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1.
Molecules ; 25(19)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987757

RESUMO

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Fármacos do Sistema Respiratório/uso terapêutico , Doença Aguda , Anti-Inflamatórios/síntese química , Antivirais/síntese química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Fatores Imunológicos/síntese química , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Peptídeos/síntese química , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/prevenção & controle , Insuficiência Respiratória/virologia , Fármacos do Sistema Respiratório/síntese química , Relação Estrutura-Atividade
2.
Int J Nanomedicine ; 15: 5345-5360, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801693

RESUMO

Background: Soft corals have been endorsed as a plentiful source of bioactive compounds with promising anti-inflammatory activities; therefore, exploring their potential as source of anti-inflammatory metabolites has stimulated a growing research interest. Purpose: To investigate the anti-inflammatory potential of the soft coral, Nephthea sp., in its bulk and silver nanostructure. Metabolomics analysis of Nephthea sp., followed by molecular docking studies, was also conducted in order to explore and predict the secondary metabolites that might provide its inhibitory actions on inflammation. Materials and Methods: The petroleum ether and ethyl acetate fractions were used to synthesize silver nanoparticles. The prepared silver nanoparticles were characterized through UV-vis spectrophotometric, transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) analyses. Testing for the anti-inflammatory activity was performed against COX-1 and COX-2. Furthermore, liquid chromatography-mass spectrometry (LC-MS) based metabolomics analysis and molecular docking were also applied. Results: A variety of secondary metabolites were identified, among them, sesquiterpenes were found to prevail. The petroleum ether and acetone fractions of Nephthea sp. showed the highest COX-2 inhibitory activities, possibly attributable to their substantial contents of terpenoids. Additionally, the green synthesized silver nanoparticles of both the petroleum ether and ethyl acetate fractions of Nephthea sp. demonstrated higher anti-COX-2 properties. Conclusion: The obtained results showed the effectiveness of non-targeted metabolomics technique in metabolic profiling of Nephthea sp., helping the search for new bioactive metabolites in future chemical studies on this soft coral. The interesting anti-inflammatory potential of the tested extracts and their nanoparticles could also be relevant to the development of new, effective anti-inflammatory agents.


Assuntos
Antozoários/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Nanopartículas Metálicas/química , Prata/química , Alcanos/química , Animais , Antozoários/química , Anti-Inflamatórios/síntese química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Química Verde , Humanos , Metabolômica , Simulação de Acoplamento Molecular , Metabolismo Secundário , Sesquiterpenos/análise , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Eur J Med Chem ; 197: 112280, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32361286

RESUMO

Herein, we demonstrate that butein (1) can prevent swelling in a murine lymphedema model by suppressing tumor necrosis factor α (TNF-α) production. Butein derivatives were synthesized and evaluated to identify compounds with in vitro anti-inflammatory activity. Among them, 20 µM of compounds 7j, 7m, and 14a showed 50% suppression of TNF-α production in mouse peritoneal macrophages after lipopolysaccharide stimulation. Compound 14a, exhibited the strongest potency with an in vitro IC50 of 14.6 µM and suppressed limb volume by 70% in a murine lymphedema model. The prodrug strategy enabled a six-fold increase in kinetic solubility of compound 1 and five-fold higher levels of active metabolite in the blood for compound 14a via oral administration in the pharmacokinetics study. We suggest that the compound 14a could be developed as a potential therapeutic agent targeting anti-inflammatory activity to alleviate lymphedema progression.


Assuntos
Anti-Inflamatórios/uso terapêutico , Chalconas/uso terapêutico , Linfedema/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Chalconas/síntese química , Chalconas/farmacocinética , Humanos , Lipopolissacarídeos/farmacologia , Linfedema/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Ratos , Fator de Necrose Tumoral alfa/metabolismo
4.
Adv Exp Med Biol ; 1195: 137-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468468

RESUMO

In the present work a series of N'-arylidene-2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazides were synthesized by refluxing the intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide with various substituted benzaldehyde in the presence of glacial acetic acid. The intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide 2 was prepared by stirring 4-((naphthalen-2-yl)methylene)-2-phenyloxazol-5(4H)-one with hydrazine hydrate in the presence of absolute ethanol. The chemical structures of the compounds were established by IR, 1H NMR and mass spectral data. All the compounds were evaluated for anti-inflammatory (in vivo, in vitro) activity and performed docking against COX-2. The compounds 3a, 3c and 3o showed good inhibition of COX-2 in in vitro studies (0.75 µM, 0.5 µM and 0.7 µM as IC50, respectively). The compounds 3c, 3e and 3f were found to be more active than standard drug phenylbutazone at equidose. Molecular docking studies showed that compound 3 m exhibited good binding affinity against COX-2 with docking score 9.328 kcal/mol, when compared to the standard celecoxib.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Hidrazonas/química , Hidrazonas/uso terapêutico , Estrutura Molecular , Relação Estrutura-Atividade
5.
Sci Rep ; 10(1): 6137, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273529

RESUMO

Different novel 1,2,4-triazolo[4,3-b][1,2,4,5]tetrazines and 1,2,4-triazolo[4,3-b][1,2,4]triazines have been obtained from heterocyclization of 3-substituted-4-amino-5-substituted-amino-1,2,4-triazoles (3a-d) and 3-substituted-4-amino-5-hydrazino-1,2,4-triazoles (9a,b) with (α and ß) bifunctional compounds like chloromethyl biphenyl-phosphanoxide, pyruvic acid, phenacyl bromide, diethyl oxalate, triethyl orthoformate, triethyl phosphite, fluorinated benzaldehydes, carbon disulfide and ethyl chloroformate under different experimental settings. Fourier transformer infrared analysis (FTIR), Proton nuclear magnetic resonance (1H NMR) and 13C nuclear magnetic resonance (13C NMR), as well as that of the mass spectral data, were used as the appropriate characterization techniques for the chemical structures of all newly synthesized compounds. The newly prepared compounds were examined as an anti-inflammatory, antibacterial agents (against E. coli (Escherichia coli) and P. aeruginosa (Pseudomonas aeruginosa) as examples for Gram-negative bacteria and S. aureus (Staphylococcus aureus) as examples for Gram-positive bacteria), as well as antifungal (against C. albicans (Candida albicans)) agents. The newly prepared compound showed high antibacterial, antifungal, and anti-inflammatory activities in comparing with the commercial antibiotics Indomethacin, Nalidixic acid, Imipenem, and Nystatin. Docking of the most active compounds was performed depending on the results of antibacterial screening and the anti-inflammatory assay.


Assuntos
Triazinas/síntese química , Triazóis/síntese química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Simulação de Acoplamento Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Triazinas/química , Triazinas/farmacologia , Triazóis/química , Triazóis/farmacologia
6.
Pak J Pharm Sci ; 33(2): 615-619, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32276906

RESUMO

Benzimidazole and its derivatives found variety of biological activities, for the searching of its potent anti-inflammatory analogues, we synthesized four novel 4-(2-keto-1-benzimidazollinyl) piperidine derivatives (Q1 to Q4) by refluxing piperidine with substituted imidazole and subjected to in-vitro anti-inflammatory (ROS, NO) and antibacterial activities, structures were elucidated using spectroscopic techniques. Results revealed that compound Q1 showed most effective anti-inflammatory activity with IC 50 7.6±1.3 µg/ml compared with standard Ibuprofen having IC50 11.2±1.9µg/mL. Compound Q3 showed good activity for Nitrite accumulation by stimulating macrophages test similar to standard NG Methyl L-arginine acetate with IC50 value 24.2±0.8µg/mL. The antibacterial activity of these compounds were evaluated against selected Gram+ve E. faecalis, C. diphtheriae, S. aureus and Gram -ve organism E. coli, Enterobacter aerogenes and P. aeruginosa. Synthesized compounds showed low to moderate level of antibacterial activity Q1 showed the highest antibacterial activity against Enterococcus faecalis and Escherichia coli with zone of inhibition 18mm and Q3 showed highest activity against Corynebacterium diptheriae (ZOI:18mm). Structure-activity relationship (SAR) study revealed that among all the synthesized compounds unsubstituted naphthalene (Q1) and phenyl (Q3) ring containing derivatives were most potent.


Assuntos
Antibacterianos/síntese química , Anti-Inflamatórios/síntese química , Piperidinas/síntese química , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Testes de Sensibilidade Microbiana/métodos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Piperidinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Relação Estrutura-Atividade
7.
J Infect Public Health ; 13(4): 472-479, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32139293

RESUMO

BACKGROUND: The present work is an extension of ongoing efforts toward the development and identification of new molecules as monotherapy displaying anti-inflammatory and anti-infective activities and a wide-range of gastrointestinal selectivity. A series of novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and evaluated for their in-vitro and in-vivo anti-inflammatory activities. Synthesized trisubstituted thiazole compounds were also evaluated for their potential antibacterial activity against clinical pathogens causing infectious disease. MATERIAL AND METHOD: The structures of synthesized compounds were characterized by FTIR, 1H NMR, Mass spectroscopic techniques and evaluated for their in-vitro and in-vivo anti-inflammatory effects using the human red blood cell (HRBC) membrane stabilization method and a carrageenan-induced rat paw oedema model, respectively, Diclofenac sodium and Ibuprofen were used as standard drugs. The synthesized compounds AR-17atoAR-27a screened for their in-vitro antibacterial activity against the gram-positive bacteria Staphylococcus aureus (ATCC25923) and Enterococcus faecalis (ATCC29212) and the gram-negative bacteria Escherichia coli (ATCC8739) and Pseudomonas aeruginosa (ATCC9027) using ciprofloxacin and cefdinir as standard drugs. RESULT: Compounds AR-17a and AR-27a elicited maximum anti-inflammatory activity, providing 59% and 61% protection at 20mg/kg, respectively, in the inflamed paw model. Among the tested compounds, AR-17a (6.25), (54) and AR-27a (1.56), (52) had the least minimum inhibitory concentration values and the highest zone of inhibition, indicating their marked antibacterial activities. The lowest conc. were observed at 1.56, 6.25µg/mL for inhibition of bacteria by most of the compounds. CONCLUSION: Novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and characterized successfully. The preliminary screening revealed that these compounds possess promising anti-inflammatory and antibacterial activities. In addition, the objective of the study was achieved with few of the promising structures like AR-17a to AR-27a, which are prove to be potential monotherapy candidates for the treatment of chronic inflammatory diseases and bacterial infections.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Anti-Inflamatórios/síntese química , Edema/tratamento farmacológico , Feminino , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química
8.
Sci Adv ; 6(12): eaay9751, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32206718

RESUMO

Rational design of potent antioxidative agent with high biocompatibility is urgently needed to treat ischemic reperfusion-induced ROS-mediated cerebrovascular and neural injury during ischemia strokes. Here, we demonstrate an in situ synthetic strategy of bioactive zeolitic imidazolate framework-8-capped ceria nanoparticles (CeO2@ZIF-8 NPs) to achieve enhanced catalytic and antioxidative activities and improved stroke therapeutic efficacy. This nanosystem exhibits prolonged blood circulation time, reduced clearance rate, improved BBB penetration ability, and enhanced brain accumulation, where it effectively inhibits the lipid peroxidation in brain tissues in middle cerebral artery occlusion mice and reduces the oxidative damage and apoptosis of neurons in brain tissue. CeO2@ZIF-8 also suppresses inflammation- and immune response-induced injury by suppressing the activation of astrocytes and secretion of proinflammatory cytokines, thus achieving satisfactory prevention and treatment in neuroprotective therapy. This study also sheds light on the neuroprotective action mechanisms of ZIF-8-capped nanomedicine against reperfusion-induced injury in ischemic stroke.


Assuntos
Imidazóis/farmacologia , Estruturas Metalorgânicas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Nanomedicina Teranóstica , Zeolitas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Técnicas de Química Sintética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Imidazóis/química , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/ultraestrutura , Camundongos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Zeolitas/química
9.
Oxid Med Cell Longev ; 2020: 2432918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215169

RESUMO

The present study was directed to investigate the effect of precotreatment with (E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide (7-hyd.HC), a novel potent synthesized coumarin, on isoproterenol- (ISO-) induced myocardial infarction (MI) in rats. The hydrazone compound was characterized by IR, 1D, and 2D NMR analyses. Experimental induction of MI in rats was established by ISO (85 mg/kg/day, s.c) for two consecutive days (6th and 7th days). 7-hyd.HC or sintrom was given for 7 days prior and simultaneous to ISO injection. 7-hyd.HC offered a cardiopreventive effect by preventing heart injury marker leakage (LDH, ALT, AST, CK-MB, and cTn-I) from cardiomyocytes and normalizing cardiac function and ECG pattern, as well as improving lipid profile (TC, TG, LDL-C, and HDL-C), which were altered by ISO administration. Moreover, 7-hyd.HC precotreatment significantly mitigated the oxidative stress biomarkers, as evidenced by the decrease of lipid peroxidation and the increased level of the myocardial GSH level together with the SOD, GSH-Px, and catalase activities. 7-hyd.HC inhibited the cardiac apoptosis by upregulating the expression of Bcl-2 and downregulating the expression of Bax and caspase-3 genes. In addition, 7-hyd.HC reduced the elevated fibrinogen rate and better prevented the myocardial necrosis and improved the interstitial edema and neutrophil infiltration than sintrom. Overall, 7-hyd.HC ameliorated the severity of ISO-induced myocardial infarction through improving the oxidative status, attenuating apoptosis, and reducing fibrinogen production. The 7-hyd.HC actions could be mediated by its antioxidant, antiapoptotic, and anti-inflammatory capacities.


Assuntos
Anti-Inflamatórios/uso terapêutico , Benzopiranos/uso terapêutico , Cumarínicos/uso terapêutico , Hidrazonas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Benzopiranos/síntese química , Benzopiranos/química , Biomarcadores/metabolismo , Cumarínicos/síntese química , Cumarínicos/química , Hidrazonas/síntese química , Hidrazonas/química , Inflamação/metabolismo , Isoproterenol/toxicidade , Masculino , Estrutura Molecular , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Resultado do Tratamento
10.
Eur J Pharm Sci ; 148: 105300, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32160953

RESUMO

In order to discover a new compound having anti-inflammatory activity, a nitro-Schiff base was evaluated. The compound was synthesized and characterized by 1H NMR and 13C NMR. The cytotoxic activity was evaluated in vitro by hemolysis and MTT cell viability assay. To evaluate genotoxicity, the micronucleus assay was performed in vivo. The anti-inflammatory effects of the compound were examined using in vivo models of inflammation such as neutrophil migration assay, paw edema, and exudation assay. The production of NO was also estimated in vivo and in vitro. The data showed that the compound did not induce hemolysis at all the tested concentrations. Similarly, the compound did not induce cytotoxicity and genotoxicity to the cells. The neutrophil migration assay showed that the compound reduced the number of neutrophils recruited to the peritoneal cavity by approximately 60% at all the tested concentrations. In the exudation assay, the compound showed a reduction in extravasation by 24%. The paw edema model demonstrated a significant reduction in the paw volume at all the evaluated time points. The production of NO was decreased both in vitro and in vivo. These results suggest that the nitro-Schiff base compound efficiently inhibited inflammation and might be a good candidate for the treatment of inflammatory-associated conditions.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Bases de Schiff/química , Animais , Permeabilidade Capilar/efeitos dos fármacos , Carragenina/farmacologia , Edema/tratamento farmacológico , Eritrócitos/efeitos dos fármacos , Feminino , Inflamação , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/efeitos dos fármacos , Óxido Nítrico/metabolismo
11.
Pak J Pharm Sci ; 33(1): 149-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32122843

RESUMO

A series of new compounds (5a-q), derived from 5-(1-(4-nitrophenylsulfonyl) piperidin-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (3) were proficiently synthesized to evaluate their biological activities. 1-(4-Nitrophenylsulfonyl) piperidine-4-carbohydrazide (2) was refluxed with phenylisothiocyanate to yield an adduct which was cyclized to compound 3 by reflux reaction with 10 % potassium hydroxide. The targeted compounds 5a-q, were synthesized by stirring alkyl/aralkyl halides (4a-q) and compound 3 in a polar aprotic solvent. 1H-NMR, 13C-NMR, EI-MS and IR spectral techniques were employed to confirm the structures of all the synthesized compounds. The compounds were biologically evaluated for BSA binding studies followed by anti-bacterial, anti-inflammatory and acetylcholinesterase (AChE) activities. The active sites responsible for the best AChE inhibition were identified through molecular docking studies. Compound 5e bearing 4-chlorobenzyl moiety found most active antibacterial and anti-inflammatory agent among the synthesized compounds. The whole library of synthesized compounds except compounds 5d and 5f was found highly active for AChE inhibition and recommended for in vivo studies so that their therapeutic applications may come in utilization.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Albumina Sérica/metabolismo , Triazóis/farmacologia , Antibacterianos/síntese química , Anti-Inflamatórios/síntese química , Inibidores da Colinesterase/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
12.
J Steroid Biochem Mol Biol ; 198: 105573, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017993

RESUMO

A series of novel diosgenin (DSG) and tigogenin (TGG) derivatives with diosgenin or tigogenin steroid aglycons linked to levulinic and 3,4-dihydroxycinnamic acids, dipeptides and various amino acids by an ester bond at the C3-oxygen atom of the steroid skeleton has been synthesized. Diosgenyl esters have been prepared by an esterification reaction (DCC/DMAP) of diosgenin with the corresponding acids. All analogues have been evaluated in vitro for their antiproliferative profile against cancer cell lines (MCF-7, MDA-MB-231, PC-3) and human umbilical vein endothelial cells (HUVEC). Analogue2c (l-serine derivative of TGG), the best representative of the series showed IC50 of 1.5 µM (MCF-7), and induced apoptosis in MCF-7 by activating caspase-3/7. The immunomodulatory properties of six synthesized analogues have been determined by examining their effects on the expression of cytokine genes essential for the functioning of the human immune system (IL-1, IL-4, IL-10, IL-12 and TNF-α). Biological evaluation has revealed that new compounds 4c and 16a do not induce the expression of pro-inflammatory cytokines in THP-1 cells after the lipopolysaccharide (LPS) stimulation. They also stimulate the expression of anti-inflammatory IL-10 that acts stronger than diosgenin itself. An in silico ADME properties(absorption, distribution, metabolism, excretion) study was also performed to predict the pharmacokinetic profile of the synthesized compounds. To shed light on the molecular interactions between the synthesized compounds and the glucocorticoid receptor and the estrogen receptor, 2c, 4c and 16a compounds were docked into the active binding sites of these receptors. The in silico and in vitro data suggested that this new group of compounds might be considered as a promising scaffold for further modification of more potent and selective anticancer and immunomodulatory agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Diosgenina/análogos & derivados , Diosgenina/farmacologia , Espirostanos/química , Espirostanos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diosgenina/síntese química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Células PC-3 , Espirostanos/síntese química
13.
Biomed Pharmacother ; 125: 110023, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32092830

RESUMO

Several studies demonstrated the pharmacological actions of carnosine as well as hyaluronic acid (HA) during joint inflammation. In that regard, the aim of this study was to investigate the protective effect of a new HA -Carnosine conjugate (FidHycarn) on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA). CIA was induced by two intradermal injections of 100 µl of an emulsion of collagen (CII) and complete Freund's adjuvant (CFA) at the base of the tail on day 0 and 21. At 35 day post CIA induction, the animals were sacrificed. CII injection caused erythema and edema in the hind paws, histological alterations with erosion of the joint cartilage as well as behavioral changes. Oral treatment with FidHycarn starting at the onset of arthritis (day 25) ameliorated the clinical signs, improved behavioral deficits as well as decreased histological and radiographic alterations. The degree of oxidative damage evaluated by inducible nitric oxide synthase (iNOS), nitrotyrosine, poly-ADP-ribose (PAR) expressions and malondialdehyde (MDA) levels, was also significantly reduced in Carnosine+HA association and FidHycarn treated mice. Moreover, the levels of proinflammatory cytokines and chemokines and cyclo-oxygenase COX-2 enzyme were also more significantly reduced by Carnosine+HA and FidHycarn compared to carnosine alone. However, interestingly, in some cases, the effects of FidHycarn were more important than Carnosine+HA association and not statistically different to methotrexate (MTX) used as positive control. Thus, the conjugation of Carnosine with HA (FidHycarn) could represent an interesting therapeutic strategy to combat arthritis disorders.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Carnosina , Ácido Hialurônico , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios/síntese química , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/etiologia , Artrite Experimental/patologia , Biomarcadores , Carnosina/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Ácido Hialurônico/química , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Substâncias Protetoras/síntese química , Radiografia
14.
Eur J Med Chem ; 190: 112089, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32014680

RESUMO

NOD1 and NOD2 are pattern recognition receptors that have important roles in innate immune responses. Although their overactivation has been linked to a number of diseases, NOD2 in particular remains a virtually unexploited target in this respect, with only one structural class of antagonist reported. To gain insight into the structure-activity relationships of NOD2 antagonists, a series of novel analogs was designed and synthesized, and then screened for antagonist activity versus NOD2, and counter-screened versus NOD1. Compounds 32 and 38 were identified as potent and moderately selective NOD2 antagonists, and 33 and 42 as dual NOD1/NOD2 antagonists, with balanced activities against both targets in the low micromolar range. These data enable in-depth exploration of their structure-activity relationships and provide deeper understanding of the structural features required for NOD2 antagonism.


Assuntos
Anti-Inflamatórios/farmacologia , Benzimidazóis/farmacologia , Proteína Adaptadora de Sinalização NOD2/antagonistas & inibidores , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/toxicidade , Benzimidazóis/síntese química , Benzimidazóis/toxicidade , Desenho de Fármacos , Células HEK293 , Humanos , Estrutura Molecular , Proteína Adaptadora de Sinalização NOD1/antagonistas & inibidores , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 190: 112079, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32028140

RESUMO

A series of novel triptolide/furoxans hybrids were designed and synthesized as analogues of triptolide, which is a naturally derived compound isolated from the thunder god vine (Tripterygium wilfordii Hook. F). Some of these synthesized compounds exhibited antiproliferative activities in the nanomolar range. Among them, compound 33 exhibited both good antiproliferative activity and NO-releasing ability and the acute toxicity of compound 33 decreased more than 160 times (LD50 = 160.9 mg/kg) than triptolide. Moreover, compound 33 significantly inhibited the growth of melanoma at a low dose (0.3 mg/kg) and showed strong anti-inflammatory activity in vitro and in vivo. These results indicate that compound 33 could be a promising candidate for further study.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Diterpenos/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Fenantrenos/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/toxicidade , Desenho de Fármacos , Compostos de Epóxi/síntese química , Compostos de Epóxi/uso terapêutico , Compostos de Epóxi/toxicidade , Feminino , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Estrutura Molecular , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/toxicidade , Fenantrenos/síntese química , Fenantrenos/toxicidade , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Molecules ; 25(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085423

RESUMO

Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure-activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets.


Assuntos
Anti-Inflamatórios/farmacologia , Pirazóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/farmacologia , Humanos , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Oxirredução , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
17.
Colloids Surf B Biointerfaces ; 188: 110737, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32004904

RESUMO

Wound dressing materials are widely used to protect wounds from the external environment and to promote wound healing. However, conventional wound dressings lack tissue adhesive properties and anti-inflammatory functions, which lead to fibrosis and stricture, in cases such as gastrointestinal wounds after endoscopic surgery. In the current study, we report tissue-adhesive and anti-inflammatory properties of a wound dressing composed of corticosteroid-modified gelatin particles. Hydrocortisone (HC), which is a class of anti-inflammatory corticosteroid, was used to modify Alaska-pollock gelatin (ApGltn) to synthesize HC-modified ApGltn (HC-ApGltn). Microparticles (MPs) of HC-ApGltn were fabricated by adding ethanol in HC-ApGltn aqueous solution and performing thermal crosslinking (TC) without the use of toxic surfactants and crosslinking reagents. Modification of ApGltn with hydrophobic HC containing cholesterol backbone structure improved its adhesion strength to gastric submucosal tissues under wet conditions owing to hydrophobic interactions. This retention of adhesive property under wet conditions allows for stable protection of wounds from the external environment. We found that HC-ApGltn MPs were taken up by macrophages and they effectively suppressed morphological changes of LPS-activated macrophages and the expression level of the inflammatory cytokine. Robust tissue adhesive and anti-inflammatory MPs may serve as an advanced wound dressing that can protect wounds and suppress inflammatory responses for promoting wound healing.


Assuntos
Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Gelatina/farmacologia , Hidrocortisona/farmacologia , Adesivos Teciduais/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Linhagem Celular , Gelatina/síntese química , Gelatina/química , Hidrocortisona/síntese química , Hidrocortisona/química , Camundongos , Conformação Molecular , Tamanho da Partícula , Propriedades de Superfície , Adesivos Teciduais/síntese química , Adesivos Teciduais/química
18.
J Med Chem ; 63(3): 1397-1414, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31934767

RESUMO

Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compounds with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compound 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addition, compound 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound 29 may serve as a new drug candidate with promising applications in inflammatory disorders.


Assuntos
Alquinos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Alquinos/síntese química , Alquinos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Feminino , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade
19.
J Med Chem ; 63(3): 1032-1050, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31904232

RESUMO

Activation of prostanoid EP2 receptor exacerbates neuroinflammatory and neurodegenerative pathology in central nervous system diseases such as epilepsy, Alzheimer's disease, and cerebral aneurysms. A selective and brain-permeable EP2 antagonist will be useful to attenuate the inflammatory consequences of EP2 activation and to reduce the severity of these chronic diseases. We recently developed a brain-permeable EP2 antagonist 1 (TG6-10-1), which displayed anti-inflammatory and neuroprotective actions in rodent models of status epilepticus. However, this compound exhibited moderate selectivity to EP2, a short plasma half-life in rodents (1.7 h) and low aqueous solubility (27 µM), limiting its use in animal models of chronic disease. With lead-optimization studies, we have developed several novel EP2 antagonists with improved water solubility, brain penetration, high EP2 potency, and selectivity. These novel inhibitors suppress inflammatory gene expression induced by EP2 receptor activation in a microglial cell line, reinforcing the use of EP2 antagonists as anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Linhagem Celular , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Solubilidade , Relação Estrutura-Atividade , Água/química
20.
Eur J Med Chem ; 189: 112066, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982653

RESUMO

The current therapeutic demand focuses more on the discovery of safer NSAIDs rather than exploring more potent alternatives. The dual COX-2/5-LOX inhibition is a promising strategy for designing compounds with an enhanced efficacy, reduced side-effects and a broader anti-inflammatory spectrum in comparison to classical NSAIDs. In the present study, a hybridization strategy was adopted to combine the binding features of the non-selective COX inhibitor "sulindac" and the selective COX-2 inhibitor "celecoxib" which show 5-LOX inhibitory activity with that of licofelone and a celecoxib pyridone analogue which show dual COX-2/5-LOX inhibitory activity to design new series of pyrazole sulfonamide derivatives which, by design, should possess dual COX-2/5-LOX inhibitory activity. All the newly synthesized compounds were initially tested for their potential analgesic activity, then candidates that showed potential analgesic activity, were selected for the subsequent anti-inflammatory activity evaluation, as well as, ulcerogenicity testing. Moreover, in vitro assessment of their COX-1, COX-2 and 5-LOX inhibitory activities were performed. The benzothiophen-2-yl pyrazole carboxylic acid derivative 5b showed the most potent analgesic and anti-inflammatory activities surpassing that of celecoxib and indomethacin. It showed potent COX-1, COX-2 and 5-LOX inhibitory activity with IC50 of 5.40, 0.01 and 1.78 µM, respectively, showing a selectivity index of 344.56 that was much better than the used reference standards and its parent compounds, confirming its selectivity towards COX-2 over COX-1. The prodrug ester derivatives 6c and 6d showed equipotent activity to their parent compound 5b with no gastric ulcerogenicity. Molecular docking simulations confirmed that the newly synthesized compounds possess the structural features required for binding to the target enzymes COX-2 and 5-LOX.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antiulcerosos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Inibidores de Lipoxigenase/farmacologia , Analgésicos/síntese química , Animais , Anti-Inflamatórios/síntese química , Antiulcerosos/síntese química , Araquidonato 5-Lipoxigenase/química , Ciclo-Oxigenase 1/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Humanos , Inibidores de Lipoxigenase/síntese química , Masculino , Camundongos , Pirazóis/química , Ratos , Ratos Wistar , Úlcera Gástrica/tratamento farmacológico , Sulfonamidas/química
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