Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.977
Filtrar
1.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652837

RESUMO

In search of anti-inflammatory compounds, novel scaffolds containing isonicotinoyl motif were synthesized via an efficient strategy. The compounds were screened for their in vitro anti-inflammatory activity. Remarkably high activities were observed for isonicotinates 5-6 and 8a-8b. The compound 5 exhibits an exceptional IC50 value (1.42 ± 0.1 µg/mL) with 95.9% inhibition at 25 µg/mL, which is eight folds better than the standard drug ibuprofen (11.2 ± 1.9 µg/mL). To gain an insight into the mode of action of anti-inflammatory compounds, molecular docking studies were also performed. Decisively, further development and fine tuning of these isonicotinates based scaffolds for the treatment of various aberrations is still a wide-open field of research.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Inflamação/tratamento farmacológico , Ácidos Isonicotínicos/síntese química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Ibuprofeno/química , Ácidos Isonicotínicos/química , Ácidos Isonicotínicos/farmacologia , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/química , Relação Estrutura-Atividade
2.
AAPS PharmSciTech ; 22(3): 85, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33650023

RESUMO

In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.


Assuntos
Composição de Medicamentos/métodos , Naproxeno/administração & dosagem , Naproxeno/síntese química , Tecnologia Farmacêutica/métodos , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Formas de Dosagem , Liberação Controlada de Fármacos , Excipientes/administração & dosagem , Excipientes/síntese química , Excipientes/farmacocinética , Naproxeno/farmacocinética , Comprimidos
3.
AAPS PharmSciTech ; 22(3): 106, 2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33719021

RESUMO

Masking the unpleasant taste of the pharmaceutically active ingredients plays a critical role in patient acceptance, particularly for children. This work's primary objective was the preparation of taste-masked ibuprofen microparticles using cocoa butter with the assistance of supercritical fluid technology. Microparticles were prepared by dissolving ibuprofen in melted cocoa butter at 40 °C. The solution was then introduced into a supercritical fluid unit and processed at 10 MPa CO2 pressure for 30 min. The product was collected after depressurizing the system. The effect of the drug to cocoa butter ratio and the supercritical fluid units' configuration on product quality was evaluated and compared with the sample prepared by a conventional method. Physicochemical characterization of the prepared product, including particle size, crystallinity, entrapment efficiency, in vitro drug release, and product taste using a human volunteer panel was conducted. The produced microparticles were in the range of 1.42 to 15.28 µm. The entrapment efficiency of the formulated microparticles ranged from 66 to 81%. The drug:polymer ratio, the configuration of the supercritical fluid unit, and the method of preparation were found to have a critical role in the formulation of ibuprofen microparticles. Taste evaluation using human volunteers showed that microparticles containing 20% drug and processed with supercritical fluid technology were capable of masking the bitter taste of ibuprofen. In conclusion, the dispersion of ibuprofen in cocoa butter using supercritical fluid technology is a a promising innovative method to mask the bitter taste of ibuprofen.


Assuntos
Dióxido de Carbono/química , Cromatografia com Fluido Supercrítico/métodos , Gorduras na Dieta/síntese química , Desenvolvimento de Medicamentos/métodos , Ibuprofeno/síntese química , Paladar/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacocinética , Humanos , Ibuprofeno/administração & dosagem , Ibuprofeno/farmacocinética , Tamanho da Partícula , Paladar/fisiologia , Difração de Raios X/métodos
4.
SAR QSAR Environ Res ; 31(10): 761-784, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32867537

RESUMO

The free COOH group of conventional NSAIDs is a structural feature for non-selective cyclooxygenase (COX) inhibition and the molecular cause of their gastrointestinal (GI) toxicity. In this context, an in house database of synthesizable ester prodrugs of some well-known NSAIDs was developed by combining their -COOH group with -OH of a newly identified antioxidant 4-(1H-benzo[d]imidazol-2-yl)phenol (BZ). The antioxidant potential of BZ was unveiled through in silico PASS prediction and in vitro/in vivo evaluation. The in house database of NSAIDs-BZ prodrugs was first subjected to screening with our previously reported pharmacophore models of hCES1 (AAHRR.430) and hCES2 (AHHR.21) for determining hydrolytic susceptibility. Biotransformation behaviour of screened prodrugs was then assessed by using QM/MM and sterimol parameterization, followed by ADMET calculations to predict the drug likeness. On the basis of in silico results, five prodrugs were duly synthesized and the best three were subject to the in vivo evaluation for their anti-inflammatory, analgesic, antioxidant activities, and ulcerogenic index. Among these prodrugs, BN2 and BN5 displayed better anti-inflammatory and analgesics potential in comparison to their parent drugs. All the prodrugs were found to be gastro sparing in the rat model and significantly improved the levels of oxidative stress biomarkers in both blood plasma as well as gastric homogenate.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Imidazóis/química , Fenóis/química , Pró-Fármacos/síntese química , Relação Quantitativa Estrutura-Atividade , Simulação por Computador
5.
Eur J Med Chem ; 193: 112216, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208222

RESUMO

Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 µM (IC50 = 6.4 µM) with the lowest cytotoxicity (IC50 > 80 µM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Chalconas/farmacologia , Desenvolvimento de Medicamentos , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/induzido quimicamente , Artrite/metabolismo , Células Cultivadas , Chalconas/síntese química , Chalconas/química , Doença Crônica , Colágeno , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 193: 112217, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182488

RESUMO

Because of the complex etiology in neuroinflammatory process, the design of multifunctional agents is a potent strategy to cure neuroinflammatory diseases including AD and PD. Herein, based on the combination principles, 23 of N-salicyloyl tryptamine derivatives as multifunctional agents were designed and their new application for anti-neuroinflammation was disclosed. In cyclooxygenase assay, two compounds 3 and 16 displayed extremely preferable COX-2 inhibition than N-salicyloyl tryptamine. In LPS-induced C6 and BV2 cell models, some compounds decreased the production of proinflammatory mediators NO, PGE2, TNF-α, iNOS, COX-2 and ROS, while increased the production of IL-10. Among them, compound 3 and 16 showed approximately six-fold better inhibition on nitric oxide production than N-salicyloyl tryptamine in C6. Besides, compounds 3, 13 and 16 attenuated the activation of BV2 and C6 cells. More importantly, in vivo, compounds 3 and 16 reduced GFAP and Iba-1 levels in the hippocampus, and displayed neuroprotection in Nissl staining. Besides, both compounds 3 and 16 had high safety (LD50 > 1000 mg/kg). Longer plasma half-life of compounds 3 and 16 than melatonin supported combination strategy. All these results demonstrated that N-salicyloyl tryptamine derivatives are potential anti-neuroinflammation agents for the treatment of neurodegenerative disorder.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Triptaminas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química
7.
J Enzyme Inhib Med Chem ; 35(1): 610-621, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32013633

RESUMO

Cyclic imides containing 3-benzenesulfonamide, oxime, and ß-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2-4, and 9), oximes (11-13), and ß-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2-82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED50 of 35.4-45.3 mg kg-1 relative to that of celecoxib (34.1 mg kg-1). For the cytotoxic evaluation, the selected derivatives 2-6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59-5/59) at 10 µM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2-5, and 9), acetophenone oxime (11-14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6-333.3 relative to that for celecoxib [SI > 387.6]. ß-Phenylalanine derivatives 21-24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46-0.68.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Imidas/farmacologia , Oximas/farmacologia , Fenilalanina/farmacologia , Sulfonamidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Edema/tratamento farmacológico , Humanos , Imidas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/química , Fenilalanina/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química
8.
J Med Chem ; 63(2): 714-746, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31904959

RESUMO

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Quimiocina CCL2/biossíntese , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
9.
Eur J Med Chem ; 188: 111955, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31893550

RESUMO

Selective kinase inhibitors development is a cumbersome task because of ATP binding sites similarities across kinases. On contrast, irreversible allosteric covalent inhibition offers opportunity to develop novel selective kinase inhibitors. Previously, we reported thiazolidine-2,4-dione lead compounds eliciting in vitro irreversible allosteric inhibition of IKK-ß. Herein, we address optimization into in vivo active anti-inflammatory agents. We successfully developed potent IKK-ß inhibitors with the most potent compound eliciting IC50 = 0.20 µM. Cellular assay of a set of active compounds using bacterial endotoxin lipopolysaccharide (LPS)-stimulated macrophages elucidated significant in vitro anti-inflammatory activity. In vitro evaluation of microsomal and plasma stabilities showed that the promising compound 7a is more stable than compound 7p. Finally, in vivo evaluation of 7a, which has been conducted in a model of LPS-induced septic shock in mice, showed its ability to protect mice against septic shock induced mortality. Accordingly, this study presents compound 7a as a novel potential irreversible allosteric covalent inhibitor of IKK-ß with verified in vitro and in vivo anti-inflammatory activity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Tiazolidinedionas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Quinase I-kappa B/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células RAW 264.7 , Choque Séptico/tratamento farmacológico , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
10.
Arch Pharm (Weinheim) ; 353(3): e1900295, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31944384

RESUMO

Some novel derivatives of 2-alkyl 6-substituted pyridazin-3(2H)-ones were synthesized by condensation of 3,6-dichloropyridazine with the sodium salt of benzyl cyanide, followed by hydrolysis and coupling with alkyl halides. The synthesized compounds were screened as cyclooxygenase (COX)-1/COX-2 inhibitors and as analgesic and anti-inflammatory agents. Among the synthesized compounds, 6-benzyl-2-methylpyridazin-3(2H)-one (4a), 6-benzoyl-2-propylpyridazin-3(2H)-one (8b), and 6-(hydroxy(phenyl)methyl)-2-methylpyridazin-3(2H)-one (9a) displayed the highest COX-2 selectivity indices of 96, 99, and 98, respectively, and analgesic efficacies of 47%, 46%, and 45% protection, respectively. Also, compounds 4a, 8b, and 9a showed anti-inflammatory activities of 65%, 60%, and 62% inhibition of edema, respectively, at a dose of 10 mg/kg, which is higher than that of diclofenac (58% inhibition of edema).


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Piridazinas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Ratos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
11.
Arch Pharm (Weinheim) ; 353(2): e1900218, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31782553

RESUMO

Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT2A and 5-HT2C receptors, as well as their functional activities at the 5-HT1A and D2 receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT1A receptor, showing, at the same time, significant selectivity over the studied 5-HT2 and D2 receptor subtypes. The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Tioureia/farmacologia , Anfetamina , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Indóis/síntese química , Indóis/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Receptores de Dopamina D2/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química
12.
Arch Pharm (Weinheim) ; 353(2): e1900264, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31886579

RESUMO

Twelve azole derivatives of emodin were designed to possess anti-inflammatory activity and synthesized via a two-step sequence composed of the Williamson ether reaction and N-alkylation. The anti-inflammatory properties of these compounds were evaluated in RAW264.7 cells by measuring lipopolysaccharide (LPS)-induced nitric oxide (NO) production. The introduction of imidazole and four carbons into the scaffold of emodin led to the discovery of the potent compound 7e, which showed the best inhibition of NO production among twelve analogs. In our experiential setting, the IC50 of compound 7e in NO production is 1.35 µM, which is lower than that of indomethacin. Mechanically, compound 7e effectively inhibited the protein and messenger RNA expressions of cyclooxygenase-2 and inducible NO synthase, as well as that of the proinflammatory cytokine interleukin-6, and the cytokines interleukin-1ß and tumor necrosis factor-α in the LPS-stimulated RAW 264.7 macrophages. Compound 7e exerted inhibitory effects on the nuclear factor κB pathway by reducing the LPS-induced phosphorylation of the inhibitor of NF-κB and the nuclear translation of p-p65. These results suggest the potential of compound 7e in improving inflammatory conditions and diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Azóis/farmacologia , Emodina/farmacologia , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Azóis/química , Relação Dose-Resposta a Droga , Emodina/síntese química , Emodina/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 186: 111863, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740050

RESUMO

In recent years, drug discovery paradigm has been shifted from conventional single target inhibition toward multitarget design concept. In current research, we have reported synthesis, in-vitro, in-vivo and acute toxicity determination of N-substituted pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents. We synthesized cycloalkyl, alkyl and aryl carbonyl derivatives by the Michael addition of ketones to N-substituted maleimides using self-assembled three component system as an organocatalyst. Anti-inflammatory potential of the compounds was determined by using different in-vitro assays, like cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase, albumin denaturation and anti-protease assays. Amongst the synthesized compounds, 13a-e series of compounds showed inhibition in low micromolar to submicromolar ranges. These compounds also demonstrated COX-2 selectivity. Compound 13e with IC50 value 0.98 µM and SI of 31.5 emerged as the most potent inhibitor of COX-2. Based on in-vitro results, in-vivo anti-inflammatory investigations were performed on compounds 3b and 13evia carrageenan induced paw edema test. The possible mode of action of compounds 3b and 13e were ascertained with various mediators like histamine, bradykinin, prostaglandin and leukotriene. In-vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The selectivity of the compounds against cyclooxygenase isoforms was supported by docking simulations. Selective COX-2 inhibitors showed significant interactions with the amino acid residues present in additional secondary COX-2 enzyme pocket. Furthermore, in-silico pharmacokinetic predictions confer the drug-like characteristics.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Pirrolidinas/farmacologia , Albuminas/antagonistas & inibidores , Albuminas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Araquidonato 5-Lipoxigenase/metabolismo , Carragenina , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade
14.
J Enzyme Inhib Med Chem ; 35(1): 187-198, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752552

RESUMO

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95 µM) and COX-2 (IC50=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Future Med Chem ; 12(1): 5-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710253

RESUMO

Aim: Over the years, indole has proved to be a versatile scaffold for the design of molecules acting as anti-inflammatory agents. Materials & Methods: A small library of 3-amino-alkylated indoles has been obtained by an optimized Mannich green approach. The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluated in RAW 264.7 macrophages. Results: The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluatedn and, among them, GLYC 4, 5 and 9 displayed the greatest inhibitory effects on nitric oxide production, with IC50 values of 5.41, 4.22 and 6.3 µM, respectively. Conclusion: Our outcomes, overall, highlight the importance of the indole substitution in the anti-inflammatory activity of these compounds, exerted by acting on the interlinked NF-κB/ERK1/2 pathways.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Alquilação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
16.
J Med Chem ; 63(2): 542-568, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31756109

RESUMO

Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, ß-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Flúor/química , Indóis/química , Nitrogênio/química , Receptor CB1 de Canabinoide/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Biotransformação , Adjuvante de Freund , Células HEK293 , Humanos , Indóis/farmacocinética , Indóis/farmacologia , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Receptor CB1 de Canabinoide/agonistas , Estereoisomerismo , Relação Estrutura-Atividade
17.
Biochem Biophys Res Commun ; 521(1): 137-144, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629465

RESUMO

We designed and synthesized a celecoxib derivative UTX-121 to enhance its anti-tumor activity. Similar to celecoxib, this compound could also inhibit matrix metalloproteinase (MMP)-9 activity. In addition, UTX-121 suppressed membrane-type 1 MMP (MT1-MMP)-mediated pro-MMP-2 activation by disturbing the cell surface expression of MT1-MMP. UTX-121 also impeded the glycosylation of cell surface proteins, resulting in the suppression of cell attachment to fibronectin. This inhibition by UTX-121 caused the reduction of fibronectin-stimulated focal adhesion kinase activation, Akt activation, and cell migration. Consequently, UTX-121 treatment significantly inhibited fibronectin-induced HT1080 cell invasion into the Matrigel. UTX-121 may be a potent lead compound that can be used to develop a novel anti-tumor drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/farmacologia , Metaloproteinase 14 da Matriz/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Celecoxib/análogos & derivados , Celecoxib/química , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Células Tumorais Cultivadas
18.
Eur J Med Chem ; 185: 111780, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655429

RESUMO

Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC50 = 0.10-22.96 µM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1-258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13-44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of COX-2. The study of SAR revealed favorable cytotoxic outcomes of the aliphatic side chain and 4-thiazolidinone moiety at C6 of the pyrrolizine nucleus, while anti-inflammatory activities was improved with the (hetero)aromatic substituents. The IC50 values which inhibit COX-2 were higher than those needed to inhibit the growth of cancer cell lines. Mechanistic studies also revealed inhibition of multiple kinases by compounds 12, 19 and 22. Moreover, compounds 12, 14, 16 and 22 induced cell cycle arrest and apoptosis in MCF-7 cells. Docking studies revealed nice fitting of the new compounds into COX-1/2. Additionally, compounds 12, 19 and 22 also exhibited higher affinity for CDK2 than CAN508. To sum up, the above-mentioned data highlight these compounds as promising anti-inflammatory and anticancer agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Pirrolidinas/farmacologia , Tiazolidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HT29 , Humanos , Células MCF-7 , Masculino , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tiazolidinas/química
19.
Eur J Med Chem ; 185: 111777, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31670201

RESUMO

Alzheimer's disease is a common neurodegenerative disease characterized by progressive degeneration and neuronal cell death, resulting in neural network dysfunction. As the underlying mechanisms, oxidative damage and neuroinflammation have been reported to contribute to the onset and deterioration of Alzheimer's disease. The nuclear factor E2-related factor 2-antioxidant responsive element signaling pathway is a pivotal cellular defense mechanism against oxidative stress. Nrf2, a transcription factor, regulates the cellular redox balance and is primarily involved in anti-inflammatory responses. In this study, we synthesized novel chalcone derivatives and found a highly potent Nrf2 activator, compound 20a. Compound 20a confirmed to activate Nrf2 and induce expression of the Nrf2-dependent enzymes HO-1 and GCLC at both mRNA and protein levels. It also suppressed the production of nitric oxide and downregulated inflammatory mediators in BV-2 microglial cells. We found that compound 20a effectively increased the expression level and the activity of superoxide dismutase in both BV-2 microglial cells and brain hippocampus region of the scopolamine-induced mouse model. In addition, compound 20a effectively recovered the learning and memory impairment in a scopolamine-induced mouse model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Chalcona/farmacologia , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Escopolamina , Relação Estrutura-Atividade
20.
Artigo em Inglês | MEDLINE | ID: mdl-30827265

RESUMO

BACKGROUND: Hydroxytriazenes and their derivatives have been studied for the biological and pharmacological applications in the past few years. These compounds possess antibacterial, antifungal, anti-inflammatory, analgesic and wound healing activities. In this study, we report the synthesis of ten hydroxytriazenes in two series derived from disubstituted aniline and studied for antimicrobial and anti-inflammatory activities. METHODS: For this purpose, 2-methyl-5-chloroaniline and 2-trifluoromethyl-5-chloroaniline were used to synthesize compounds A1-5 and B1-5 series, respectively. All compounds were synthesized by the reported method which involves three steps of the method (i) Reduction, (ii) Diazotization, (iii) Coupling. All synthesized compounds were characterized by various techniques CHN elemental analysis, FTIR, 1H NMR, and MASS spectral analysis. The antibacterial activities of the compounds were screened against S. aureus, S. pyogenes, E. coli, P. aeruginosa, and antifungal activities were against C. albicans, A. clavatus by the zone of inhibition method. In addition, anti-inflammatory activity was also evaluated by carrageenan-induced paw edema method and results were reported as % inhibition. RESULTS: All the synthesized compounds were obtained in pure form and their spectral data are in good agreement with their structure. The synthesized compounds have shown good antimicrobial activity and zone of inhibition was ranging 21 to 24 mm. Further antiinflammatory effect of the compounds was 96.58 to 98.71 % inhibition. CONCLUSION: The results of the present study indicate that chloro and trifluoromethyl substitution at hydroxytriazenes skeleton could improve anti-inflammatory and antimicrobial activities.


Assuntos
Anti-Infecciosos , Anti-Inflamatórios não Esteroides , Triazinas , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspergillus/efeitos dos fármacos , Aspergillus/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Carragenina , Edema/induzido quimicamente , Edema/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Ratos Wistar , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/crescimento & desenvolvimento , Triazinas/síntese química , Triazinas/farmacologia , Triazinas/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...