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1.
J Enzyme Inhib Med Chem ; 35(1): 506-510, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31928252

RESUMO

The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and - hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Anidrases Carbônicas/metabolismo , Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IX/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/metabolismo , Células Tumorais Cultivadas
2.
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
3.
J Agric Food Chem ; 68(4): 975-981, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31891504

RESUMO

In this study, a series of coumarin derivatives containing dithioacetals were synthesized, characterized, and assessed for their anti-tobacco mosaic virus (TMV) activities. Biological tests showed that most of the title compounds exhibited significant anti-TMV biological activities; in particular, compound b21 showed good inactivating activity anti-TMV, with an EC50 of 54.2 mg/L, superior to that of ribavirin (134.2 mg/L). Transmission electron microscopy analyses showed that compound 21 severely ruptured TMV particles. The interaction of compound b21 with TMV coat protein (TMV CP) was investigated using microscale thermophoresis and molecular docking. Compound b21 exhibited a strong binding ability to TMV CP, with a value of 2.9 µM, superior to ribavirin.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Cumarínicos/síntese química , Cumarínicos/farmacologia , Antivirais/química , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Cumarínicos/química , Desenho de Drogas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/fisiologia
4.
Eur J Med Chem ; 186: 111900, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771827

RESUMO

Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 µM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
5.
Chem Biodivers ; 17(1): e1900462, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31788939

RESUMO

A series of coumarin-tagged ß-lactam triazole hybrids (10a-10o) were synthesized and tested for their cytotoxic activity against MDA-MB-231 (triple negative breast cancer), MCF-7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK-293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF-7 cancer cell lines with IC50 values of 53.55 and 58.62 µm, respectively. More importantly, compounds 10b and 10d were non-cytotoxic against HEK-293 cell lines. Structure-activity relationship (SAR) studies suggested that the nitro and chloro group at the C-3 position of phenyl ring are favorable for anticancer activity, particularly against MCF-7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Triazóis/farmacologia , beta-Lactamas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Relação Estrutura-Atividade , Triazóis/química , beta-Lactamas/química
6.
Eur J Med Chem ; 185: 111790, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699535

RESUMO

Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-ß-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-ß-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100 mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-ß/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (F = 39.88%) and suitable eliminated half-life time (T1/2 = 13.09 h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases.


Assuntos
Cumarínicos/uso terapêutico , Descoberta de Drogas , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cumarínicos/síntese química , Cumarínicos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Células RAW 264.7 , Relação Estrutura-Atividade
7.
Anal Chim Acta ; 1094: 122-129, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761038

RESUMO

Hypochlorite (HClO) is involved in various physiological and pathological processes as well as regulation of lysosomal functions. Thus, it is appreciated to develop efficient molecule tools for precisely detecting HClO in lysosomes. Although several lysosomal-targetable fluorogenic probes for HClO have been developed to date, they still suffered from the discounted sensing performance under lysosomal acidic condition. Herein, on the basis of the "AND" logic gate strategy, a novel dual-activatable fluorogenic probe CS has been rationally designed by simultaneously incorporating HClO recognition site and pH-sensitive group with lysosomal-targetable characteristic into a coumarin fluorophore. Different from the single-activated ones previously reported, CS exhibited good sensitivity, high specificity and fast response towards HClO under the acidic conditions but was out of operation in the neutral or alkaline environment. Importantly, it had been successfully applied for spatial-resolution imaging of exogenous or endogenous HClO in lysosomes.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Lisossomos/metabolismo , Cumarínicos/síntese química , Cumarínicos/toxicidade , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Modelos Químicos , Espectrometria de Fluorescência/métodos
8.
Org Biomol Chem ; 17(44): 9636-9645, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31670332

RESUMO

A bifunctional squaramide catalyzed enantioselective formal [2 + 4] annulation reaction with 3-nitro-3,4-dihydrocoumarins and ortho-quinone methide has been developed. Novel chiral masked quaternary α-amino acid derivatives with a 3,4-dihydrocoumarin scaffold are obtained in a highly stereocontrolled manner. Representative transformation of the annulation product to a biologically important quaternary α-amino acid derivative is achieved without any appreciable loss in the diastereo- and enantioselectivity.


Assuntos
Aminoácidos/química , Cumarínicos/química , Cumarínicos/síntese química , Estrutura Molecular , Estereoisomerismo
9.
Molecules ; 24(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581746

RESUMO

A series of fluorescent coumarin derivatives 2a-e were systematically designed, synthesized and studied for their Cu2+ sensing performance in aqueous media. The sensitivities and selectivities of the on-to-off fluorescent Cu2+ sensing signal were in direct correlation with the relative arrangements of the heteroatoms within the coordinating moieties of these coumarins. Probes 2b and 2d exhibited Cu2+ concentration dependent and selective fluorescence quenching, with linear ranges of 0-80 µM and 0-10 µM, and limits of detection of 0.14 µM and 0.38 µM, respectively. Structural changes of 2b upon Cu2+ coordination were followed by fluorescence titration, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), mass spectrometry, and single crystal X-ray diffraction on the isolated Cu2+-coumarin complex. The results revealed a 1:1 stoichiometry between 2b and Cu2+, and that the essential structural features for Cu2+-selective coordination are the coumarin C=O and a three-bond distance between the amide NH and heterocyclic N. Probe 2b was also used to determine copper (II) levels in aqueous soil extracts, with recovery rates over 80% when compared to the standard soil analysis method: inductively coupled plasma-mass spectrometry (ICP-MS).


Assuntos
Cobre/análise , Cumarínicos/síntese química , Corantes Fluorescentes/química , Solo/química , Técnicas Biossensoriais , Cumarínicos/química , Espectrometria de Massas , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química
10.
Eur J Med Chem ; 184: 111779, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629165

RESUMO

The burst of reactive oxygen species (ROS) contributes to and exacerbates cardiac injury. Exogenous supplementation of antioxidants or upregulation of endogenous antioxidant defense genes should be the potential therapies for cardiovascular disease. Sixteen coumarin-derived imino sulfonates compounds were synthesized with the ability of attenuating oxidative stress directly by reducing intracellular ROS level via promoting Nrf2 pathway. The cell-based assays showed that most of the compounds had significant protective activity against H2O2-induced oxidative injury in H9c2 cells. Compound 5h with the highest activity and low cytotoxicity was demonstrated to remarkably remove the intracellular ROS accumulation by activating expressions of Nrf2 and its downstream antioxidant proteins (ie. HO-1 and NQO1), indicating a novel promising antioxidant and Nrf2 activator. Overall, these findings demonstrated that compound 5h could serve as a potential cardioprotective agent. Moreover, our study features developing new antioxidants and Nrf2 activators by introducing a sulfonyl group and nitrogen atom to the α,ß-unsaturated carbonyl entity in coumarin, rather than adding new functional groups or active fragments to coumarin itself.


Assuntos
Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Cumarínicos/farmacologia , Descoberta de Drogas , Iminas/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Cardiotônicos/síntese química , Cardiotônicos/química , Células Cultivadas , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Iminas/química , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Ácidos Sulfônicos/química
11.
Molecules ; 24(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590289

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.


Assuntos
Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Cumarínicos/síntese química , Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Domínio Catalítico , Simulação por Computador , Cumarínicos/química , Cumarínicos/farmacologia , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
12.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547417

RESUMO

Aiming at the assessment of the pro-health, and especially anti-hypochlorite properties of Moringa oleifera species a representative, commercially available Moringa oleifera dietary supplement was used as a substrate for the preparation of aqueous Moringa extract. The anti-hypochlorite activity of the extract was assessed using the hypochlorite-specific coumarin-based fluorescence turn-off sensor, namely 7-diethylamino-coumarin-3-carboxylic acid (7-DCCA). This compound was synthesized via the Knoevenagel condensation of 4-diethylamino-2-hydroxybenzaldehyde with Meldrum's acid and the Moringa extract was employed as a medium and catalyst. Moreover, the total phenolic content (TPC) as well as the reactive oxygen species (ROS)-scavenging ability of the aqueous Moringa extract were determined. The results obtained demonstrated the applicability of Moringa extract as an anti-hypochlorite agent. Additionally, the satisfactory yield of the 7-DCCA obtained suggests the usefulness of the extract as a catalyst and the reaction medium. The antioxidative potential of the extract was notably lower than that of the standard (TROLOX). Determination of TPC in 100 g of the dry weight (DW) of studied material revealed a high number of polyphones present.


Assuntos
Antioxidantes/química , Suplementos Nutricionais , Ácido Hipocloroso/química , Moringa oleifera/química , Extratos Vegetais/química , Catálise , Cumarínicos/síntese química , Cumarínicos/química , Concentração de Íons de Hidrogênio , Fenóis/análise , Extratos Vegetais/análise , Folhas de Planta/química , Espécies Reativas de Oxigênio/química
13.
Eur J Med Chem ; 182: 111651, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31479975

RESUMO

Twenty four 6-aminocoumarin based derivatives were synthesized according to two schemes. All the compounds were screened for their acetylcholinesterase inhibitory activity where compound 5b proved to be the most potent AChE inhibitor with (IC50 = 37 nM) compared to tacrine and donepezil (IC50 = 55.0 and 59.0 nM, respectively). Six compounds 2f, 2g, 4b, 5b, 8b and 9b revealed superior activity over donepezil and a conclusive structure activity relationship study was conducted explaining the obtained results. Furthermore, compounds 2f, 4b and 5b were investigated for their neurobehavioral effect in vivo. All the tested compounds showed improvement of neurobehavioral experiments using donepezil as reference drug. In addition, compounds 2f, 4b and 5b were able to reduce extracellular deposition of amyloid beta 42 in a comparable manner to donepezil. The binding modes of the synthesized compounds were evaluated in silico via molecular docking in the active site of AChE, as well as molecular dynamics simulation study. A pharmacophore model was generated for the newly synthesized compounds.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 182: 111637, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494471

RESUMO

Natural products like coumarins, chalcones, and resveratrol have inherent biological activity in several models of diseases; therefore, their natural dimeric forms are highlighted in this review and their key structural similarities, isolation and pharmacological significance is discussed. These natural products may be dimerized during their biosynthesis, which proceeds through atom- and energy-sufficient methods involving dimeric enzymes, to provide complex structures from simple compounds. Coumarin-derived dimers features the C-C or C-O-C biaryl, terpene sidechain linkages or by cyclobutane ring and acts as inhibitors of α-glucosidase, and cytochrome p450 while some show anti-inflammatory and anti-viral activities, while chalcone-derived dimers have the 1,3-dihydroxy phenyl (resorcinol) substitution on the periphery of cyclobutane or cyclohexane ring and inhibit topoisomerase, protein tyrosine phosphatase 1B (PTP1B), and cathepsins and others possess anti-cancer, anti-inflammatory, and anti-plasmodial activities. Resveratrol-derived dimers have the resorcinol structure and are formed by oxidative coupling showing antioxidant, neuroprotective, anti-HIV, anti-tyrosinase, and cytotoxic activity. Bioavailability evidence of closely related structural monomers could be applicable to their dimeric forms. Application of bioisosteric principles to such dimeric compounds is also discussed. Overall, these dimeric natural products can provide potent templates for the natural product-based drug discovery against several diseases.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , DNA Topoisomerases/metabolismo , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Dimerização , Humanos , Estrutura Molecular , Resveratrol/síntese química , Resveratrol/química , Resveratrol/farmacologia , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
15.
J Enzyme Inhib Med Chem ; 34(1): 1489-1497, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31416364

RESUMO

MAO-B leads to an increase in the levels of hydrogen peroxide and oxidative free radicals, which contribute to the aetiology of the AD. Thus, both iron ion chelators and MAO-B inhibitors can be used to treat AD. Taking the coumarin derivatives and hydroxypyridinones as the lead compounds, a series of dual-target hybrids were designed and synthesised by Click Chemistry. The compounds were biologically evaluated for their iron ion chelating and MAO-B inhibitory activity. Most of the compounds displayed excellent iron ion chelating activity and moderate to good anti-MAO-B activity. Compounds 27b and 27j exhibited the most potent MAO-B inhibitory activity, with IC50 values of 0.68 and 0.86 µM, respectively. In summary, these dual-target compounds have the potential anti-AD activity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cumarínicos/farmacologia , Quelantes de Ferro/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Piridonas/farmacologia , Doença de Alzheimer/metabolismo , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Quelantes de Ferro/síntese química , Quelantes de Ferro/química , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 182: 111617, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442684

RESUMO

A number of compounds targeting different processes of the Human Immunodeficiency Virus type 1 (HIV-1) life cycle have been developed in the continuing fight against AIDS. Coumarin-based molecules already proved to act as HIV-1 Protease (PR) or Integrase (IN) inhibitors and also to target HIV-1 reverse transcriptase (RT), blocking the DNA-dependent DNA-polymerase activity or the RNA-dependent DNA-polymerase activity working as common NNRTIs. In the present study, with the aim to exploit a coumarin-based scaffold to achieve the inhibition of multiple viral coded enzymatic functions, novel 4-hydroxy-2H, 5H-pyrano (3, 2-c) chromene-2, 5-dione derivatives were synthesized. The modeling studies calculated the theoretical binding affinity of the synthesized compounds on both HIV-1 IN and RT-associated Ribonuclease H (RNase H) active sites, which was confirmed by biological assays. Our results provide a basis for the identification of dual HIV-1 IN and RT RNase H inhibitors compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , HIV-1/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Relação Estrutura-Atividade
17.
Arch Pharm (Weinheim) ; 352(10): e1900013, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31397503

RESUMO

Coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones (8k-z) were synthesized via copper(I)-catalyzed azide-alkyne cycloaddition click chemistry. The synthesized hybrid molecules were characterized by spectral studies. Compounds 8k-z were screened for their in vitro anti-TB activity by using the Microplate Alamar Blue assay and for cytotoxicity using the MTT assay. Some of the compounds were found to be most potent against the tested Mycobacterium tuberculosis H37Rv strain with a MIC of 1.60 µg/ml. Further, docking the compounds into the InhA binding pocket showed strong binding interactions and effective overall docking scores were recorded. The drug-likeness and toxicity studies were computed using Molinspiration and Protox, respectively.


Assuntos
Antituberculosos/síntese química , Química Click/métodos , Cumarínicos/síntese química , Desenho de Drogas , Mycobacterium tuberculosis/efeitos dos fármacos , Triazóis/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Triazóis/química , Triazóis/farmacologia
18.
Talanta ; 205: 120095, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450452

RESUMO

pH value is one of the most important parameters, which show significant application in environmental monitoring, chemistry and biology. Abnormal pH values always associate with some serious diseases, including cancer and Alzheimer's disease. Thus, development of highly sensitive and selective method for pH sensing and imaging is of great importance. In this paper, we synthesized a water-soluble organic probe for pH sensing either through its absorption or through its fluorescent signals. The probe was synthesized from the intermediate containing a phenol group, and the reaction was carried out in concentrated H2SO4 at 90 °C. In this way, the probe can introduce a sulfonic acid group into its structure, and thus improve its water solubility. The synthesized probe is pH-responsive, and the response process is reversible, because that the phenol group in the probe can transfer to deprotonation state with increasing the pH values to improve the intramolecular charge transfer. Meanwhile, the synthesized probe also showed high specificity and excellent biocompatibility, which is suitable for cell imaging applications.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/toxicidade , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal/métodos , Solubilidade , Espectrometria de Fluorescência/métodos , Espectrofotometria/métodos , Água/química
19.
Analyst ; 144(15): 4687-4693, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31268078

RESUMO

Dying cell clearance is critical for myriad biological processes such as tissue homeostasis. We herein report an enzyme-activated fluorescence cell labeling approach and its use for multicolor imaging of dying cell clearance. Diacetylated 4-hydroxymandelic acid (DHA)-conjugated dyes give rise to reactive quinone methides upon deacetylation in live cells, which in turn covalently labels cellular proteins. With partner cells tagged with distinct fluorescence, apoptotic cell clearance by Raw 264.7 macrophages and epithelial HeLa cells was captured by confocal microscopy, showing the potential of DHA-based cell labeling for investigating cell-cell interactions.


Assuntos
Apoptose , Corantes Fluorescentes/química , Ácidos Mandélicos/química , Necrose , Animais , Bovinos , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/toxicidade , Esterases/química , Fluoresceínas/síntese química , Fluoresceínas/química , Fluoresceínas/toxicidade , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Ácidos Mandélicos/síntese química , Ácidos Mandélicos/toxicidade , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Estudo de Prova de Conceito , Células RAW 264.7 , Rodaminas/síntese química , Rodaminas/química , Rodaminas/toxicidade , Coloração e Rotulagem/métodos , Suínos
20.
Chem Commun (Camb) ; 55(65): 9629-9632, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31353368

RESUMO

Excessive accumulation of reducing agents in the ER leads to a constitutively high UPR. And the co-function of GSH, Cys and HOCl in biological processes is not well understood. To address this, a TP probe, NPCC, was developed for monitoring reductive stress in the ER. It can also distinguish cancer cells from normal cells.


Assuntos
Cumarínicos/química , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes/química , Pirazóis/química , Animais , Cumarínicos/síntese química , Cisteína/química , Cisteína/metabolismo , Corantes Fluorescentes/síntese química , Glutationa/química , Glutationa/metabolismo , Cabras , Células HeLa , Humanos , Ácido Hipocloroso/química , Ácido Hipocloroso/metabolismo , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Oxirredução , Pirazóis/síntese química , Peixe-Zebra
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