitro. Moreover, AQ worked best in the pH range of 5-10 and had a limit of detection of 50 nM and 354 nM for Cu2+ and S2- respectively. It was employed for the detection of sulfide in human lung cancer A549 cells with low cytotoxicity.


Assuntos
Benzimidazóis/química , Corantes Fluorescentes/química , Neoplasias Pulmonares/patologia , Sulfetos/análise , Sulfetos/química , Células A549 , Cor , Cobre/química , Humanos , Limite de Detecção , Compostos Organometálicos/química , Solubilidade , Água/química
8.
J Med Chem ; 63(8): 4047-4068, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32275432

RESUMO

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.


Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/química , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Proteínas Proto-Oncogênicas c-bcl-6/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Science ; 368(6486)2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32241924

RESUMO

The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Quebras de DNA/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Neoplasias/enzimologia , Poli(ADP-Ribose) Polimerase-1/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Humanos , Isoindóis/química , Isoindóis/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Domínios Proteicos
10.
Dalton Trans ; 49(14): 4491-4501, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32191249

RESUMO

Reaction between 2-(2'-pyridyl)benzimidazole derivatives and [{IrCl(η5-C5Me5)}2(µ-Cl)2] afforded mono- and binuclear "piano-stool" Ir(iii) compounds of type [IrnCln(η5-C5Me5)n(L)]Cln (n = 1, L = LET (1) and LSO3H (2); n = 2, L = LBN (3)), which were fully characterized, including the X-ray crystallographic analysis of 1. While the free ligands and compound 3 exhibited no toxicity to the tested microbes, compound 1 was highly potent against bacteria (MIC = 12.9-25.8 nM) and fungi (MIC < 0.40 nM). However, complex 1 induced damage to non-malignant cell lines (human embryonic kidney (HEK293), CC50 = 0.995 µg mL-1) and human RBCs (HC10 = 10.9 µg mL-1 and HC50 > 32 µg mL-1). Interestingly, complex 2, bearing the benzimidazole ligand with an alkylated sulfonate side chain (LSO3H), was selectively potent against C. neoformans with MIC value of 11.2 nM and was non-toxic to HEK293. According to DNA binding studies, compounds 1-3 could be considered as moderate metallo intercalators with a binding constant of 5.0 × 104-1.0 × 105 M-1. Alternatively, evidence was obtained, from ESI-MS measurements, for the non-covalent mode of binding of 2 to hen egg white lysozyme, while compounds 1 and 3 decomposed during the interaction with that protein. This may be attributed to the electrostatic and H-bonding interactions between the polar sulfonate group and charged protein side-chains.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Complexos de Coordenação/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Candida albicans/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cryptococcus neoformans/efeitos dos fármacos , Cristalografia por Raios X , Ciclopentanos/química , Ciclopentanos/farmacologia , Teoria da Densidade Funcional , Escherichia coli/efeitos dos fármacos , Irídio/química , Irídio/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
11.
J Chromatogr A ; 1620: 461003, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32156458

RESUMO

The enormous growth in drug discovery paradigm has necessitated continuous exploration of new methods for drug-protein interaction analysis. To enhance the role of these methodologies in designing rational drugs, this work extended an immobilized angiotensin II type I receptor (AT1R) based affinity chromatography in antihypertensive compound identification. We fused haloalkane dehalogenase at C-terminus of AT1R and expressed the fusion receptor in E. coli. The expressed receptor was covalently immobilized onto 8.0 µm microspheres by mixing the cell lysate with 6-chlorocaproic acid-modified amino polystyrene microspheres. The immobilized AT1R was utilized for thermodynamic and kinetic interaction analysis between the receptor and four specific ligands. Following confirmation of these interactions by molecular docking, we identified puerarin and rosmarinic acid by determining their binding to the receptor. Azilsartan, candesartan, valsartan and olmesartan displayed two kinds of binding sites to AT1R by injection amount-dependent method. By molecular docking, we recognize the driving forces of the interaction as electrostatic interaction, hydrogen bonds and van der Waals force. The dissociation rate constants (kd) of azilsartan, candesartan, valsartan and olmesartan to AT1R were 0.01138 ± 0.003, 0.05142 ± 0.003, 0.07547 ± 0.004 and 0.01310 ± 0.005 min-1 by peak profiling assay. Comparing with these parameters, puerarin and rosmarinic acid presented lower affinity (KA: 0.12 × 104 and 1.5 × 104/M) and slower kinetics (kd: 0.6864 ± 0.03 and 0.3005 ± 0.01 min-1) to the receptor. These results, taking together, indicated that the immobilized AT1R has the capacity to probe antihypertensive compounds.


Assuntos
Anti-Hipertensivos/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Receptor Tipo 1 de Angiotensina/metabolismo , Anti-Hipertensivos/química , Benzimidazóis/química , Benzimidazóis/metabolismo , Sítios de Ligação , Cromatografia de Afinidade , Cinamatos/metabolismo , Depsídeos/metabolismo , Imidazóis/química , Imidazóis/metabolismo , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Isoflavonas/metabolismo , Cinética , Ligantes , Simulação de Acoplamento Molecular , Oxidiazóis/química , Oxidiazóis/metabolismo , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Tetrazóis/química , Tetrazóis/metabolismo , Termodinâmica , Valsartana/química , Valsartana/metabolismo
12.
Molecules ; 25(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218301

RESUMO

Respiratory RNA viruses are responsible for recurrent acute respiratory illnesses that still represent a major medical need. Previously we developed a large variety of benzimidazole derivatives able to inhibit these viruses. Herein, two series of (thio)semicarbazone- and hydrazone-based benzimidazoles have been explored, by derivatizing 5-acetyl benzimidazoles previously reported by us, thereby evaluating the influence of the modification on the antiviral activity. Compounds 6, 8, 16 and 17, bearing the 5-(thio)semicarbazone and 5-hydrazone functionalities in combination with the 2-benzyl ring on the benzimidazole core structure, acted as dual inhibitors of influenza A virus and human coronavirus. For respiratory syncytial virus (RSV), activity is limited to the 5-thiosemicarbazone (25) and 5-hydrazone (22) compounds carrying the 2-[(benzotriazol-1/2-yl)methyl]benzimidazole scaffold. These molecules proved to be the most effective antiviral agents, able to reach the potency profile of the licensed drug ribavirin. The molecular docking analysis explained the SAR of these compounds around their binding mode to the target RSV F protein, revealing the key contacts for further assessment. The herein-investigated benzimidazole-based derivatives may represent valuable hit compounds, deserving subsequent structural improvements towards more efficient antiviral agents for the treatment of pathologies caused by these human respiratory viruses.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Coronavirus/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Infecções Respiratórias/virologia , Semicarbazonas/farmacologia , Animais , Antivirais/química , Benzimidazóis/química , Células Cultivadas , Cães , Humanos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Modelos Moleculares , Semicarbazonas/química , Relação Estrutura-Atividade
13.
J Med Chem ; 63(6): 3047-3065, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32150677

RESUMO

In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of a novel class of IDO1 inhibitors based on a benzimidazole substructure. This family of compounds is endowed with an extensive bonding network in the protein active site, including the interaction with pocket C, a region not commonly exploited by previously reported IDO1 inhibitors. The tight packing of selected compounds within the enzyme contributes to the strong binding interaction with IDO1, to the inhibitory potency at the low nanomolar level in several tumoral settings, and to the selectivity toward IDO1 over TDO and CYPs. Notably, a significant reduction of L-Kyn levels in plasma, together with a potent effect on abrogating immunosuppressive properties of MDSC-like cells isolated from patients affected by pancreatic ductal adenocarcinoma, was observed, pointing to this class of molecules as a valuable template for boosting the antitumor immune system.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Animais , Benzimidazóis/sangue , Linhagem Celular Tumoral , Células Cultivadas , Inibidores Enzimáticos/sangue , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
14.
Food Chem ; 319: 126539, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32193060

RESUMO

Two molecularly imprinted microspheres and two fluorescent tracers for benzimidazoles and pyrethroids were synthesized respectively. The two types of microspheres were coated in the wells of conventional microplate simultaneously. Then the sample extracts and the two traces were added for differential competition. The fluorescence intensities at two different emission wavelengths were excited and recorded for quantification of the two classes of drugs respectively. The optimized multiplexed fluorescence method could be used to determine 8 benzimidazoles and 10 pyrethroids in mutton and beef samples simultaneously. The limits of detection of the method for the 18 drugs were in the range of 5.2-17 ng/mL, and the recoveries from the standards fortified blank samples were in the range of 67.7%-109%. From the analysis of 60 real mutton and beef samples, this method could be used for multi-screening the residues of benzimidazoles and pyrethroids in meat samples.


Assuntos
Benzimidazóis/análise , Piretrinas/análise , Carne Vermelha/análise , Animais , Benzimidazóis/química , Fluorescência , Microesferas , Impressão Molecular , Estrutura Molecular , Piretrinas/química
15.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32013037

RESUMO

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer's disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs).


Assuntos
Benzimidazóis/síntese química , Donepezila/química , Solventes/síntese química , Benzimidazóis/química , Química Verde , Solventes/química , Relação Estrutura-Atividade
16.
Molecules ; 25(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053964

RESUMO

In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 µM in comparison to sorafenib (IC50 = 10.99 µM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Benzimidazóis/síntese química , Sítios de Ligação , Carcinoma Hepatocelular , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
17.
Artigo em Inglês | MEDLINE | ID: mdl-32004940

RESUMO

Flibanserin (FLB) is the first FDA approved drug showed to have significant activity against sexual desire disorder of premenopausal and postmenopausal women. Unfortunately, FLB is used as an adulterant in dietary supplement products as a performance enhancer in sports. Identification of FLB and its metabolites in the biological samples requires an authenticated analytical technique. The aim of this study was to identify N-oxide metabolite of FLB in microsomal and S9 human liver enzyme fractions, rat urine and feces. There are several N-oxide reported as genotoxic impurity or reactive metabolites based on position of N-oxide in piperazine ring. This study also describes the strategy to utilize degradation chemistry for isolation of N-oxide and its step-wise characterization. An LC-MS method has been developed and employed for identifying the N-oxide metabolite of FLB. The targeted N-oxide metabolite in the extracted ion chromatogram of the in vitro and in vivo samples has been confirmed by analyzing the changes in observed mass at m/z 407.1693. Major distinguished abundant ions at m/z 243.1104, 190.0974, 161.0705, 119.0601 confirmed the structure of the metabolite. This study will help to understand the oxidative potential of FLB in toxicokinetic study. The developed method can be useful to identify FLB or its N-oxide metabolite in dope testing in future. This is the first time to report a strategy to utilize degradation chemistry for N-oxide metabolite characterization. In this study, isolated N-oxidative degradation product was used to confirm N-oxide metabolite which was characterized by LC-MS through H/D exchange and structure was ensured by NMR spectroscopy (1H, COSY).


Assuntos
Benzimidazóis , Medição da Troca de Deutério/métodos , Fezes/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/análise , Benzimidazóis/química , Benzimidazóis/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
18.
J Med Chem ; 63(2): 714-746, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31904959

RESUMO

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Quimiocina CCL2/biossíntese , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
19.
Mater Sci Eng C Mater Biol Appl ; 108: 110479, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923963

RESUMO

Membranes which have an osseointegration abilty are often selected as biomaterials in oral and maxillofacial surgery. Although these membranes are often the best option for certain uses, it is a challenge to create functionally attractive membranes. In this research, electro-spun titanium oxide (TiO2)/hydroxyapatite (HA)/polyurethane (PU) membranes were fabricated with different ratios of HA and TiO2: 100: 0, 70:30, 50:50, 30:70 and 0:100 w/w. The morphologies of the different mixtures were assessed with a Scanning Electron Microscope (SEM) and Field Emission Microscope (FESEM). Element analysis was performed with EDX. The physical properties of the water contact angles and mechanical strength were tested and the membranes cultured with osteoblasts to evaluate their biological functions, cell adhesion, viability, proliferation, alkaline phosphatase (ALP) activity, and calcium content. The results showed that the membranes with TiO2 and HA had smaller fibers than those without TiO2 and HA. The TiO2- and HA-including compounds showed the formation of particle aggregation on the surface of the fibers. They also had higher water contact angles, mechanical strength, and stiffness than those without TiO2 and HA, and they had better cell adhesion, viability, proliferation, ALP activity and calcium content. The membrane with a 50:50 TiO2:HA ratio had more unique biological functions than the others. Finally, our research demonstrated that osseointegrated membranes with 50:50 TiO2:HA are promising for oral and maxillofacial surgery.


Assuntos
Osso e Ossos/efeitos dos fármacos , Durapatita/química , Procedimentos Cirúrgicos Bucais , Osseointegração , Poliuretanos/química , Titânio/química , Células 3T3 , Animais , Benzimidazóis/química , Cálcio/química , Adesão Celular , Proliferação de Células , Sobrevivência Celular , Materiais Revestidos Biocompatíveis , Íons , Camundongos , Microscopia Eletrônica de Varredura , Nanotecnologia , Osteoblastos , Tamanho da Partícula , Faloidina/química , Estresse Mecânico , Propriedades de Superfície , Engenharia Tecidual/métodos , Tecidos Suporte , Molhabilidade
20.
Mater Sci Eng C Mater Biol Appl ; 108: 110482, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923971

RESUMO

Covalent triazine-based polymers (CTPs) are a new class of porous materials that can be used for the intercalation of therapeutic agents. The main purposes of designing new drug carriers include protecting them from degradation, enhancing their poor aqueous solubility, and investigating their controlled release properties. In this context, a novel polybenzimidazole-based CTP (BZ-CTP) was prepared by a solvothermal reaction between 4,4',4″-((1,3,5-triazine-2,4,6-triyl) tris(azanediyl)) tribenzoic acid (TCA) and 3,3'-diaminobenzidine. Piroxicam (PRX) and mefenamic acid (MFA) were loaded thoroughly into the CTP by using ultrasonication to form MFA-loaded CTP (MFA@BZ-CTP) and PRX-loaded CTP (PRX@BZ-CTP) with drug loading efficiencies of 49% and 53%, respectively. We attribute the increased loading efficiencies to the formation of π-π stacking forces between the aromatic rings present in the CTP structure and drugs. The in vitro release experiments were assessed in simulated physiological conditions using the dialysis method. Moreover, the release mechanisms were evaluated by Korsmeyer-Peppas kinetic studies and the obtained results showed excellent sustained releases of 81% after 96 h and 87% after 24 h for the PRX@BZ-CTP and MFA@BZ-CTP hybrids, respectively.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Benzimidazóis/química , Portadores de Fármacos/química , Polímeros/química , Triazinas/química , Dióxido de Carbono , Cinética , Ácido Mefenâmico/química , Nanopartículas/química , Piroxicam/química , Porosidade , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios X
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