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1.
Acta Crystallogr C Struct Chem ; 76(Pt 9): 874-882, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32887858

RESUMO

Five 2-aroyl-5-bromobenzo[b]furan-3-ol compounds (two of which are new) and four new 2-aroyl-5-iodobenzo[b]furan-3-ol compounds were synthesized starting from salicylic acid. The compounds were characterized by mass spectrometry and 1H NMR and 13C NMR spectroscopy. Single-crystal X-ray diffraction studies of four compounds, namely, (5-bromo-3-hydroxybenzofuran-2-yl)(4-fluorophenyl)methanone, C15H8BrFO3, (5-bromo-3-hydroxybenzofuran-2-yl)(4-chlorophenyl)methanone, C15H8BrClO3, (5-bromo-3-hydroxybenzofuran-2-yl)(4-bromophenyl)methanone, C15H8Br2O3, and (4-bromophenyl)(3-hydroxy-5-iodobenzofuran-2-yl)methanone, C15H8BrIO3, were also carried out. The compounds were tested for their in vitro cytotoxicity on the four human cancer cell lines KB, Hep-G2, Lu-1 and MCF7. Six compounds show good inhibiting abilities on Hep-G2 cells, with IC50 values of 1.39-8.03 µM.


Assuntos
Antineoplásicos/química , Benzofuranos/síntese química , Células Hep G2/química , Antineoplásicos/farmacologia , Benzofuranos/química , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular
2.
Biomolecules ; 10(8)2020 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784891

RESUMO

Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural glycosaminoglycans are known to modulate the functions of various MMPs. The screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds led to the identification of only two scaffolds, including sulfated benzofurans and sulfated quinazolinones, as promising inhibitors of MMP-8. Interestingly, the sulfated quinazolinones displayed full antagonism of MMP-8 and sulfated benzofuran appeared to show partial antagonism. Of the two, sulfated quinazolinones exhibited a >10-fold selectivity for MMP-8 over MMP-9, a closely related metalloproteinase. Molecular modeling suggested the plausible occupancy of the S1' pocket on MMP-8 as the distinguishing feature of the interaction. Overall, this work provides the first proof that the sulfated mimetics of glycosaminoglycans could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8.


Assuntos
Glicosaminoglicanos/química , Metaloproteinase 8 da Matriz/química , Inibidores de Metaloproteinases de Matriz/química , Sulfatos/química , Benzofuranos/química , Biomimética , Biologia Computacional , Descoberta de Drogas , Metaloproteinase 9 da Matriz/química , Modelos Moleculares , Quinazolinonas/química , Bibliotecas de Moléculas Pequenas
3.
Chemosphere ; 260: 127632, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32693261

RESUMO

In this study, the incineration fly ash (IFA) of municipal solid waste (MSW) and municipal sewage sludge (MSS) was synergistically subjected to hydrothermal treatment coupled with pyrolysis (HTP). The regulation of Cl removal and the destruction and detoxification of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) were investigated. The results demonstrated that during hydrothermal treatment (HTT), the Cl removal rate increased with temperature, most of the soluble chlorides were removed, and the acid dissolution of Cl in the hydro-residue was significantly reduced. At hydrothermal temperatures exceeding 180 °C, the variation in the Cl removal rate decreased. Although a certain quantity of PCDD/Fs dissolved in the hydrothermal liquid, the total destruction rate achieved by HTT remained more than 90%. The detoxification rate did not exceed 60% owing to the formation of low-chlorinated PCDD/Fs. Subsequent pyrolysis of the hydro-residue further improved the Cl removal rate, which increased with pyrolysis temperature; the Cl content of pyro-char was reduced to 1.8% and that of the leached acid was less than 0.5 mg/g at 800 °C. In addition, PCDD/Fs in tar and pyrolysis gas were not detected under optimal conditions; the PCDD/F concentration of pyro-char was reduced to 0.17 ng I-TEQ/kg. The destruction and detoxification efficiencies of PCDD/Fs reached 98.49% and 92.50%, respectively. Thus, the method of HTP was conducive to the co-disposal of IFA and MSS.


Assuntos
Incineração , Benzofuranos/química , Cinza de Carvão/química , Dibenzofuranos , Dibenzofuranos Policlorados , Dibenzodioxinas Policloradas/química , Pirólise , Esgotos , Resíduos Sólidos , Temperatura
4.
J Pharmacol Exp Ther ; 374(2): 283-294, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32409422

RESUMO

Lysophosphatidic acid (LPA) is the natural ligand for two phylogenetically distinct families of receptors (LPA1-3, LPA4-6) whose pathways control a variety of physiologic and pathophysiological responses. Identifying the benefit of balanced activation/repression of LPA receptors has always been a challenge because of the high lability of LPA and the limited availability of selective and/or stable agonists. In this study, we document the discovery of small benzofuran ethanolamine derivatives (called CpX and CpY) behaving as LPA1-3 agonists. Initially found as rabbit urethra contracting agents, their elusive receptors were identified from [35S]GTPγS-binding and ß-arrestin2 recruitment investigations and then confirmed by [3H]CpX binding studies (urethra, hLPA1-2 membranes). Both compounds induced a calcium response in hLPA1-3 cells within a range of 0.4-1.5-log lower potency as compared with LPA. The contractions of rabbit urethra strips induced by these compounds perfectly matched binding affinities with values reaching the two-digit nanomolar level. The antagonist, KI16425, dose-dependently antagonized CpX-induced contractions in agreement with its affinity profile (LPA1≥LPA3>>LPA2). The most potent agonist, CpY, doubled intraurethral pressure in anesthetized female rats at 3 µg/kg i.v. Alternatively, CpX was shown to inhibit human preadipocyte differentiation, a process totally reversed by KI16425. Together with original molecular docking data, these findings clearly established these molecules as potent agonists of LPA1-3 and consolidated the pivotal role of LPA1 in urethra/prostate contraction as well as in fat cell development. The discovery of these unique and less labile LPA1-3 agonists would offer new avenues to investigate the roles of LPA receptors. SIGNIFICANCE STATEMENT: We report the identification of benzofuran ethanolamine derivatives behaving as potent selective nonlipid LPA1-3 agonists and shown to alter urethra muscle contraction or preadipocyte differentiation. Unique at this level of potency, selectivity, and especially stability, compared with lysophosphatidic acid, they represent more appropriate tools for investigating the physiological roles of lysophosphatidic acid receptors and starting point for optimization of drug candidates for therapeutic applications.


Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Descoberta de Drogas , Etanolamina/química , Receptores de Ácidos Lisofosfatídicos/agonistas , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Benzofuranos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Diferenciação Celular/efeitos dos fármacos , Cricetulus , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Simulação de Acoplamento Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Conformação Proteica , Coelhos , Ratos , Receptores de Ácidos Lisofosfatídicos/química , Receptores de Ácidos Lisofosfatídicos/metabolismo , beta-Arrestina 2/metabolismo
5.
J Med Chem ; 63(11): 5879-5955, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32470302

RESUMO

Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products (i.e., rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.


Assuntos
Benzofuranos/química , Desenho de Fármacos , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Animais , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Feminino , Meia-Vida , Humanos , Ligantes , Camundongos , Camundongos Nus , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Estrutura Terciária de Proteína , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Ratos , Relação Estrutura-Atividade
6.
Chemosphere ; 256: 127065, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32454353

RESUMO

Dibenzo-p-dioxin (DD) and dibenzofuran (DF) chlorination mediated by Cu and Fe chlorides can make a direct contribution to the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in combustion flue gas. In this study, a kind of composite Cu and Fe chlorides and oxides (CuFe9O9.5Cl10) was prepared by impregnating oxides with HCl solution to imitate the coexistence status of Cu and Fe species in combustion flue gas. Composite CuFe9O9.5Cl10 was active in promoting the electrophilic chlorination of DD/DF at 150-300 °C, with the highest activity at 200 °C. DD/DF chlorination could occur under inert atmosphere, and 5% O2 atmosphere was most favorable for DD/DF chlorination. Electrophilic chlorination of DD/DF primarily favored at 2,3,7,8 positions. Hybridization of Cu and Fe chlorides and oxides not only decreased the starting temperature and activation energy of DD/DF chlorination, but also induced a synergistic effect for accelerating the chlorination of DD/DF. The measured activities of composite CuFe9O9.5Cl10 for promoting the chlorination of DD/DF were near to those of composite Cu chloride and oxide (CuO0.2Cl1.6), whereas 2 orders of magnitude higher than those of composite Fe chloride and oxide (FeO0.3Cl2.4). Comparison of PCDD/F congener distribution patterns indicated that DD/DF chlorination should be a main source of Cl1-3DFs and Cl1-2DDs in combustion flue gases.


Assuntos
Benzofuranos/química , Cobre/química , Dioxinas/química , Dibenzodioxinas Policloradas/química , Cloretos , Cloro , Dibenzofuranos , Dibenzofuranos Policlorados , Halogenação , Incineração , Ferro , Óxidos , Temperatura
7.
Bull Environ Contam Toxicol ; 104(6): 864-870, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32342111

RESUMO

Fraxinellone is an important botanical lactone compound and has been demonstrated to have insecticidal activity. To provide theoretical support to the assessment on the safety of utilizing fraxinellone as a natural insecticidal agent, the interactions between fraxinellone and armyworm DNA, salmon sperm DNA and calf thymus DNA were investigated using UV-Vis absorption spectroscopy, isothermal titration calorimetry, and molecular docking. Results showed that there were two types of combinations between fraxinellone and three kinds of DNA. Type I combination had an equilibrium constant of combination (Ka1) of about 105 and binding sites (n1) of 0.40-0.70, while type II combination had an equilibrium constant of combination (Ka2) of 103 and binding sites (n2) of 1.35-3.15. Results of molecular docking showed that there were non-classical embedding type interactions between fraxinellone and three kinds of DNA, with the reaction taking place in small groove areas of the DNA structure, resulting in relatively weak interactive forces.


Assuntos
Benzofuranos/química , Agentes de Controle Biológico/química , DNA/química , Inseticidas/química , Animais , Calorimetria , Simulação de Acoplamento Molecular , Mariposas/efeitos dos fármacos , Análise Espectral , Termodinâmica
8.
J Enzyme Inhib Med Chem ; 35(1): 805-814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32183602

RESUMO

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer's disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC50 value of anti-acetylcholinesterase inhibition of Compound 20 (0.089 ± 0.01 µM) is similar to the positive drug donepezil (0.059 ± 0.003 µM). According to the experimental results, Compounds 7, 13 show a certain effect in the in vitro evaluation performed and have the potential as drug candidates for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ansiolíticos/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Picratos/antagonistas & inibidores , Ratos , Ratos Wistar , Relação Estrutura-Atividade
9.
Free Radic Res ; 54(4): 221-230, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32216486

RESUMO

Moracin T is a natural product isolated from Morus mesozygia (Moraceae), which acts as potent antioxidant agent. In this study, density functional theory-based computational methods have been performed to evaluate systematically the radical scavenging behaviour of this compound. Structural characteristics such as frontier molecular orbitals and molecular electrostatic potential mapping have been investigated. Thermodynamic parameters related to the three main antiradical mechanisms, hydrogen atom transfer (HAT), sequential electron transfer proton transfer (SETPT), and sequential proton loss electron transfer (SPLET) have been studied. In addition, two variants of SPLET mechanism namely sequential proton loss hydrogen atom transfer (SPLHAT) and double sequential proton loss electron transfer (D-SPLET) have been investigated. The reaction of moracin T with hydroperoxyl radical (HOO•), as representative reactive oxygen species, was also studied. The obtained results are of great significance in better understanding the chemical mechanism of the radical-scavenging action and open new perspectives for the design of new potent antioxidant agents.


Assuntos
Antioxidantes/química , Benzofuranos/química , Estilbenos/química , Cromanos/química , Radicais Livres/química , Humanos , Modelos Moleculares , Morus/química , Peróxidos/química , Extratos Vegetais/química , Termodinâmica
10.
Int J Mol Sci ; 21(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013250

RESUMO

Lung squamous cell carcinoma (LUSC) has a poor prognosis, in part due to poor therapeutic response and limited therapeutic alternatives. Lichens are symbiotic organisms, producing a variety of substances with multiple biological activities. (+)-Usnic acid, an important biologically active metabolite of lichens, has been shown to have high anti-cancer activity at low doses. However, there have been no reports regarding the effect of (+)-usnic acid on LUSC cells. This study found that (+)-usnic acid reduced viability and induced apoptosis in LUSC cells by reactive oxygen species (ROS) accumulation. (+)-Usnic acid induced mitochondria-derived ROS production via inhibition of complex I and complex III of the mitochondrial respiratory chain (MRC). Interestingly, the elimination of mitochondrial ROS by Mito-TEMPOL only partially reversed the effect of (+)-usnic acid on cellular ROS production. Further study showed that (+)-usnic acid also induced ROS production via reducing Nrf2 stability through disruption of the PI3K/Akt pathway. The in vitro and in vivo xenograft studies showed that combined treatment of (+)-usnic acid and paclitaxel synergistically suppressed LUSC cells. In conclusion, this study indicates that (+)-usnic acid induces apoptosis of LUSC cells through ROS accumulation, probably via disrupting the mitochondrial respiratory chain (MRC) and the PI3K/Akt/Nrf2 pathway. Therefore, although clinical use of (+)-usnic acid will be limited due to toxicity issues, derivatives thereof may turn out as promising anticancer candidates for adjuvant treatment of LUSC.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Benzofuranos/química , Benzofuranos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Complexo de Proteínas da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
11.
Chem Commun (Camb) ; 56(24): 3567-3570, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32104795

RESUMO

Fluorescent small molecules are powerful tools for imaging α-synuclein pathology in vitro and in vivo. In this work, we explore benzofuranone as a potential scaffold for the design of fluorescent α-synuclein probes. These compounds have high affinity for α-synuclein, show fluorescent turn-on upon binding to fibrils, and display different binding to Lewy bodies, Lewy neurites and glial cytoplasmic inclusion pathologies in post-mortem brain tissue. These studies not only reveal the potential of benzofuranone compounds as α-synuclein specific fluorescent probes, but also have implications for the ways in which α-synucleinopathies are conformationally different and display distinct small molecule binding sites.


Assuntos
Benzofuranos/química , Corantes Fluorescentes/química , alfa-Sinucleína/análise , Doença de Alzheimer , Fluorescência , Humanos , Microscopia de Fluorescência , Atrofia de Múltiplos Sistemas , Doença de Parkinson
12.
J Photochem Photobiol B ; 205: 111814, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32092663

RESUMO

This study focused on the investigation of photodegradation of usnic acid (UA) which is a natural UV absorbing agent in lichens. Despite years of historical use in food supplement, traditional medicine or cosmetic products in many countries, liver toxicity has been found to be one of the severe and life threatening adverse effects in early 2000's. Such severe side effect has limited UA or its synthesized derivatives for further use clinically or commercially. In this study, extracted UA from Usnea longissima in methanol was exposed to natural sunlight for 21 days. Five photodegraded derivatives (1 to 5) with two new and three previously explored compounds were isolated and purified by column chromatography and preparative liquid chromatography. The structures of these derivatives were identified based on the data of nuclear magnetic resonance spectrum, mass spectrum, optical rotation, infrared spectrum, X-ray crystallography and/or electronic circulation dichroism. The cytotoxicity of (+)-UA and 2 to 5 in liver L02 cells and melanocytes were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Experimental results indicated that IC50 of (+)-UA in liver L02 cells and melanocytes were 24.4 and 6.9 µM respectively, while compound 2 to 5 have lower cytotoxicity with IC50 of 326.7, 1085.0, 62.7 and 152.4 µM in L02 cells and 87.7, 297.7, 60.2 and 85.0 µM in melanocytes respectively. Besides, (+)-UA and these derivatives were exposed to fix dosed of UVA or UVB. The anti-UVA/UVB activity was determined via Hoechst33342/propidium iodide double staining method, and quantified by computer linked fluorescence microscope equipped with CellsSense Dimension system. Based on analysis, Compound 2 to 5 captured prominent UVA/UVB protection capacity in both hepatocytes and melanocytes (p < .001). In addition, the effects of chemicals on tyrosinase were evaluated via Western Blot analysis. In terms of tyrosinase expression, only 2 showed significant stimulating effect (p < .05). However, the safe use of these derivatives cutaneously should be further studied. In conclusion, the photodegraded derivatives (2 to 5) of extracted UA have lower hepatotoxicity than (+)-UA and captured significant UV protection activities.


Assuntos
Benzofuranos , Hepatócitos/efeitos dos fármacos , Melanócitos/efeitos dos fármacos , Raios Ultravioleta , Benzofuranos/química , Benzofuranos/efeitos da radiação , Benzofuranos/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Melanócitos/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Fotólise
13.
RNA ; 26(5): 541-549, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32014999

RESUMO

The PI3K/Akt/mTOR kinase pathway is extensively deregulated in human cancers. One critical node under regulation of this signaling axis is eukaryotic initiation factor (eIF) 4F, a complex involved in the control of translation initiation rates. eIF4F-dependent addictions arise during tumor initiation and maintenance due to increased eIF4F activity-generally in response to elevated PI3K/Akt/mTOR signaling flux. There is thus much interest in exploring eIF4F as a small molecule target for the development of new anticancer drugs. The DEAD-box RNA helicase, eIF4A, is an essential subunit of eIF4F, and several potent small molecules (rocaglates, hippuristanol, pateamine A) affecting its activity have been identified and shown to demonstrate anticancer activity in vitro and in vivo in preclinical models. Recently, a number of new small molecules have been reported as having the capacity to target and inhibit eIF4A. Here, we undertook a comparative analysis of their biological activity and specificity relative to the eIF4A inhibitor, hippuristanol.


Assuntos
Antineoplásicos/química , Fator de Iniciação 4A em Eucariotos/química , Neoplasias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Esteróis/química , Antineoplásicos/farmacologia , Benzofuranos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Compostos de Epóxi/química , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4F em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4F em Eucariotos/química , Humanos , Macrolídeos/química , Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Esteróis/farmacologia , Serina-Treonina Quinases TOR/genética , Tiazóis/química
14.
Molecules ; 25(1)2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31948127

RESUMO

Novel (4-methoxy or 4,8-dimethoxy)-3-methyl-N-(6-oxo-2-thioxo-1,2,3, 6-tetrahydro- pyrimidin-4-yl) benzo [1,2-b: 5, 4-b'] difuran-2-carboxamide (5a-b) has been synthesized by the reaction of visnagenone-ethylacetate (2a) or khellinone-ethylacetate (2b) with 6-aminothiouracil in dimethylformamide or refluxing of benzofuran-oxy-N-(2-thioxopyrimidine) acetamide (4a-b) in sodium ethoxide to give the same products (5a,b) in good yields. Thus, compounds 5a-b are used as an initiative to prepare many new heterocyclic compounds such as 2-(4-(3-methylbenzodifuran- 2-carbox-amido) pyrimidine) acetic acid (6a-b), N-(thiazolo[3, 2-a]pyrimidine)-3-methylbenzo- difuran-2-carboxamide (7a-b), N-(2-thioxopyrimidine)-methylbenzodifuran-2-carbimidoylchloride (8a-b), N-(2-(methyl-thio) pyrimidine)-3-methylbenzodifuran-2-carbimidoylchloride (9a-b), N-(2, 6 -di(piperazine or morpholine)pyrimidine)-1-(3-methylbenzodifuran)-1-(piperazine or morpholine) methanimine(10a-d), 8-(methylbenzodifuran)-thiazolopyrimido[1,6-a][1,3,5]triazine-3,5-dione (11a -b), 8-(3-methyl benzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-trione (12a-b), and 2,10 -di(sub-benzylidene)-8-(3-methylbenzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-3,5,11- trione (13a-f). All new chemical structures were illustrated on the basis of elemental and spectral analysis (IR, NMR, and MS). The new compounds were screened as cyclooxygenase-1/ cyclooxygenase-2 (COX-1/COX-2) inhibitors and had analgesic and anti-inflammatory activities. The compounds 10a-d and 13a-f had the highest inhibitory activity on COX-2 selectivity, with indices of 99-90, analgesic activity of 51-42% protection, and anti-inflammatory activity of 68%-59%. The inhibition of edema for the same compounds, 10a-d and 13a-f, was compared with sodium diclofenac as a standard drug.


Assuntos
Analgésicos/química , Analgésicos/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Benzofuranos/química , Triazinas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 189: 112075, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31986405

RESUMO

A series of 4H-chromen-4-one derivatives obtained by scaffold morphing of the benzofuran compound, TAM16, were tested for antitubercular activity. Compound 8d was active against drug-sensitive and multidrug-resistant tuberculosis. A preliminary druggability evaluation showed that compound 8d displayed favorable mouse and human microsomal stability, low cytotoxicity, and acceptable oral bioavailability. An in vivo study indicated that compound 8d exhibited modest efficacy in an acute mouse model of TB after 3 weeks of treatment. Thus, 8d is a promising antituberculosis lead compound.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Benzopiranos/síntese química , Benzopiranos/farmacologia , Desenho de Fármacos , Microssomos Hepáticos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Benzofuranos/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
16.
Molecules ; 25(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952313

RESUMO

Herein, we present a short and highly modular synthetic route that involves 8-aminoquinoline directed C-H arylation and transamidation chemistry, and which enables access to a wide range of elaborate benzofuran-2-carboxamides. For the directed C-H arylation reactions, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a one-pot, two-step transamidation procedure, which proceeded via the intermediate N-acyl-Boc-carbamates. Given the high efficiency and modularity of this synthetic strategy, it constitutes a very attractive method for generating structurally diverse collections of benzofuran derivatives for small molecule screening campaigns.


Assuntos
Amidas/química , Aminoquinolinas/química , Derivados de Benzeno/química , Benzofuranos/química , Catálise , Estrutura Molecular
17.
J Photochem Photobiol B ; 204: 111787, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31958676

RESUMO

The sensitivity for singlet oxygen (1O2) of two convenient 1O2 probes, 1,3-diphenylisobenzofuran (DPBF) and 9,10-Anthracenediyl-bis(methylene)dimalonic acid (ABDA), has been investigated in different aqueous environments. Both probes are commercially available at reasonable cost and can be used with standard UV-vis spectrometers. Although DPBF is not soluble in neat water and is not specific to the detection of 1O2, it has very high, essentially diffusion-limited, reactivity towards 1O2; it can trap up to 50% of all 1O2 created in alcohol/water or micellar solution, and even more when replacing H2O by D2O, which makes it highly useful when the process under investigation does not yield much 1O2. On the other hand, ABDA has a much lower reactivity, reacting with only 2% of the singlet oxygen generated in H2O, as well as a smaller extinction coefficient, resulting in a much smaller spectroscopic response, but is soluble in neat water and is specific for 1O2, allowing for discrimination from other reactive oxygen species. The results presented here not only allow a comparative assessment of the usefulness of the two 1O2 probes, but also provide a reference for an accurate absolute quantification of the amount of 1O2 generated in an experiment from the observed absorbance bleach.


Assuntos
Antracenos/química , Benzofuranos/química , Oxigênio Singlete/análise , Água/química , Óxido de Deutério/química , Luz , Solventes/química , Espectrofotometria
18.
Exp Parasitol ; 208: 107779, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634474

RESUMO

Here, we report enhanced the in vitro effect of potassium usnate on coupled adult Schistosoma mansoni worms at different time intervals and concentrations. The evaluated schistosomicidal parameters were the following: motility, mortality, fecundity and integumentary changes, as viewed in photomicrographs. Potassium usnate was able to cause 100 and 50% mortality at 100 and 50 µM concentrations, respectively, after 24 h of exposure, while 25 and 12.5 µM concentrations caused changes in motility at 48 and 72 h, and lethality at 96 and 120 h respectively. Eggs were not detected at any of the concentrations analyzed. Photomicrographs revealed morphological tegument alterations within all periods of observation, such as swelling, blisters, dorsoventral contraction, short and curved worms. In conclusion, our results indicate that potassium usnate represents a possible candidate for a new drug in the control of schistosomiasis.


Assuntos
Anti-Helmínticos/farmacologia , Benzofuranos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/prevenção & controle , Análise de Variância , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/química , Benzofuranos/administração & dosagem , Benzofuranos/química , Relação Dose-Resposta a Droga , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Camundongos , Movimento/efeitos dos fármacos , Fotomicrografia , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/tratamento farmacológico , Fatores de Tempo
19.
Chem Biol Interact ; 316: 108913, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838052

RESUMO

Protein kinases play an indispensable role in signaling pathways that regulate tumor cell functions, which represent potent therapeutic targets in cancers. Dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) as a serine/threonine kinase has recently been reported to be upregulated in pancreatic ductal adenocarcinoma (PDAC) and show protumorigenic effect. By activity-guided phytochemical investigation of the extracts from Glycyrrhiza uralensis Fisch, we expect to find the effective constituents that can suppress pancreatic cancer cell proliferation and/or induce cells apoptotic by inhibiting DYRK1A. Eight isopentenyl-substituted compounds (1-8), including four coumarins (1-4), one benzofuran (5), and three flavonoids (6-8), were isolated and identified from G. uralensis Fisch. Among them, licocoumarone (LC, 5) showed effective inhibitory activity against DYRK1A with an IC50 value of 12.56 µM. Molecular docking analysis suggested that LC completely occupied the whole pocket of DYRK1A and formed obvious hydrophobic interactions and hydrogen bonds with DYRK1A residues. Further in vitro validation, including Microscale Thermophoresis (MST) and drug affinity responsive target stability (DARTS) techniques, demonstrated the specific combining capacity of LC to DYRK1A. Meanwhile, LC induced significant cytotoxicity against DYRK1A-overexpressing BxPC-3 cells with an IC50 value of 50.77 µM. Mechanism studies revealed that LC reduced c-MET protein level by inhibiting DYRK1A. These findings provide preliminary evidences that LC as a natural DYRK1A inhibitor suppresses human pancreatic adenocarcinoma BxPC-3 cell proliferation and induces cell apoptotic, which might present new options and possibilities for targeted therapies in pancreatic cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Resorcinóis/farmacologia , Benzofuranos/química , Benzofuranos/metabolismo , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Glycyrrhiza/química , Glycyrrhiza/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Resorcinóis/química , Resorcinóis/metabolismo
20.
Nat Prod Res ; 34(7): 923-929, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30587038

RESUMO

A three-component Strecker-type reactions was applied for the synthesis of benzofuran derivatives through the reaction of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone (euparin), primary amines and trimethylsilyl cyanide (TMSCN) in the presence of catalytic amount of ZnO-nanorods (ZnO-NR) and piperidine in acetonitrile at room temperature. The method has proved to be synthetically simple, and effective with high atom economy and yield. The catalyst also revealed significant reusability. Moreover, the antioxidant activity and free radical scavenging capacity of the newly synthesized such as 4a, 4c, 6a and 6c was screened using free radical scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays and compared with hydroxytoluene (BHT) and tert-butylhydroquinone (TBHQ). These compounds exhibit good DPPH radical scavenging and ferric reducing antioxidant power (FRAP) assays.


Assuntos
Antioxidantes/farmacologia , Benzofuranos/síntese química , Antioxidantes/síntese química , Antioxidantes/química , Benzofuranos/química , Benzofuranos/farmacologia , Catálise , Depuradores de Radicais Livres/química , Ferro/química , Óxido de Zinco
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