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1.
Yakugaku Zasshi ; 140(9): 1087-1094, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879240

RESUMO

This review, based on my research work, introduces and summarizes the synthesis and characterization of novel cyclic compounds containing aminobenzenesulfonamide. The review discusses the (1) development of sequential Nicholas and Pauson-Khand reactions for the synthesis of unique polyheterocyclic compounds, (2) production of 2-aminobenzenesulfonamide-containing cyclononyne (ABSACN) as a multifunctional click cycloalkyne agent, and (3) improvement of the intramolecular Pauson-Khand reaction of the nitroarene-enyne substrate for the synthesis of cyclopenta[c]piperidine alkaloids. This research work will facilitate the discovery of sulfonamide or sultam-based functional molecules and pharmaceuticals. Thus, I believe that aminobenzenesulfonamide derivatives are versatile and valuable chemical moieties not only in organic syntheses but also in the pharmaceutical industry. If you are interested in the details of this topic, please refer to the original papers.


Assuntos
Sulfonamidas/síntese química , Ciclização , Cicloparafinas/síntese química , Fenômenos de Química Orgânica , Piperidinas/síntese química , Sulfonamidas/química
2.
Nat Commun ; 11(1): 3859, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737298

RESUMO

Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases. Protein-responsive soft materials capable of the controlled release of drugs and proteins have potential for use in next-generation diagnosis and therapies. Here, we describe a supramolecular/agarose hydrogel composite that can release a protein in response to a non-enzymatic protein. A non-enzymatic protein-responsive system is developed by hybridization of an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation set. In situ imaging shows that the supramolecular/agarose hydrogel composite consists of orthogonal domains of supramolecular fibers and agarose, which play distinct roles in protein entrapment and mechanical stiffness, respectively. Integrating the enzyme activation set with the composite allows for controlled release of the embedded RNase in response to an antibody. Such composite hydrogels would be promising as a matrix embedded in a body, which can autonomously release biopharmaceuticals by sensing biomarker proteins.


Assuntos
Anidrase Carbônica II/química , Preparações de Ação Retardada/síntese química , Hidrogéis/química , Ribonucleases/química , Sefarose/química , Animais , Anticorpos/química , Avidina/química , Biotina/química , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Bovinos , Ativação Enzimática , Transição de Fase , Reologia , Ribonucleases/antagonistas & inibidores , Sulfonamidas/química
3.
J Chromatogr A ; 1625: 461275, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709327

RESUMO

Efficient extraction of polar sulfonamides antibiotics from aqueous samples and food is very challenging, because they are hydrophilic, their concentration is very low, and the matrix is complex. Covalent organic frameworks (COFs), a novel porous organic material, have attracted great attention. In this work, the spherical triphenylbenzene-dimethoxyterephthaldehyde-COFs (TPB-DMTP-COFs) were synthesized by a simple room temperature method, and due to their attractive properties, such as high outstanding acid-base stability, large specific surface area, low skeletal density, inherent porosity and high crystallinity, so TPB-DMTP-COFs as ideal solid phase extraction adsorbents showed excellent adsorption performance for trace polar sulfonamides in food and water. TPB-DMTP-COFs were characterized by scanning electron microscopy, Fourier-transform infrared spectroscopy, powder X-ray diffraction, and so on. The important parameters were optimized to improve the extraction efficiency of TPB-DMTP-COFs toward sulfonamides. Analysis of sulfonamides was performed by liquid chromatography-tandem mass spectrometry. The developed method based on TPB-DMTP-COFs material achieved low limits of detection (0.5-1.0 ng L-1), wide linearity (5-1000 ng L-1), and good repeatability (2.5%-8.7%). The possible extraction mechanism was also discussed. Finally, the method was successfully applied to the enrichment and detection of sulfonamides in environmental water samples and food samples. The present study indicated that TPB-DMTP-COFs had splendid prospects in highly sensitive analysis of other pollutants in complex matrix.


Assuntos
Análise de Alimentos , Estruturas Metalorgânicas/química , Extração em Fase Sólida/métodos , Sulfonamidas/análise , Espectrometria de Massas em Tandem/métodos , Poluentes Químicos da Água/análise , Adsorção , Animais , Cromatografia Líquida , Contaminação de Alimentos/análise , Leite/química , Carne de Porco/análise , Porosidade , Sulfonamidas/química , Água/química
4.
PLoS One ; 15(7): e0235483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697773

RESUMO

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.


Assuntos
Inibidores Enzimáticos/química , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Piperidinas/farmacologia , Cristalografia por Raios X , Darunavir/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Infecções por HIV/virologia , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/química , HIV-1/patogenicidade , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
5.
J Chromatogr A ; 1624: 461180, 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32540058

RESUMO

The basis of interpretive optimisation in liquid chromatography is the prediction of resolution, from appropriate solute retention models. The reliability of the process depends critically on the quality of the experimental design. This work develops, validates and applies a general methodology aimed to evaluate the quality of any training experimental design, which will be applied in Part II to design optimisation. The methodology is based on the systematic evaluation of the uncertainties associated to the prediction of retention times in comprehensive scans of both isocratic and gradient experimental conditions. It is able to evaluate comprehensively experimental designs of arbitrary complexity. Five common training experimental designs were used to model the retention, according to the Linear Solvent Strength (LSS) and the Neue-Kuss (NK) equations, using a set of 14 sulphonamides of different polarity. The results are presented in terms of relative uncertainties in predictions, which provide significant and interpretable results. The magnitude of such uncertainties, together with the systematic, coherent and logical changes observed at increasing solute hydrophobicity, give support to the results. The NK model gave smaller errors and unbiased predictions, whereas the LSS model gave rise to lack of fit. Isocratic training designs, which are widely accepted as the most informative, are confirmed as the best. As a general conclusion, gradients are predicted with intrinsically smaller uncertainties, independently of the training experimental design. In addition, gradients are more insensitive than isocratic predictions with regard to the type of training design used. Isocratic predictions deteriorate quickly with mobile phase composition. This explains the better performance of gradient predictions, even with biased models.


Assuntos
Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Projetos de Pesquisa , Solventes/química , Sulfonamidas/química
6.
Virus Res ; 286: 198068, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32565126

RESUMO

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.


Assuntos
Antivirais/química , Betacoronavirus/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Indóis/química , Perileno/análogos & derivados , Glicoproteína da Espícula de Coronavírus/química , Sulfonamidas/química , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Expressão Gênica , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Indóis/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Perileno/química , Perileno/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Sulfonamidas/farmacologia , Termodinâmica , Interface Usuário-Computador , Internalização do Vírus/efeitos dos fármacos
7.
Nat Struct Mol Biol ; 27(7): 605-614, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541897

RESUMO

Controlled perturbation of protein activity is essential to study protein function in cells and living organisms. Small molecules that hijack the cellular protein ubiquitination machinery to selectively degrade proteins of interest, so-called degraders, have recently emerged as alternatives to selective chemical inhibitors, both as therapeutic modalities and as powerful research tools. These systems offer unprecedented temporal and spatial control over protein function. Here, we review recent developments in this field, with a particular focus on the use of degraders as research tools to interrogate complex biological problems.


Assuntos
Descoberta de Drogas/métodos , Fatores Imunológicos/farmacologia , Proteínas/metabolismo , Humanos , Fatores Imunológicos/química , Ácidos Indolacéticos/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Ubiquitinação/efeitos dos fármacos
8.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: covidwho-459137

RESUMO

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Assuntos
Betacoronavirus/enzimologia , Maraviroc/farmacologia , Inibidores de Proteases/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Maraviroc/química , Maraviroc/metabolismo , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
9.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: covidwho-343226

RESUMO

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Assuntos
Betacoronavirus/enzimologia , Maraviroc/farmacologia , Inibidores de Proteases/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Maraviroc/química , Maraviroc/metabolismo , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
10.
Nat Commun ; 11(1): 2528, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32433521

RESUMO

Arene dearomatization reactions are an important class of synthetic technologies for the rapid assembly of unique chemical architectures. Herein, we report a catalytic protocol to initiate a carboamination/dearomatization cascade that proceeds through transient sulfonamidyl radical intermediates formed from native sulfonamide N-H bonds leading to 1,4-cyclohexadiene-fused sultams. Importantly, this work demonstrates a facile approach to employ two-dimensional aromatic compounds as modular building blocks to generate richly substituted, three-dimensional compounds. These reactions occur at room temperature under visible light irradiation and are catalyzed by the combination of an iridium(III) photocatalyst and a dialkyl phosphate base. Reaction optimization, substrate scope, mechanistic features, and synthetic applications of this transformation are presented.


Assuntos
Radicais Livres/química , Irídio/química , Catálise/efeitos da radiação , Ligação de Hidrogênio , Luz , Estrutura Molecular , Fosfatos/química , Sulfonamidas/química
11.
Int J Nanomedicine ; 15: 3161-3180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440116

RESUMO

Aim: With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects. Materials and Methods: Novel quinazolinone-benzenesulfonamide derivatives 5-18 were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound 16 was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV-Visible, TEM examination, XRD patterns and DLS. Moreover, compound 16 was used to synthesize two nanoformulations: 16-CNPs by loading 16 in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against Staphylococcus aureus DNA gyrase was assayed. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of 16 was performed inside the active site of S. aureus DNA gyrase. Results: Compound 16 was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25-36 mm and 0.31-5.0 µg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of 16 and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against S. aureus DNA gyrase showed IC50 ranging from 10.57 to 27.32 µM. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC50= 927, 543 and 637 µg/mL, respectively). Molecular docking of 16 inside the active site of S. aureus DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin. Conclusion: Compound 16 could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.


Assuntos
Antibacterianos/farmacologia , Quinazolinonas/farmacologia , Sulfonamidas/farmacologia , Tioacetamida/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Cobre/farmacologia , DNA Girase/metabolismo , Raios gama , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Quinazolinonas/síntese química , Quinazolinonas/química , Sulfonamidas/síntese química , Sulfonamidas/química , Tioacetamida/síntese química , Tioacetamida/química , Inibidores da Topoisomerase II/farmacologia
12.
An Acad Bras Cienc ; 92(1): e20181021, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401841

RESUMO

Fosamprenavir calcium is an amprenavir prodrug of the protease inhibitors class used in the treatment of patients with acquired immunodeficiency syndrome (AIDS). Different solid forms of this drug are described in patents, in this sense studies on the physico-chemical characterization and stability are relevant for the selection of a solid form with adequate features for pharmaceutical purposes. In the present work form I (commercial) and amorphous of fosamprenavir calcium were characterized by the techniques of Differential Scanning Calorimetry (DSC), Thermogravimetry (TGA), Powder X-ray Diffraction (PXRD), Fourier-Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). Furthermore, the chemical and polymorphic stability of the commercial form were evaluated by DSC, PXRD, FTIR and High-Performance Liquid Chromatography (HPLC). In the studies of characterization, thermal analyses allied to spectroscopic methods (PXRD and FTIR) demonstrated that the presence of water in the crystalline structure of Form I is fundamental for maintaining its crystallinity. In studies of accelerated stability the techniques of DSC, PXRD and FTIR showed that Form I does not suffer phase change when submitted to controlled conditions of temperature and humidity. Moreover, HPLC and FTIR proved the chemical stability of this solid form of fosamprenavir, thus demonstrating its suitability for pharmaceutical purposes.


Assuntos
Carbamatos/química , Organofosfatos/química , Preparações Farmacêuticas/análise , Sulfonamidas/química , Tecnologia Farmacêutica/métodos , Umidade , Microscopia Eletrônica de Varredura , Análise Espectral/métodos , Temperatura , Termodinâmica
13.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32441299

RESUMO

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Assuntos
Betacoronavirus/enzimologia , Maraviroc/farmacologia , Inibidores de Proteases/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Maraviroc/química , Maraviroc/metabolismo , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
14.
J Med Chem ; 63(10): 5185-5200, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32364386

RESUMO

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/toxicidade , Animais , Antineoplásicos/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Temperatura Baixa/efeitos adversos , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
15.
Mol Pharmacol ; 97(6): 355-364, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32241959

RESUMO

Voltage-gated potassium 11.1 (Kv11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g., dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use because of their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-Kv11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 µM dofetilide or 10 µM dofetilide + 5 µM LUF7244. In trafficking defective G601S-Kv11.1 cells, dofetilide (10 µM) or dofetilide + LUF7244 (10 + 5 µM) also restored Kv11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 µM) increased IKv 11.1 despite the presence of dofetilide (1 µM) in WT Kv11.1 cells. In G601S-expressing cells, long-term treatment (24-48 hour) with LUF7244 (10 µM) and dofetilide (1 µM) increased IKv11.1 compared with nontreated or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1 Thus, combined administration of LUF7244 and an IKv11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects. SIGNIFICANCE STATEMENT: Decreased levels of functional Kv11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of Kv11.1 channel protein is an important factor in acquired and congenital long QT syndrome. LUF7244 as a negative allosteric modulator/activator in combination with dofetilide corrected both congenital and acquired Kv11.1 trafficking defects, resulting in functional Kv11.1 current.


Assuntos
Antiarrítmicos/farmacologia , Canal de Potássio ERG1/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/química , Western Blotting , Simulação por Computador , Sinergismo Farmacológico , Canal de Potássio ERG1/fisiologia , Células HEK293 , Humanos , Microscopia de Fluorescência , Modelos Moleculares , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Compostos Orgânicos/química , Fenetilaminas/química , Bloqueadores dos Canais de Potássio/química , Sulfonamidas/química
16.
Nat Commun ; 11(1): 1996, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332723

RESUMO

Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.


Assuntos
Envelhecimento/efeitos dos fármacos , Compostos de Anilina/farmacologia , Plaquetas/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Compostos de Anilina/química , Animais , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Cultura Primária de Células , Proteólise/efeitos dos fármacos , Sulfonamidas/química , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismo
17.
J Med Chem ; 63(8): 4306-4314, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223141

RESUMO

We report for the first time a novel series of tellurides bearing sulfonamide as selective and potent inhibitors of the ß-class carbonic anhydrase (CA; EC 4.2.1.1) enzyme expressed in Leishmania donovani protozoa. Such derivatives showed high activity against axenic amastigotes, and among them, compound 5g (4-(((3,4,5-trimethoxyphenyl)tellanyl)methyl)benzenesulfonamide) showed an IC50 of 0.02 µM being highly selective for the parasites over THP-1 cells with a selectivity index of 300. The in vitro and in vivo toxicity experiments showed compound 5g to possess a safe profile and thus paving the way for tellurium-containing compounds as novel drug entities.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Leishmania donovani/efeitos dos fármacos , Sulfonamidas/farmacologia , Tripanossomicidas/farmacologia , Animais , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Feminino , Jejuno/efeitos dos fármacos , Jejuno/patologia , Leishmania donovani/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Sulfonamidas/química , Tripanossomicidas/química
18.
J Med Chem ; 63(10): 5212-5241, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32321240

RESUMO

Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/antagonistas & inibidores , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Sulfonamidas/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Células HEK293 , Humanos , Ligação Proteica/fisiologia , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/fisiologia , Estrutura Secundária de Proteína , Sulfonamidas/química , Sulfonamidas/farmacologia
19.
J Environ Sci Health B ; 55(7): 630-645, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32338140

RESUMO

Effect of the wheat straw ash (WSA) on pretilachlor and the rice straw ash (RSA) on sulfosulfuron kinetics and adsorption behavior was studied. Kinetics study suggested that adsorption of herbicides in soil/soil + 0.2% ash mixture was best explained by the pseudo second order model. Ashes at 0.1%-0.5% levels increased adsorption of respective herbicide; but, effect varied with ash content and soil type. Effect of ash (0.2%) on herbicide's adsorption was more in the sandy loam soil (144%-188%) than in the clay loam soil (112%-122%) suggesting masking of ash particles. The Freundlich adsorption isotherm explained the adsorption of herbicides in the soils/soil + ash mixtures and sorption was highly nonlinear as 1/n (slope) values varied between 0.57 and 1.25 for pretilachlor and 0.32 and 0.77 for sulfosulfuron. Adsorption increased with increase in temperature. High surface area unburnt carbon in ashes was responsible for increase in adsorption and decrease in desorption of herbicides in ash mixed soils. The pH of soil/soil + ash mixtures affected herbicide adsorption, but effect was significant for pretilachlor. The negative free energy change (ΔG) values suggested that the sorption process was exothermic and spontaneous in nature. This study has implications in identifying the role of crop residue burning on fate of herbicides applied in succeeding crop.


Assuntos
Produtos Agrícolas/química , Herbicidas/química , Poluentes do Solo/química , Acetanilidas/química , Adsorção , Carbono , Argila , Índia , Cinética , Oryza/química , Pirimidinas/química , Solo/química , Sulfonamidas/química , Triticum/química
20.
Chemistry ; 26(34): 7631-7637, 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32187755

RESUMO

Bis-sulfonamide bis-amide TAML activator [Fe{4-NO2 C6 H3 -1,2-(NCOCMe2 NSO2 )2 CHMe}]- (2) catalyzes oxidative degradation of the oxidation-resistant neonicotinoid insecticide, imidacloprid (IMI), by H2 O2 at pH 7 and 25 °C, whereas the tetrakis-amide TAML [Fe{4-NO2 C6 H3 -1,2-(NCOCMe2 NCO)2 CF2 }]- (1), previously regarded as the most catalytically active TAML, is inactive under the same conditions. At ultra-low concentrations of both imidacloprid and 2, 62 % of the insecticide was oxidized in 2 h, at which time the catalyst is inactivated; oxidation resumes on addition of a succeeding aliquot of 2. Acetate and oxamate were detected by ion chromatography, suggesting deep oxidation of imidacloprid. Explored at concentrations [2]≥[IMI], the reaction kinetics revealed unusually low kinetic order in 2 (0.164±0.006), which is observed alongside the first order in imidacloprid and an ascending hyperbolic dependence in [H2 O2 ]. Actual independence of the reaction rate on the catalyst concentration is accounted for in terms of a reversible noncovalent binding between a substrate and a catalyst, which usually results in substrate inhibition when [catalyst]≪[substrate] but explains the zero order in the catalyst when [2]>[IMI]. A plausible mechanism of the TAML-catalyzed oxidations of imidacloprid is briefly discussed. Similar zero-order catalysis is presented for the oxidation of 3-methyl-4-nitrophenol by H2 O2 , catalyzed by the TAML analogue of 1 without a NO2 -group in the aromatic ring.


Assuntos
Complexos de Coordenação/química , Ferro/química , Neonicotinoides/química , Nitrocompostos/química , Sulfonamidas/química , Amidas/química , Catálise , Cinética , Oxirredução , Praguicidas
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