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1.
Adv Exp Med Biol ; 1195: 189-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468477

RESUMO

In the present work, new indole derivatives, i.e., 5-[N,N-di alkyl amino alkoxy] azaindole 2,3- di-one derivatives, are synthesized and characterized. These compounds were subjected to acute toxicity and then screened for antiepileptic activity on maximal electroshock seizure (MES) model in albino Wistar rats. In that study 5-[2-dimethyl amino ethoxy] Azaindole-3-hydrazone,2-one and 5-[2- dimethyl amino ethoxy] Azaindole 2-one,3-thiothiosemicarbazone(IIIa) showed good antiepileptic activity and less neurotoxicity compared to phenytoin. The purpose of the present study is to investigate the effect of 5-[2-dimethyl amino ethoxy] Indole 2,3- di one and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone(IIIa) derivatives on biogenic amines concentrations in rat brain after induction of seizures by MES method. The aim of study was relationship between seizure activities and altered the monoamines such as Noradrenaline (NA), Dopamine (DA), Serotonin (5-HT) in forebrain of rats in MES seizure models. In MES model, study of 5-[2-dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one(Va) and 5-[2-dimethyl amino ethoxy]Azaindole 2-one,3-thiosemicarbazone(IIIa) (100 mg/kg) showed significant restoration of the decreased levels of brain monoamines such as noradrenaline, dopamine, and 5-hydroxytryptamine. Thus, this study suggests that 5-[2-Dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one (V) and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone (IIIa) increased the monoamines on rat brain, which may decrease the susceptibility to MES-induced seizure in rats.


Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Indóis/síntese química , Indóis/uso terapêutico , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/uso terapêutico , Álcoois/síntese química , Álcoois/química , Álcoois/farmacologia , Álcoois/uso terapêutico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Indóis/química , Indóis/farmacologia , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
2.
J Med Chem ; 63(6): 3215-3226, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32142284

RESUMO

Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound (2) led to bromobenzothiophene (11g) with potent inhibitory activity against DHPS. X-ray crystallographic analysis of 11g complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.


Assuntos
Inibidores Enzimáticos/química , Indóis/química , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Tiofenos/química , Sítio Alostérico , Cristalografia por Raios X , Descoberta de Drogas , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Guanina/análogos & derivados , Guanina/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Indóis/síntese química , Indóis/metabolismo , Estrutura Molecular , NAD/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Espermidina/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/metabolismo
3.
Molecules ; 25(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936003

RESUMO

: A series of free base and Zn(II) phthalocyanines featuring fluorenyl antennae linked by methoxy or oxo bridges to the phthalocyanine core (Pc) were synthesized and characterized. Selected linear and nonlinear (two-photon absorption) optical properties of these new compounds were subsequently studied. As previously observed for related porphyrin dendrimers bearing 2-fluorenyl peripheral dendrons, an efficient energy transfer occurs from the peripheral antennae to the central phthalocyanine core following excitation in the fluorenyl-based π-π* absorption band of these chromophores. Once excited, these compounds relax to the ground state, mostly by emitting intense red light or by undergoing intersystem crossing. As a result, the tetrafunctionalized Zn(II) phthalocyanines are fluorescent, but can also efficiently photosensitize molecular oxygen in tetrahydrofurane (THF), forming singlet oxygen with nearly comparable yields to bare Zn(II) phthalocyanine (ZnPc). In comparison with the latter complex, the positive role of the fluorenyl-containing antennae on one- and two-photon brightness (2PA) is presently demonstrated when appended in peripheral (ß) position to the phthalocyanine core. Furthermore, when compared to known porphyrin analogues, the interest in replacing the porphyrin by a phthalocyanine as the central core to obtain more fluorescent two-photon oxygen photosensitizers is clearly established. As such, this contribution paves the way for the future development of innovative biphotonic photosensitizers usable in theranostics.


Assuntos
Fluorenos/química , Indóis/química , Fármacos Fotossensibilizantes/química , Oxigênio Singlete/química , Transferência de Energia , Fluorenos/síntese química , Indóis/síntese química , Luz , Luminescência , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fótons , Porfirinas/química , Oxigênio Singlete/isolamento & purificação , Análise Espectral
4.
Chem Commun (Camb) ; 56(8): 1219-1222, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31895373

RESUMO

To monitor delicate changes of biological HOCl in vivo, a new probe (OH-substituted coumarin-hemicyanine, probe 2) was synthesized for NIR and ratiometric HOCl detection. Selectivity studies indicated that the electron-donating group (OH) substituted on the indolium moiety enhanced the selectivity to detect HOCl. With HOCl, the probe showed a ratiometric fluorescence (I500/I650) with a low detection limit (49.1 nM) and a rapid response (within 2 min). In addition, probe 2 was successfully applied to visualize exogenous and endogenous HOCl in living cells and animals and exhibited a perfect mitochondria target ability. This probe has been further studied as a potential and powerful tool to probe HOCl in arthritis models.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Indóis/química , Animais , Artrite/induzido quimicamente , Artrite/diagnóstico , Carragenina , Cumarínicos/síntese química , Cumarínicos/toxicidade , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Indóis/síntese química , Indóis/toxicidade , Limite de Detecção , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Mitocôndrias/metabolismo , Células RAW 264.7 , Espectrometria de Fluorescência/métodos , Peixe-Zebra
5.
J Med Chem ; 63(3): 1032-1050, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31904232

RESUMO

Activation of prostanoid EP2 receptor exacerbates neuroinflammatory and neurodegenerative pathology in central nervous system diseases such as epilepsy, Alzheimer's disease, and cerebral aneurysms. A selective and brain-permeable EP2 antagonist will be useful to attenuate the inflammatory consequences of EP2 activation and to reduce the severity of these chronic diseases. We recently developed a brain-permeable EP2 antagonist 1 (TG6-10-1), which displayed anti-inflammatory and neuroprotective actions in rodent models of status epilepticus. However, this compound exhibited moderate selectivity to EP2, a short plasma half-life in rodents (1.7 h) and low aqueous solubility (27 µM), limiting its use in animal models of chronic disease. With lead-optimization studies, we have developed several novel EP2 antagonists with improved water solubility, brain penetration, high EP2 potency, and selectivity. These novel inhibitors suppress inflammatory gene expression induced by EP2 receptor activation in a microglial cell line, reinforcing the use of EP2 antagonists as anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Linhagem Celular , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Solubilidade , Relação Estrutura-Atividade , Água/química
6.
J Med Chem ; 63(3): 1156-1177, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31922756

RESUMO

Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species and contributes to oxidative stress. The p47phox-p22phox interaction is critical for the activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2500 fragments using fluorescence polarization and a thermal shift assay and validation by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phoxSH3A-B) with KD values of 400-600 µM. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phoxSH3A-B and these competed with p22phox for binding to p47phoxSH3A-B. Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phoxSH3A-B-p22phox interaction (Ki of 20 µM). Thereby, we reveal a new way of targeting p47phox and present the first report of drug-like molecules with the ability to bind p47phox and inhibit its interaction with p22phox.


Assuntos
Indóis/síntese química , NADPH Oxidases/antagonistas & inibidores , Azóis/química , Descoberta de Drogas , Humanos , Indóis/química , Estrutura Molecular , NADPH Oxidase 2/metabolismo , NADPH Oxidases/metabolismo , Compostos Organosselênicos/química , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
7.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936442

RESUMO

A novel generation of indole-2,3-quinodimethanes via the deamination of 1,2,3,4-tetrahydropyrrolo[s3,4-b]indoles is reported.


Assuntos
Indóis/química , Pirróis/química , Desaminação , Indóis/síntese química , Nitritos/química , Pirróis/síntese química
8.
Molecules ; 25(2)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963102

RESUMO

Two novel phthalonitrile derivatives, bearing two hexyloxy groups and a benzodioxin (or a naphthodioxin) annulated ring, along with their corresponding metal-free phthalocyanines (H2Pc) were prepared. FT-IR, mass, electronic absorption, 1H NMR, and 13C NMR spectroscopy were employed for the characterization of all compounds. The effect of hexadeca substituents on the photophysical properties of metal-free Pcs was investigated. Photophysical properties of H2Pc were studied in tetrahydrofuran (THF). Fluorescent quantum yields of phthalocyanines (Pcs) were calculated and compared with the unsubstituted phthalocyanine. 1,4-Benzoquinone effectively quenched the fluorescence of these compounds in THF. Cyclic and square wave voltammetry methods were applied to metal-free phthalocyanines and Pc-centered oxidation and reduction processes were obtained.


Assuntos
Indóis/química , Técnicas de Química Sintética , Eletroquímica , Indóis/síntese química , Metais/química , Processos Fotoquímicos , Análise Espectral
9.
Eur J Med Chem ; 187: 111919, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31810783

RESUMO

Phosphatidylcholine-specific phospholipase C (PC-PLC) is a promising target for new anticancer treatment. Herein, we report our work in the discovery of novel drug-like PC-PLC inhibitors. Virtual screening led to the identification of promising hits from four different structural series that contain the molecular scaffold of benzenesulphonamides (10), pyrido[3,4-b]indoles (22), morpholinobenzoic acid (84) and benzamidobenzoic acid (80). 164 structural analogues were tested to investigate the chemical space around the hit series and to generate preliminary structurally activity relationships (SAR). Two of the pyrido[3,4-b]indoles (22_10 and 22_15) had comparable or better potency as D609, an established but non-drug-like PC-PLC inhibitor. Furthermore, three morpholinobenzoic acids (84, 84_4 and 84_5) had superior potency than D609. Therefore, this study paves the way towards the development of drug-like PL-PLC inhibitors as potential anticancer agents.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Ácido Benzoico/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Fosfolipases Tipo C/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ácido Benzoico/síntese química , Ácido Benzoico/química , 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 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Fosfolipases Tipo C/metabolismo
10.
J Chromatogr A ; 1613: 460676, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-31727351

RESUMO

Due to the trace levels of polycyclic aromatic hydrocarbons (PAHs) in soil and the complexity of soil matrices, effective sample pretreatment methods are of great significance to obtain accurate analytical results. In this paper, polydopamine (PDA) encapsulated Fe3O4 particles were used as seeds for in situ polymerization of divinylbenzene (DVB) to derive magnetic hybrid material Fe3O4@PDA@PDVB. Coupled with pressurized liquid extraction, Fe3O4@PDA@PDVB was investigated as a selective adsorbent for the extraction and cleanup of PAHs in soil. The prepared magnetic material was characterized and demonstrated to possess strong hydrophobicity and superparamagnetism. Under optimal conditions, Fe3O4@PDA@PDVB can effectively extract 15 PAHs from a 30% methanol solution within 2 min, and it is more selective for PAHs than for n-alkane in soil extracts. The matrix effect significantly decreased after extraction by the prepared material, which showed superiority to a silica gel column method (EPA 3630C Method). The developed method was linear (5-1000 ng g-1) with coefficient of determination (R2) ranging from 0.9986-0.9998, and the limits of detection were 0.13-0.54 ng g-1. Additionally, repetitive experiments indicated that the prepared material was reproducible and reusable with relative standard deviations below 8.4% and 8.6%, respectively. Finally, the new method was successfully employed to determine the concentrations of PAHs in genuine soil and standard reference material, and the results were comparable to those of widely utilized EPA methodology.


Assuntos
Técnicas de Química Analítica/métodos , Indóis/síntese química , Hidrocarbonetos Policíclicos Aromáticos/isolamento & purificação , Polímeros/síntese química , Poluentes do Solo/isolamento & purificação , Solo/química , Compostos de Vinila/química , Interações Hidrofóbicas e Hidrofílicas , Limite de Detecção , Extração Líquido-Líquido , Fenômenos Magnéticos , Hidrocarbonetos Policíclicos Aromáticos/análise , Polimerização , Poluentes do Solo/análise
11.
Eur J Med Chem ; 186: 111856, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734021

RESUMO

Inhibiting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway is an attractive strategy for tumor immunotherapy. Here, a novel series of indoline-containing compounds were developed, among which, A13 was identified as the most promising PD-1/PD-L1 pathway inhibitor. At the biochemical level, A13 demonstrated strong inhibition of the PD-1/PD-L1 interaction, with an IC50 of 132.8 nM. Notably, it exhibited outstanding immunoregulatory activity, and significantly elevated interferon-γ secretion in a Hep3B/OS-8/hPD-L1 and CD3 T cell co-culture model, without significant toxic effect. Therefore, A13 could be employed as a suitable lead compound for further design of non-peptide inhibitors targeting the PD-1/PD-L1 interaction. In addition, the preliminary structure-activity relationships of these new indoline compounds were investigated in this study, providing valuable information for future drug development.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Descoberta de Drogas , Indóis/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Células Jurkat , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor de Morte Celular Programada 1/metabolismo , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 187: 111918, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830635

RESUMO

Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays an important role in T cell signaling downstream of the T-cell receptor (TCR). Herein we report the discovery of a series of indolylindazole based covalent ITK inhibitors with nanomolar inhibitory potency against ITK, good kinase selectivity and potent inhibition of the phosphorylation of PLCγ1 and ERK1/2 in living cells. A computational study provided insight into the interactions between inhibitors and Phe437 at the ATP binding pocket of ITK, suggesting that both edge-to-face π-π interaction and the dihedral torsion angle contribute to inhibitors' potency. Compounds 43 and 55 stood out as selective covalent inhibitors with potent cellular activity, which could be used as chemical tools for further study of ITK functions.


Assuntos
Desenho de Fármacos , Indazóis/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indazóis/síntese química , Indazóis/química , Indóis/síntese química , Indóis/química , Células Jurkat , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
13.
J Enzyme Inhib Med Chem ; 35(1): 96-108, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31690133

RESUMO

A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.


Assuntos
Indóis/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Lipase Lipoproteica/metabolismo , Linfócitos/efeitos dos fármacos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
14.
Eur J Med Chem ; 185: 111815, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732252

RESUMO

In order to identify new aromatase enzyme inhibitors, thirty aryl sulfonamide derivatives containing an indole nucleus have been synthesized. The enzyme inhibition assay showed that four compounds inhibit aromatase in the sub-micromolar range. Loading concentrations of these four compounds were afterwards tested for cell viability and cytotoxicity on MCF7 human breast cancer cells, revealing a time- and dose-dependent decrease of active metabolizing cells over the time of the culture (0-72 h), starting from a concentration of 100 µM. Likewise LDH released raised up to 40% at early time of exposures (24 h). Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Indóis/farmacologia , Sulfonamidas/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Nat Commun ; 10(1): 5553, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804483

RESUMO

Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.


Assuntos
Carbolinas/química , Ciclização , Alcaloides Indólicos/química , Indóis/química , Carbolinas/síntese química , Catálise , Cromatografia Líquida de Alta Pressão , Sinergismo Farmacológico , Alcaloides Indólicos/síntese química , Indóis/síntese química , Modelos Químicos , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo
16.
Molecules ; 24(23)2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31783706

RESUMO

The bis-glyoxylamide peptidomimetics have been synthesized from bis-N-acetylisatins linked at C5 by ring-opening with alcohols, amines, and amino acid methyl ester hydrochlorides. X-ray images of single crystals of bis-glyoxylamide peptidomimetics have been obtained.


Assuntos
Indóis/síntese química , Peptidomiméticos/síntese química , Álcoois/química , Aminas/química , Aminoácidos/química , Ésteres/química , Indóis/química , Isatina/química , Metano/análogos & derivados , Metano/química , Modelos Moleculares , Estrutura Molecular , Oxigênio/química , Peptidomiméticos/química , Raios X
17.
Molecules ; 25(1)2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877731

RESUMO

There is a continuous search for more reliable and effective alternatives to control phytopathogens through different strategies. In this context, indole-containing phytoalexins are stimuli-induced compounds implicated in plant defense against plant pathogens. However, phytoalexins' efficacy have been limited by fungal detoxifying mechanisms, thus, the research on bioisosteres-based analogs can be a friendly alternative regarding the control of Fusarium phytopathogens, but there are currently few studies on it. Thus, as part of our research on antifungal agents, a set of 21 synthetic indole-containing phytoalexin analogs were evaluated as inhibitors against the phyopathogen Fusarium oxysporum. Results indicated that analogs of the N,N-dialkylthiourea, N,S-dialkyldithiocarbamate and substituted-1,3-thiazolidin-5-one groups exhibited the best docking scores and interaction profiles within the active site of Fusarium spp. enzymes. Vina scores exhibited correlation with experimental mycelial growth inhibition using supervised statistics, and this antifungal dataset correlated with molecular interaction fields after CoMFA. Compound 24 (tert-butyl (((3-oxo-1,3-diphenylpropyl)thio)carbonothioyl)-l-tryptophanate), a very active analog against F. oxysporum, exhibited the best interaction with lanosterol 14α-demethylase according to molecular docking, molecular dynamics and molecular mechanic/poisson-boltzmann surface area (MM/PBSA) binding energy performance. After data analyses, information on mycelial growth inhibitors, structural requirements and putative enzyme targets may be used in further antifungal development based on phytoalexin analogs for controlling phytopathogens.


Assuntos
Antifúngicos/síntese química , Fusarium/crescimento & desenvolvimento , Indóis/síntese química , Sesquiterpenos/química , Antifúngicos/química , Antifúngicos/farmacologia , Domínio Catalítico/efeitos dos fármacos , Simulação por Computador , Enzimas/química , Enzimas/farmacologia , Proteínas Fúngicas/química , Proteínas Fúngicas/farmacologia , Fusarium/efeitos dos fármacos , Fusarium/enzimologia , Indóis/química , Indóis/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular
18.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614517

RESUMO

Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors' ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3-6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 µM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Pirimidinonas/química , Receptor A2A de Adenosina/genética , Receptor A3 de Adenosina/genética , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Piperazina/síntese química , Piperazina/química , Piperazina/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Receptor A2A de Adenosina/química , Relação Estrutura-Atividade
19.
Anal Chim Acta ; 1090: 125-132, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31655637

RESUMO

NAD(P)H: Quinone Oxidoreductase 1 (hNQO1) is a cytosolic flavin two-electron reductase involved in many physiological and pathological processes that is overexpressed in many cancers and recognized as a potential cancer biomarker. However, it is still challenging for highly sensitive and selective monitoring hNQO1 in living cells. Here, we developed a highly selective and ultrasensitive hemicyanine-based near-infrared (NIR) fluorescence probe (probe HCYSN) for the sensing of hNQO1 activity and discrimination of human cancer cells. The fluorescent sensing system with NIR emission is low phototoxic to normal cells but is highly selective and ultrasensitive to hNQO1 in a linear range from 0.03 µg/mL to 0.6 µg/mL with detection limit (LOD) of 4.9 ng/mL (0.49 mU/mL), which is better than most of other hNQO1 probes reported. In particular, the NIR fluorescent probe was successfully applied to distinguish various cancer cells through the different distribution of endogenous hNQO1. All the present results demonstrated that the probe HCYSN exhibited great potential for human hNQO1 assay and in vivo imaging for the early cancers diagnosis and pathological studies.


Assuntos
Corantes Fluorescentes/química , Indóis/química , NAD(P)H Desidrogenase (Quinona)/sangue , Linhagem Celular Tumoral , Ensaios Enzimáticos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Indóis/síntese química , Indóis/toxicidade , Cinética , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , NAD(P)H Desidrogenase (Quinona)/química , Espectrometria de Fluorescência/métodos
20.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652581

RESUMO

Herein we report a significant, valuable extension of a recently implemented pyrrole benzannulation methodology that, employing versatile nitrodienes from our lab as useful C4 building blocks, led to indole derivatives characterized by unusual patterns of substitution. The 6-nitro-7-arylindoles resulting from suitably derivatized, non-symmetric dienes are of foreseeable synthetic interest in search for new polyheterocyclic systems. As an example, pyrrolocarbazoles with a rarely reported ring fusion were synthesized with the classical Cadogan protocol. Furthermore, the proven easy reducibility of the nitro group to amine will surely open the way to further interesting elaborations.


Assuntos
Carbazóis/química , Indóis/química , Pirróis/química , Carbazóis/síntese química , Indóis/síntese química , Estrutura Molecular , Pirróis/síntese química
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