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1.
J Agric Food Chem ; 67(40): 11236-11243, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539244

RESUMO

A method for the simultaneous determination of 27 sulfonamides in poultry feathers using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established in this study. The samples were extracted using 0.1 mol/L HCl solutions in a 60 °C water bath for 2 h, purified using hydrophilic-lipophilic balance solid-phase extraction, nitrogen-dried, and then reconstituted for UPLC-MS/MS analysis, which was performed with a CSH-C18 column. Linearity, limit of detection, limit of quantification, recovery, and precision were calculated in accordance with Commission Decision 2002/657/EC. For linearity, all standard curves showed a standard coefficient greater than 0.99, and the recoveries and coefficient of variation were 89-115% and <20%, respectively. The limit of detection and limit of quantification were 0.2-5 and 0.5-20 ng/g, respectively. The method was successfully applied to sulfamethazine (SMZ) residue accumulation monitoring in laying hen feathers and sulfonamide residue monitoring on poultry feathers. SMZ residue accumulation in the laying hen feathers was studied after administration with 100 mg/kg of SMZ for 21 consecutive days. SMZ residues were still detected in feathers 14 days after drug administration and persisted for up to 85 days. Results from 42 poultry feather samples showed that the feather is a suitable medium to monitor the illegal use of sulfonamides in poultry production.


Assuntos
Resíduos de Drogas/farmacocinética , Plumas/química , Sulfametazina/farmacocinética , Sulfonamidas/química , Animais , Galinhas/metabolismo , Cromatografia Líquida de Alta Pressão , Resíduos de Drogas/química , Resíduos de Drogas/isolamento & purificação , Resíduos de Drogas/metabolismo , Feminino , Limite de Detecção , Extração em Fase Sólida , Sulfametazina/química , Sulfametazina/isolamento & purificação , Sulfametazina/metabolismo , Sulfonamidas/isolamento & purificação , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem
2.
J Enzyme Inhib Med Chem ; 34(1): 1388-1399, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392901

RESUMO

Fourteen novel dipeptide carboxamide derivatives bearing benzensulphonamoyl propanamide were synthesized and characterized using 1H NMR, 13C NMR, FTIR and MS spectroscopic techniques. In vivo antimalarial and in vitro antimicrobial studies were carried out on these synthesized compounds. Molecular docking, haematological analysis, liver and kidney function tests were also evaluated to assess the effect of the compounds on the organs. At 200 mg/kg body weight, 7i inhibited the multiplication of the parasite by 81.38% on day 12 of post-treatment exposure. This was comparable to the 82.34% reduction with artemisinin. The minimum inhibitory concentration (MIC) in µM ranged from 0.03 to 2.34 with 7h having MIC of 0.03 µM against Plasmodium falciparium. The in vitro antibacterial activity of the compounds against some clinically isolated bacteria strains showed varied activities with some of the new compounds showing better activities against the bacteria and the fungi more than the reference drug ciprofloxacin and fluconazole.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antimaláricos/síntese química , Bactérias/efeitos dos fármacos , Dipeptídeos/síntese química , Fungos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Ratos , Sulfonamidas/química
3.
J Enzyme Inhib Med Chem ; 34(1): 1380-1387, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401884

RESUMO

Novel sulfonamide-dithiocarbamate hybrids were designed and synthesised via the molecular hybridisation strategy. Among them, compound 13d displayed a potent activity with IC50 values of 0.9, 0.7, 1.9 and 2.6 µM against UM-UC-3, RT-112, RT4 and T24. Compound 13d inhibited the migration and regulated the migration-related markers (E-cadherin, N-cadherin, Vimentin, Snail and Slung) against RT-112 cells in a concentration dependent manner. By the tubulin polymerisation assay in vitro and immunostaining assay, compound 13d was identified as a novel tubulin polymerisation inhibitor. Intragastric administration of compound 13d could inhibit the growth of RT-112 cells in vivo in a xenograft mouse model with the low toxicity, indicating that it may be a leading candidate with antitumor properties to treat bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Neoplasias da Bexiga Urinária/patologia , Animais , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectrometria de Massas , Camundongos , Camundongos Nus , Espectroscopia de Prótons por Ressonância Magnética , Sulfonamidas/química , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Enzyme Inhib Med Chem ; 34(1): 1457-1464, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411080

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses. We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were in vitro evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with KIs in the range of 0.966-9.091 µM, whereas hCA II in the range of 0.083-3.594 µM. The primary 7-chloro-6-flouro substituted sulphfonamide derivative 6e (KI = 0.083 µM) proved to be the most active quinoline in inhibiting hCA II, whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 µM, confirming the crucial role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/química , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Sulfonamidas/química
5.
Bull Environ Contam Toxicol ; 103(3): 484-489, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31399772

RESUMO

Burning of wheat and rice straw on field, after crop harvest, is a quick, cheap and an easy way for land clearing. The ashes generated after burning are mixed with soils and due to their alkaline nature, they may affect the degradation of applied herbicides. Therefore, present paper reports degradation of sulfosulfuron in aqueous suspension of the wheat (WSA) and rice (RSA) straw ashes. The results suggested that both ashes significantly enhanced sulfosulfuron dissipation in water and effect was more with the RSA. The solution pH affected sulfosulfuron dissipation and in control buffers (no ash) herbicide degradation followed the order: acidic > alkaline > neutral. Addition of the RSA significantly increased sulfosulfuron degradation in buffers, but effect was more evident at neutral and alkaline pH. The study has relevance in assessing degradation of sulfosulfuron in soils where crop residues are burned for land clearing.


Assuntos
Recuperação e Remediação Ambiental/métodos , Oryza/química , Pirimidinas/química , Poluentes do Solo/química , Sulfonamidas/química , Triticum/química , Herbicidas/química , Concentração de Íons de Hidrogênio , Suspensões
6.
J Enzyme Inhib Med Chem ; 34(1): 1186-1192, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282228

RESUMO

A series of sixteen benzenesulfonamide derivatives has been synthesised and tested as inhibitors of Vibrio cholerae carbonic anhydrase (CA) enzymes, belonging to α-CA, ß-CA, and γ-CA classes (VchCAα, VchCAß, and VchCAγ). The determined Ki values were compared to those of selected human CA isoforms (hCA I and hCA II). Structure-affinity relationship analysis highlighted that all tested compounds proved to be active inhibitors of VchCAα at nanomolar concentration. The VchCAß activity was lower to respect inhibitory efficacy toward VchCAα, whereas, these benzenesulfonamide derivatives failed to inhibit VchCAγ. Interestingly, compound 7e combined the best activity toward VchCAα and VchCAß. In order to obtain a model for binding mode of our inhibitors toward bacterial CAs, we carried out docking simulations by using the available crystal structures of VchCAß.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Cólera/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Inibidores da Anidrase Carbônica/química , Cólera/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Vibrio cholerae/enzimologia
7.
Chem Asian J ; 14(18): 3145-3148, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31359597

RESUMO

The N-acylsulfonamide group, known as a safety-catch linker, has been applied to photoaffinity labeling (PAL) using a cinnamate-type photocrosslinker to improve the efficiency of PAL-based target identification. A bioorthogonal sulfo-click reaction was used to stably link a photocrosslinker unit with N-acylsulfonamide linkage to produce a photoactivatable probe without any protection. In addition, the crosslinked protein was selectively isolated with a small cinnamate tag via linkage disruption upon N-alkylation. Furthermore, the tag moiety was photochemically converted to a stable coumarin derivative by losing a water molecule, which is a useful property in MS-based identification.


Assuntos
Cinamatos/química , Reagentes para Ligações Cruzadas/química , Marcadores de Fotoafinidade/química , Proteínas/análise , Sulfonamidas/química , Estrutura Molecular , Processos Fotoquímicos
8.
Eur J Med Chem ; 179: 547-556, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276899

RESUMO

Herein we report the design and synthesis of three different sets of novel benzenesulfonamides (5a-e, 7a-e and 10a-d) incorporating hydrophilic/hydrophobic tails by hydrazido or hydrazino linkers. The newly synthesized benzenesulfonamides were examined in vitro for their inhibitory activity towards four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the sulfonamides (5a-e, 7a-e and 10a-d) with variable degrees in the following KI ranges: 76.8-357.4 nM for hCA I, 8.2-94.6 nM for hCA II, 2.0-46.3 nM for hCA XI, and 8.3-88.3 nM for hCA XII. The sulfonamide 7d exhibited potent anti-proliferative activity against breast MCF-7 cancer cell line under both normoxic and hypoxic conditions with IC50 values equal 3.32 ±â€¯0.06 and 8.53 ±â€¯0.32 µM, respectively, which are comparable to the reference drug doxorubicin (IC50 = 2.36 ±â€¯0.04 and 8.39 ±â€¯0.25 µM, respectively). Furthermore, 7d was screened for cell cycle disturbance and apoptosis induction in MCF-7 cells. It was found to persuade cell cycle arrest at G2-M stage as well as to alter the Sub-G1 phase, also, 7d resulted in a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Molecular docking study was carried out for 7d within the hCA IX and hCA XII active sites to rationalize the obtained inhibition results.


Assuntos
Antineoplásicos/farmacologia , Benzeno/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzeno/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Domínio Catalítico/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
9.
J Agric Food Chem ; 67(31): 8459-8467, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31339701

RESUMO

Novel purine nucleoside derivatives containing a sulfonamide moiety were prepared, as well as their antiviral activities against potato virus Y (PVY), cucumber mosaic virus (CMV), and tobacco mosaic virus (TMV) were evaluated. The antiviral mechanisms of the compounds were investigated. Results showed that most of the compounds had good antiviral activities. Compound 5 at 500 µg/mL exhibited excellent curative and protective activities of 52.5% and 60.0% and of 52.0% and 60.2% for PVY and CMV, respectively, which are higher than those of ningnanmycin (48.1%, 49.6%; 45.3%, 47.7%), ribavirin (38.3%, 48.2%; 40.8%, 45.5%), and chitosan oligosaccharide (32.5%, 33.8%; 35.1%, 34.6%). Moreover, compound 5 displayed good inactivating activity against TMV, with an EC50 value of 48.8 µg/mL, which is better than that of ningnanmycin (84.7 µg/mL), ribavirin (150.4 µg/mL), and chitosan oligosaccharide (521.3 µg/mL). The excellent antiviral activity of compound 5 is related to its immune induction effect which can regulate the physiological and biochemical processes in plants, including defense-related enzyme activities, defense-related genes, and photosynthesis-related proteins. These results indicate that purine nucleoside derivatives containing a sulfonamide moiety are worthy of further research and development as new antiviral agents.


Assuntos
Antivirais/química , Antivirais/farmacologia , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Antivirais/síntese química , Cucumovirus/efeitos dos fármacos , Desenho de Drogas , Estrutura Molecular , Potyvirus/efeitos dos fármacos , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos
10.
J Sci Food Agric ; 99(14): 6167-6172, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31226227

RESUMO

BACKGROUND: Grape is an important fruit consumed either fresh or processed, therefore, fungicide misuse of grape has become an issue of global food safety and human health. Pyraclostrobin, and cyazofamid have been applied to grape frequently. RESULTS: Here a simple QuEChERS (quick, easy, cheap, effective, rugged, and safe) liquid chromatography mass spectrometry technique has been developed and validated for the determination of pyraclostrobin, cyazofamid and its metabolite CCIM in open field grape samples. The recoveries of these three in the range of 0.01 to 5 mg kg-1 (n = 5) ranged from 73.1% to 97.9%. The relative standard deviations (RSDs) were below 12% for all cases. The limits of quantitation of each analyte was 0.005 mg kg-1 , which was lower than maximum residue limits of not only pyraclostrobin but also cyazofamid. Not only dissipation kinetics but also residue determination was obtained in grape for those three pesticides. Furthermore, their half-lives in grapes were 10.7-30.1 days, recommending the pre-harvest intervals for these three of 14 days. The calculated hazard quotient and acute hazard index lower than 100% illustrated the safety of intake of grape for the Chinese population for not only long-term but also short-term dietary risk assessment. CONSLUSIONS: The less than 30 day half-life illustrated that pyraclostrobin and cyazofamid could degrade relatively easily in the environment. The long-term and short-term dietary risk assessment also illustrated the intake safety of these three. Thus, a 14 day pre-harvest interval was safe and recommended. The results of this study contributed to environmental protection, food safety and human health. © 2019 Society of Chemical Industry.


Assuntos
Resíduos de Drogas/química , Fungicidas Industriais/química , Imidazóis/química , Estrobilurinas/química , Sulfonamidas/química , Vitis/química , China , Qualidade de Produtos para o Consumidor , Resíduos de Drogas/metabolismo , Contaminação de Alimentos/análise , Frutas/química , Fungicidas Industriais/metabolismo , Meia-Vida , Humanos , Imidazóis/metabolismo , Cinética , Medição de Risco , Estrobilurinas/metabolismo , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem , Vitis/metabolismo
11.
J Enzyme Inhib Med Chem ; 34(1): 1199-1209, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237458

RESUMO

The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the "click-tail" approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with Kis in the range of 50.8-966.8 nM, while the glaucoma associated hCA II was inhibited with Kis in the range of 6.5-760.0 nM. Isoform hCA IV was inhibited with Kis in the range of 65.3-957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with Kis in the range of 30.8-815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.


Assuntos
Inibidores da Anidrase Carbônica/síntese química , Isoenzimas/antagonistas & inibidores , Sulfonamidas/farmacologia , Triazóis/química , Triazóis/farmacologia , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/química , Relação Estrutura-Atividade , Sulfonamidas/química
12.
Int J Mol Sci ; 20(9)2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083645

RESUMO

Novel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII over hCA I and II. Six compounds showed KI values lower than 10 nM against hCA IX or XII. Molecular modeling studies were performed to suggest binding interactions between the ligand and the hCA active sites.


Assuntos
Antineoplásicos/síntese química , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Humanos , Hidrazonas/química , Indóis/química , Simulação de Acoplamento Molecular , Ligação Proteica , Sulfonamidas/química
13.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137489

RESUMO

In this work, we present the synthesis and biological evaluation of novel series of diamide-based benzenesulfonamides 5a-h as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were undeniably the most affected ones (KIs: 8.3-123.3 and 9.8-134.5 nM, respectively). Notably, diamides 5a and 5h stood out as a single-digit nanomolar hCA IX inhibitors (KIs = 8.8 and 8.3 nM). The SAR outcomes highlighted that bioisosteric replacement of the benzylidene moiety, compounds 5a-g, with the hetero 2-furylidene moiety, compound 5h, achieved the best IX/I and IX/II selectivity herein reported with SIs of 985 and 13.8, respectively. Molecular docking simulations of the prepared diamides within CA IX active site revealed the ability of 5h to establish an additional H-bond between the heterocyclic oxygen and HE/Gln67. Moreover, benzenesulfonamides 5a, 5b and 5h were evaluated for their antitumor activity against renal cancer UO-31 cell line. Compound 5h was the most potent derivative with about 1.5-fold more enhanced activity (IC50 = 4.89 ± 0.22 µM) than the reference drug Staurosporine (IC50 = 7.25 ± 0.43 µM). Moreover, 5a and 5h were able to induce apoptosis in UO-31 cells as evidenced by the significant increase in the percent of annexinV-FITC positive apoptotic cells by 22.5- and 26.5-folds, respectively.


Assuntos
Antineoplásicos/síntese química , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/química , Antineoplásicos/farmacologia , Derivados de Benzeno/química , Sítios de Ligação , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica
14.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052167

RESUMO

Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC50 of 0.86 ± 0.02 µM than Celecoxib (IC50 = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Drogas , Oxigênio/química , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo , Inibidores de Ciclo-Oxigenase 2/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirazóis/síntese química , Relação Quantitativa Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Eur J Med Chem ; 174: 252-264, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31048140

RESUMO

The superfamily of adenylate-forming enzymes all share a common chemistry. They activate a carboxylate group, on a specific substrate, by catalyzing the formation of a high energy mixed phosphoanhydride-linked nucleoside intermediate. Members of this diverse enzymatic family play key roles in a variety of metabolic pathways and therefore many have been regarded as drug targets. A generic approach to inhibit such enzymes is the use of non-hydrolysable sulfur-based bioisosteres of the adenylate intermediate. Here we compare the activity of compounds containing a sulfamoyl and sulfonamide linker respectively. An improved synthetic strategy was developed to generate inhibitors containing the latter that target isoleucyl- (IleRS) and seryl-tRNA synthetase (SerRS), two structurally distinct representatives of Class I and II aminoacyl-tRNA synthetases (aaRSs). These enzymes attach their respective amino acid to its cognate tRNA and are indispensable for protein translation. Evaluation of the ability of the two similar isosteres to inhibit serRS revealed a remarkable difference, with an almost complete loss of activity for seryl-sulfonamide 15 (SerSoHA) compared to its sulfamoyl analogue (SerSA), while inhibition of IleRS was unaffected. To explain these observations, we have determined a 2.1 Šcrystal structure of Klebsiella pneumoniae SerRS in complex with SerSA. Using this structure as a template, modelling of 15 in the active site predicts an unfavourable eclipsed conformation. We extended the same modelling strategy to representative members of the whole adenylate-forming enzyme superfamily, and were able to disclose a new classification system for adenylating enzymes, based on their protein fold. The results suggest that, other than for the structural and functional orthologues of the Class II aaRSs, the O to C substitution within the sulfur-sugar link should generally preserve the inhibitory potency.


Assuntos
Adenosina/análogos & derivados , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Inibidores Enzimáticos/química , Sulfonamidas/química , Adenosina/síntese química , Aminoacil-tRNA Sintetases/química , Aminoacilação , Bacillus subtilis/enzimologia , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Klebsiella pneumoniae/enzimologia , Modelos Moleculares , Mycobacterium tuberculosis/enzimologia , Pectobacterium chrysanthemi/enzimologia , Sulfolobus/enzimologia , Sulfonamidas/síntese química , Thermus thermophilus/enzimologia
16.
Talanta ; 201: 111-118, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122400

RESUMO

Thiophenols as high toxic environmental pollutants are poisonous for animals and aquatic organisms. Therefore, it is indispensable to monitor thiophenols in the environment. Herein, a novel near-infrared fluorescent probe was developed for the detection of thiophenols, which was easily prepared by one-step coupling of 2,4-dinitrobenzenesulfonyl chloride with Nile blue. The probe showed a significant near infrared (∼675 nm) fluorescence "turn-on" response to thiophenols with some good features including chromogenic reaction, high sensitivity and selectivity, fast response, near-infrared emission along with low detection limit (1.8 nM). The probe was employed to rapidly and visually determine thiophenols in several industrial wastewaters with good recoveries (90-110%). Moreover, this probe has been demonstrated good capability for imaging thiophenol in HeLa cells.


Assuntos
Corantes Fluorescentes/química , Oxazinas/química , Fenóis/análise , Compostos de Sulfidrila/análise , Sulfonamidas/química , Águas Residuárias/análise , Poluentes Químicos da Água/análise , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Limite de Detecção , Microscopia Confocal/métodos , Modelos Químicos , Oxazinas/síntese química , Oxazinas/efeitos da radiação , Oxazinas/toxicidade , Espectrometria de Fluorescência/métodos , Sulfonamidas/síntese química , Sulfonamidas/efeitos da radiação , Sulfonamidas/toxicidade
17.
J Enzyme Inhib Med Chem ; 34(1): 1030-1040, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074303

RESUMO

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Radiossensibilizantes/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
18.
J Enzyme Inhib Med Chem ; 34(1): 1051-1061, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074307

RESUMO

A large library of fibrate-based N-acylsulphonamides was designed, synthesised, and fully characterised in order to propose them as zinc binders for the inhibition of human carbonic anhydrase (hCA) enzymatic activity. Synthesised compounds were tested against four hCAs (I, II, IX, and XII) revealing a promising submicromolar inhibitory activity characterised by an isozyme selectivity pattern. Structural modifications explored within this scaffold are: presence of an aryl ring on the sulphonamide, p-substitution of this aryl ring, benzothiazole or benzophenone as core nuclei, and an n-propyl chain or a geminal dimethyl at Cα carbon. Biological results fitted well with molecular modelling analyses, revealing a putative direct interaction with the zinc ion in the active site of hCA I, II and IX. These findings supported the exploration of less investigated secondary sulphonamides as potential hCA inhibitors.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Domínio Catalítico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
19.
Chem Commun (Camb) ; 55(40): 5720-5723, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31038135

RESUMO

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigated in vitro as a human (h) Carbonic Anhydrase Inhibitor (CAI). The kinetic data clearly show, for the first time, EPA to be a highly effective and selective inhibitor for the tumor-associated isoforms hCA IX/XII. We report the high resolution X-ray crystal structure of the EPA-hCA II adduct, and assessed its binding mode to CA IX/XII by means of computational techniques. EPA may exert antitumor effects also due to the potent inhibition of the tumor-associated CAs.


Assuntos
Anidrase Carbônica IX/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Neoplasias/enzimologia , Oximas/farmacologia , Polifarmacologia , Sulfonamidas/farmacologia , Anidrase Carbônica IX/química , Anidrases Carbônicas/química , Domínio Catalítico , Cristalografia por Raios X , Humanos , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/química , Sulfonamidas/química
20.
Comput Biol Chem ; 80: 292-306, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31054542

RESUMO

Human meprin beta metalloprotease, a small subgroup of the astacin family, is a potent drug target for the treatment of several disorders such as fibrosis, neurodegenerative disease in particular Alzheimer and inflammatory bowel diseases. In this study, a ligand-based pharmacophore approach has been used for the selection of potentially active compounds to understand the inhibitory activities of meprin-ß by using the sulfonamide scaffold based inhibitors. Using this dataset, a pharmacophore model (Hypo1) was selected on the basis of a highest correlation coefficient (0.959), lowest total cost (105.89) and lowest root mean square deviation (1.31 Å) values. All the pharmacophore hypotheses generated from the candidate inhibitors comprised four features: two hydrogen-bond acceptor, one hydrogen-bond donor and one zinc binder feature. The best validated pharmacophore model (Hypo1) was used for virtual screening of compounds from several databases. The selective hit compounds were filtered by drug likeness property, acceptable ADMET profile, molecular docking and DFT study. Molecular dynamic simulations with the final 10 hit compounds revealed that a large number of non-covalent interactions were formed with the active site and specificity sub-pockets of the meprin beta metalloprotease. This study assists in the development of the new lead molecules as well as gives a better understanding of their interaction with meprin-ß.


Assuntos
Metaloendopeptidases/química , Inibidores de Proteases/química , Sulfonamidas/química , Domínio Catalítico , Conjuntos de Dados como Assunto , Teoria da Densidade Funcional , Desenho de Drogas , Humanos , Ligantes , Metaloendopeptidases/metabolismo , Modelos Químicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/metabolismo , Ligação Proteica , Sulfonamidas/metabolismo
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