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1.
J Enzyme Inhib Med Chem ; 35(1): 1-20, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31619080

RESUMO

Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-10, and TGF-ß), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Piridinas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Células Cultivadas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/patologia , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ácido Trinitrobenzenossulfônico , Células U937
2.
Eur J Med Chem ; 188: 111974, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31883489

RESUMO

A series of 28 novel 1,2,3-triazole hybrids of myrrhanone B have been designed and synthesized by employing regioselective Cu catalyzed Huisgen 1,3-dipolar cycloaddition reaction in highly efficient manner. All the synthesized analogues were assessed for their antiproliferative potential against A549 (Lung), DU145 (Prostate), MDA-MB-231 (Breast), SiHa (Cervical), U87MG (Glioblastoma), PC-3 (Prostate), HT-29 (Colon), L132 (Normal lung) cell lines. Further, the synthesized hybrids have also been screened for anti-inflammatory activity (TNF-α and IL-1ß) and α-glucosidase inhibitory activity. The biological results revealed that compound 11 (meta hydroxy phenyl 1,2,3-triazole) and compound 29 (deoxyuridine 1,2,3-triazole) found to be the most potent antiproliferative ones against PC-3 cell line. Compound 11 (IC50: 6.57 ± 0.62 µM) showed six folds more potent than parent compound 1 (IC50: 40.67 ± 2.2 µM) and displayed almost identical inhibitory activity with standard doxorubicin (IC50: 5.05 ± 0.25 µM), whereas compound 29 (IC50: 10.85 ± 0.90 µM) exhibited four folds more potent than parent myrrhanone B (1). In view of potent activity of compounds 11 and 29 they have been subjected to detailed flowcytometry analysis. Compound 29 treated cells significantly increased the SubG1 population of cells indicative of apoptosis compared to compound 11. Further, the results of anti-inflammatory studies indicated that compounds 3, 6, 9, 27, 28, 29 and 30 exhibited significant inhibitory activity against both TNF-α and IL-1ß than the parent compound 1. Interestingly, compound 27 exhibited good activity towards inflammatory cytokines TNF-α (IC50: 7.83 ± 0.95 µM). Interestingly, α-glucosidase inhibitory assay results revealed that compounds 14 (IC50: 2.77 ± 0.59 µM) and 16 (IC50: 4.12 ± 0.77 µM) as the most potent ones. In fact, compound 14 exhibited highest activity and found to be several times more potent than the parent compound 1 as well as standard acarbose (IC50: 2124 ± 170 µM).


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Commiphora/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Triazóis/farmacologia , Triterpenos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Estrutura Molecular , Resinas Vegetais , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Triterpenos/síntese química , Triterpenos/isolamento & purificação
3.
Eur J Pharm Sci ; 140: 105101, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639436

RESUMO

Gastric irritation and ulcerogenic effect of the acidic NSAIDs are of the most challenging problems in designing novel anti-inflammatory agents. In this study, the new prodrugs were prepared through Steglich esterification reaction between the carboxylic acid functional group of etodolac or tolfenamic acid and thymol. The structures were confirmed by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analysis. Their chemical stability in addition to a kinetic study of their hydrolysis in 20% liver homogenate and 10% buffered plasma were investigated. In vitro enzymatic hydrolysis showed half-life times 88.84 and 106.61 min for the prodrugs of etodolac and tolfenamic acid, respectively. Their ability to inhibit paw edema and their ulcerogenic potential were assessed in rats and compared to their parent drugs. the prodrugs were found to be stable in different pHs at room and body temperatures. Both prodrugs proved to possess high percentage of inhibition of paw edema (94.68 & 97.1%) in rats comparable to that of the parent drugs (90.33 & 93.23%) and, most importantly with lower ulcerogenic potential. The prodrugs are expected to be converted to their parent drugs rapidly in plasma and liver in vivo and proved to be safer than their parent drugs. The study opens a perspective chance that can be a backbone for further investigations.


Assuntos
Anti-Inflamatórios/síntese química , Edema/tratamento farmacológico , Etodolac/síntese química , Pró-Fármacos/síntese química , Úlcera Gástrica/induzido quimicamente , ortoaminobenzoatos/síntese química , Animais , Anti-Inflamatórios/farmacologia , Desenho de Drogas , Estabilidade de Medicamentos , Etodolac/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Fígado/metabolismo , Masculino , Estrutura Molecular , Plasma/metabolismo , Pró-Fármacos/farmacologia , Ratos , Ratos Wistar , Úlcera Gástrica/prevenção & controle , Relação Estrutura-Atividade , Temperatura Ambiente , ortoaminobenzoatos/farmacologia
4.
Eur J Med Chem ; 183: 111684, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520926

RESUMO

This article reports the synthesis of new triarylpyrazole derivatives possessing urea or amide linker, and their biological activities at molecular, cellular, and in vivo levels. Compound 2b was the most potent inhibitor of p38α/MAPK14 kinase (IC50 = 22 nM) among this series. Molecular docking studies were conducted to understand the kinase inhibitory variations and the basis of selectivity. Compound 2b was able to inhibit p38α/MAPK14 kinase inside HEK293 cells in nanoBRET cellular kinase assay with EC50 value of 0.55 µM, comparable to the potency of dasatinib. Compound 2b inhibited TNF-α production in lipopolysaccharide-induced THP-1 cells with IC50 value of 58 nM. In addition, compound 2b showed low potency against hERG. It is 622.38 times less potent than E-4031 against hERG, so the risk of cardiotoxicity of the compound is very minimal. Compound 2b showed also high plasma stability in vitro in human and rat plasmas. The in vivo PK profile of compound 2b is acceptable, and its antiinflammatory effect was comparable to diclofenac with no ulcerogenic side effect on stomach.


Assuntos
Anti-Inflamatórios/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirazóis/síntese química , Amidas/química , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Descoberta de Drogas , Humanos , Masculino , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Ratos , Ureia/química
5.
Eur J Med Chem ; 182: 111623, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473417

RESUMO

Fowlicidin-1 (Fowl-1), a cathelicidin expressed in chicken intestine, is known to have both antimicrobial and anti-inflammatory properties. However, its pharmaceutical development has been ultimately compromised by its high host cytotoxicity. In this study, a series of N- and C-terminal-truncated 19-meric Fowl-1 peptides were synthesized. Among these truncated peptides, Fowl-1 (8-26) exhibited broad-spectrum antimicrobial activity without human erythrocyte cytotoxicity while reducing anti-inflammatory activity. Further, Fowl-1 (8-26)-WRK was designed via Thr5→Trp, Ile7→Arg, and Asn11→Lys substitutions in Fowl-1 (8-26) to exhibit more amphipathicity. The results revealed that it exhibited both antimicrobial and anti-inflammatory properties. This study also demonstrated that the inhibitory activity of Fowl-1 (8-26)-WRK against LPS-induced inflammation was mainly due to the binding of LPS to the peptide. Interestingly, compared with human cathelicidin LL-37 and melittin, Fowl-1 (8-26)-WRK showed more potent activity against drug-resistant bacteria. It was also resistant to physiological salts and human serum and acted synergistically in combination with conventional antibiotics, such as chloramphenicol, ciprofloxacin, and oxacillin, suggesting that combined with conventional antibiotics, it is a promising adjuvant. Furthermore, membrane depolarization, SYTOX Green uptake, and flow cytometry revealed that it kills bacteria by damaging their membrane integrity. Therefore, this study suggests that Fowl-1 (8-26)-WRK has considerable potential for future development as an antimicrobial and anti-inflammatory agent for treating antibiotic-resistant infections.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Catelicidinas/farmacologia , Desenho de Drogas , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Catelicidinas/síntese química , Catelicidinas/química , Sobrevivência Celular/efeitos dos fármacos , Galinhas , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Células RAW 264.7 , Ovinos , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 181: 111564, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376563

RESUMO

The P2Y14 receptor (P2Y14R) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2Y14R antagonists. The most potent antagonist, 16c, showed comparable activity (IC50 = 1.77 nM) to PPTN, the most potent P2Y14R antagonist reported. Compound 16c demonstrated dramatically improved aqueous solubility and excellent metabolic stability in rat and human microsomes. Investigation of the anti-inflammatory effect of 16c was performed in MSU treated THP-1 cells by flow cytometry, Western Blot and immunofluorescence labeling technology, which exhibited that 16c might be a promising candidate for further research.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ácido Benzoico/química , Ácido Benzoico/farmacologia , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Ácido Benzoico/síntese química , Linhagem Celular , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Antagonistas do Receptor Purinérgico P2/síntese química , Ratos , Receptores Purinérgicos P2/metabolismo
7.
Molecules ; 24(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323775

RESUMO

Curcumin, derived from the rhizome Curcuma longa, has been scientifically proven to possess anti-inflammatory activity but is of limited clinical and veterinary use owing to its low bioavailability and poor solubility. Hence, analogs of curcuminoids with improved biological properties have been synthesized to overcome these limitations. This study aims to provide the pharmacological basis for the use of 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), a synthetic curcuminoid analog, as an anti-edematogenic and anti-granuloma agent. The carrageenan-induced paw edema and the cotton pellet-induced granuloma assays were used to assess the anti-inflammatory activity of DHHPD in mice. The effects of DHHPD on the histaminergic, serotonergic, and bradykininergic systems were determined by the histamine-, serotonin-, and bradykinin-induced paw edema tests, respectively. DHHPD (0.1, 0.3, 1, and 3 mg/kg, intraperitoneal) evoked significant reductions (p < 0.05) in carrageenan-induced paw edema at different time intervals and granuloma formation (p < 0.0001) by 22.08, 32.57, 37.20, and 49.25%, respectively. Furthermore, DHHPD significantly reduced paw edema (p < 0.05) induced by histamine, serotonin, and bradykinin. The present study suggests that DHHPD exerts anti-edematogenic activity, possibly by inhibiting the synthesis or release of autacoid mediators of inflammation through the histaminergic, serotonergic, and bradykininergic systems. The anti-granuloma effect may be attributed to the suppression of transudative, exudative, and proliferative activities associated with inflammation.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diarileptanoides/química , Diarileptanoides/farmacologia , Animais , Anti-Inflamatórios/síntese química , Diarileptanoides/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/etiologia , Granuloma/tratamento farmacológico , Granuloma/etiologia , Masculino , Camundongos , Estrutura Molecular , Testes de Toxicidade Aguda
8.
Eur J Med Chem ; 180: 486-508, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31330449

RESUMO

From many decades, S-heterocycles have maintained their status as an important part and core of FDA approved drugs and medicinally active compounds. With exhaustive exploration of nitrogen heterocycles in medicinal chemistry, researchers have shifted their interest towards other heterocycles, especially, S-heterocycles. Thus several attempts have been made to synthesize a variety of new sulphur containing compounds with high medicinal value and low toxicity profile, in comparison to previous N-heterocycles. Till today, S-heterocycle containing compounds have been largely reported as anticancer, antidiabetic, antimicrobial, antihypertension, antivral, antinflammatory etc. In this review, the authors have tried to provide a critical analysis of synthesis and medicinal attributes of sulphur containing heterocycles such as thiirane, thiophene, thiazole, thiopyran, thiazolidine etc reported within last five years to emphasize the significance and usefulness of these S-heterocycles in the drug discovery process.


Assuntos
Compostos Heterocíclicos/farmacologia , Enxofre/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Química Farmacêutica , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Enxofre/química
9.
J Biosci ; 44(2)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31180043

RESUMO

In this study, zinc oxide nanoparticles (ZnO-NPs) were synthesized using the extract of Hyssops officinalis L. via green method and confirmed by transmission electron microscopy, field emission scanning electron microscopy, X-ray powder diffraction and Fourier transforms infrared spectroscopy techniques. In the in vivo section, the anti-angiogenesis and antiinflammatory properties of the NPs were evaluated by the chorioallantoic membrane (CAM) assay and mouse paw edema test (induced by carrageenan), respectively. In the in vitro section, changes in the expression of angiogenesis genes (VEGF and VEGFR) and inflammatory genes (IL-1B and IL-10) were investigated by real-time quantitative polymerase chain reaction technique. In order to evaluate the cytotoxicity of ZnO-NPs, 3-5, 4-dimethylthiazol-2-yl) -5, 2-tetrazolium bromide (MTT) test was used on MDA-MB231 breast adenocarcinoma cell line. The results of the CAM assay showed that the ZnO-NPs significantly reduced the number and length of blood vessels, as well as the size and weight of the embryos. Evaluation of mouse paw edema showed that the NPs are able to decrease inflammation. Changes in the expression pattern of VEGF and VEGFR genes in MCF7 cells showed that the NPs have inhibitory effect on the expression of both genes. Expression levels of IL-10 and IL-1B genes also increased and decreased, respectively. The MTT test showed that the NP have the ability to decrease breast cancer cells. In conclusion, our results confirm that the ZnO-NPs synthesized by green method have promising anti-cancer properties.


Assuntos
Inibidores da Angiogênese/síntese química , Anti-Inflamatórios/síntese química , Citotoxinas/síntese química , Edema/tratamento farmacológico , Hyssopus/química , Nanopartículas/administração & dosagem , Óxido de Zinco/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Carragenina/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Citotoxinas/farmacologia , Edema/induzido quimicamente , Edema/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Química Verde , Membro Posterior , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Células MCF-7 , Camundongos , Nanopartículas/química , Extratos Vegetais/química , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Óxido de Zinco/química
10.
Molecules ; 24(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31247960

RESUMO

Natural products play an important role in drug discovery. This work employed a natural product 1-methylhydantoin as the lead compound to develop novel dual-active drugs. 1-Methylhydantoin was isolated from Oviductus Ranae, which is a traditional Chinese medicine that has been used for tussive and inflammation treatment for a long time. An in silico study screened the more active 1-methylhydantoin derivatives. Antitussive assessment indicated that the newly synthesized agent had similar bioactivity with the natural product. An anti-inflammatory model used xylene induced ear edema model. At the same dosage (100 mg/Kg), the newly prepared agent had an inhibition rate 53.18% which was much higher than that of the lead compound (22.69%). The results might be ascribed to the cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2) selectivity, and the fitness of the compound, and the binding pocket. The anti-particulate matter (PM 2.5) acute pneumonia was evaluated through an in vivo model constructed by nasal instillation with PM 2.5 suspension. The results of the above models suggested that this novel agent had remarkable antitussive, anti-inflammatory, and anti-PM 2.5 acute pneumonia activities.


Assuntos
Anti-Inflamatórios/farmacologia , Antitussígenos/farmacologia , Produtos Biológicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Hidantoínas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antitussígenos/síntese química , Antitussígenos/química , Produtos Biológicos/química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Desenho de Drogas , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/química , Hidantoínas/síntese química , Hidantoínas/química , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
11.
Int J Biol Macromol ; 136: 738-754, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220500

RESUMO

Water soluble hydrazide based O-carboxymethyl chitosan Schiff base ligands have been prepared from chitosan and a mixture of benzoic acidhydrazide with ß-diketone by carboxymethylation using mono chloroaceticacid (MCA) through in-situ reaction. The degree of deacetylation of chitosan was determined by elemental analysis and potentiometric titration. Schiff base ligands and the functional groups were characterised by FT-IR, 1H, and 13C NMR spectroscopic techniques. The crystallinity of ligands and complexes was evaluated by X-ray powder diffraction (XRD) studies. Thermal stability of all the synthesized compounds was investigated by thermo gravimetric analysis and differential thermal analysis (TGA-DTA) which revealed the presence of metal oxide (CuO) residue to elevate the temperature to >500 °C. Filed emission scanning electron microscopic (FESEM) analysis revealed that Cu (II) complexes were more amorphous in nature than chitosan and Schiff base ligands. Vibrating sample magnetometer (VSM) studies reported that the d9 configuration of the metal complex was paramagnetic in nature and the geometry of the complex was square pyramidal. The antimicrobial activity of the synthesized hydrazide Cu (II) complexes was characterised by agar plate method, anti-inflammatory study was characterised by egg albumin denaturation technique and total antioxidant activity was characterised by phosphomolybdenum method.


Assuntos
Quitosana/análogos & derivados , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Hidrazinas/química , Água/química , Albuminas/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Técnicas de Química Sintética , Quitosana/química , Complexos de Coordenação/química , Ligantes , Nitrogênio/química , Oxigênio/química , Desnaturação Proteica/efeitos dos fármacos , Bases de Schiff/química , Solubilidade
12.
Eur J Med Chem ; 177: 171-187, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132532

RESUMO

Nur77, an orphan member of the nuclear receptor superfamily, plays an important role in the regulation of inflammatory processes. Our previous work found that celastrol, a pentacyclic triterpene, bound to Nur77 to inhibit inflammation in a Nur77-dependent manner. Celastrol binding to Nur77 promotes Nur77 translocation from nucleus to cytoplasm, resulting in clearance of inflamed mitochondria and then alleviation of inflammation. Here, we report the design, synthesis, SAR study and biological evaluation of a series of celastrol analogs. A total of 24 celastrol derivatives were made. Compound 3a with a Kd of 0.87 µM was found to be less toxic than celastrol and could be a hit molecule for further optimization.


Assuntos
Anti-Inflamatórios/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/toxicidade , Sítios de Ligação , Desenho de Drogas , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/química , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismo , Relação Estrutura-Atividade , Fator 2 Associado a Receptor de TNF/metabolismo , Triterpenos/síntese química , Triterpenos/metabolismo , Triterpenos/toxicidade , Peixe-Zebra
13.
Molecules ; 24(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035404

RESUMO

Cancer patients frequently suffer from cancer-related fatigue (CRF), which is a complex syndrome associated with weakness and depressed mood. Neuroinflammation is one of the major inducers of CRF. The aim of this study is to find a potential agent not only on the treatment of cancer, but also for reducing CRF level of cancer patients. In this study, total-thirty new Dihydroartemisinin-Coumarin hybrids (DCH) were designed and synthesized. The in vitro cytotoxicity against cancer cell lines (HT-29, MDA-MB-231, HCT-116, and A549) was evaluated. Simultaneously, we also tested the anti-neuroinflammatory activity of DCH. DCH could inhibit the activated microglia N9 release of NO, TNF-α, and IL-6. The docking analysis was shown that MD-2, the coreceptor of TLR4, might be one of the targets of DCH.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Anti-Inflamatórios/síntese química , Artemisininas/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 175: 114-128, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077997

RESUMO

In order to discover novel anti-inflammatory agents, total thirty-seven new resveratrol-based flavonol derivatives were designed and synthesized. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Their toxicity was also assessed in vitro. Structure-activity relationships (SARs) have been concluded, and finally 2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-4H-chromen-4-one was found to be the most active scaffold with low toxicity. This compound could significantly decrease productions of NO, IL-6 and TNF-α with IC50 values of 1.35, 1.12 and 1.92 µM, respectively in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4 protein, resulting in activation of the NF-ĸB cell signaling pathway. The in vivo anti-inflammatory activity of this compound could reduce pulmonary inflammation by mouse model of LPS-induced acute lung injury (ALI). We believe these findings would further support studies of rational design of more efficient acute lung injury regulatory inhibitors.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Interleucina-6/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Resveratrol/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios/toxicidade , Flavonoides/química , Flavonoides/toxicidade , Técnicas In Vitro , Concentração Inibidora 50 , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
J Microbiol Biotechnol ; 29(6): 856-862, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31091864

RESUMO

A series of thienopyrimidine compounds (6Aa-g and 6Ba-d) were synthesized and characterized by NMR spectroscopy and mass spectrometry. These compounds (6Aa-g and 6Ba-d) potently inhibited STAT3 expression induced by IL-6 in a dose-dependent manner with IC50 values of 5.73-0.32 µM. Among the prepared thienopyrimidine derivatives, 6Aa, 6Ab, 6Ba and 6Bc significantly suppressed the phosphorylation of STAT3 and ERK1/2 stimulated by IL-6 in Hep3B cells. Furthermore, the synthesized compounds might be useful remedies for the treatment of inflammatory diseases by inhibiting the action of IL-6.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Anti-Inflamatórios/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/farmacologia , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas , Pirimidinas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
16.
Drug Dev Res ; 80(5): 666-679, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31112325

RESUMO

Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti-inflammatory effects. The objective of this study was to investigate the anti-inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP-VT), in mice. The results of this study indicated that ISP-VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP-VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor-α and interleukin-6), and vascular permeability. ISP-VT also significantly reduced the expression of cyclooxygenase-2 (COX-2) in subplantar tissue of mice. ISP-VT inhibited COX-2 selectively compared to the standard drug. Our results showed that although ISP-VT binds to COX-1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP-VT significantly reduced rectal temperature in yeast-induced hyperthermia in mice. Our results showed that the main mechanism ISP-VT-induced anti-inflammatory activity is by inhibition of COX-2. In conclusion, our results indicate that ISP-VT has potential as an anti-inflammatory and antipyretic therapeutic compound.


Assuntos
Anti-Inflamatórios/administração & dosagem , Carragenina/efeitos adversos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inflamação/tratamento farmacológico , Fenóis/efeitos adversos , Ácido Vanílico/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Modelos Moleculares , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
17.
Eur J Med Chem ; 176: 456-475, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31128448

RESUMO

H2S donors are substitutes of H2S with various biological activities like inhibiting the inflammatory response and protecting myocardial cells from injury. In order to confirm whether the H2S donors have drug-like properties, two series thiophosphamide H2S donors were evaluated including toxicity, bioactivity and pharmacokinetic properties in vivo and in vitro. The following results were obtained. Firstly, all the compounds released H2S under measuring condition; with the increase of pH value, the H2S release rate of all the compounds decreased and the amount reduced, but pH value had little effect on the maximum release of H2S. Secondly, in the organs and tissues of rats, the compounds released H2S in the same way as in PBS. In plasma, compound 1 reached the Cmax after administration 55 min, and no compound 1 was detected after 12 h; for compound 18, the Cmax reached only after administration 100 min, and after 6 h, compound 18 was not detected; in organs and tissues, the H2S-release rates were different from those in PBS, but the mechanism of H2S release was the same. Thirdly, in the test of toxicity, all the compounds displayed low toxicities to 5 cancer cells and W138 cell lines; compounds 1 and 18 had slight effect on the physiological tissue and function of rat liver at low concentration; the compounds had almost no effect on the hatching rate, survival rate of zebrafish embryos, and the spontaneous movement of zebrafish embryos at below 0.5 µM, but when they were over 1 µM, the compounds displayed inhibitory effect in the manner of concentration dependence. Fourthly, in the course of anti-inflammatory test, all the tested compounds significantly reduced the level of TNF-α and increased the level of IL-10; when they were 100 µM, the levels of IL-10 were three times as high as those in the control group. Among them, compounds 10 and 18 displayed stronger activities than the others. In addition, the compounds protected H9c2 cells from injure and improved myocardial injury through anti-oxidation pathway. In summary, the compounds have druglike properties due to low toxicity, better activity and good pharmacokinetic property. Therefore, they have potential to be as candidates to investigate further.


Assuntos
Anti-Inflamatórios/farmacocinética , Cardiotônicos/farmacocinética , Sulfeto de Hidrogênio/metabolismo , Compostos Organotiofosforados/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Cardiotônicos/síntese química , Cardiotônicos/química , Cardiotônicos/toxicidade , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Humanos , Sulfeto de Hidrogênio/sangue , Sulfeto de Hidrogênio/química , Concentração de Íons de Hidrogênio , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Modelos Químicos , Miocárdio/metabolismo , Compostos Organotiofosforados/síntese química , Compostos Organotiofosforados/química , Compostos Organotiofosforados/toxicidade , Células RAW 264.7 , Ratos Wistar , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Temperatura Ambiente , Teratogênios/síntese química , Teratogênios/química , Teratogênios/farmacocinética , Teratogênios/toxicidade , Peixe-Zebra
18.
Acta Crystallogr C Struct Chem ; 75(Pt 4): 388-397, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30957784

RESUMO

Three new diclofenac-based copper(II) complexes, namely tetrakis{µ-2-[2-(2,6-dichloroanilino)phenyl]acetato-κ2O:O'}bis(methanol-κO)copper(II), [Cu2(µ-dicl)4(CH3OH)2] (1), bis{2-[2-(2,6-dichloroanilino)phenyl]acetato-κ2O,O'}bis(1-vinyl-1H-imidazole-κN3)copper(II), [Cu(dicl)2(vim)2] (2), and bis{2-[2-(2,6-dichloroanilino)phenyl]acetato-κ2O,O'}bis(1H-imidazole-κN3)copper(II), [Cu(dicl)2(im)2] (3) [dicl is diclofenac (C14H10Cl2NO2), vim is 1-vinylimidazole (C5H6N2) and im is imidazole (C3H4N2)], have been synthesized and characterized by elemental analysis, FT-IR spectroscopy, thermal analysis and single-crystal X-ray diffraction. X-ray diffraction analysis shows that complex 1 consists of dimeric units in which the dicl ligand exhibits a bidentate syn,syn-µ2 coordination mode linking two copper(II) centres. Complexes 2 and 3 have mononuclear units with the general formula [Cu(dicl)2L2] (L is vim or im) in which the CuII ions are octahedrally coordinated by two L and two dicl chelating ligands. The L and dicl ligands both occupy the trans positions of the coordination octahedron. The different coordination modes of dicl in the title complexes were revealed by Fourier transform IR (FT-IR) spectroscopy. The spin matching between the copper(II) centres in the dimeric [Cu2(µ-dicl)4(CH3OH)2] units was also confirmed by magnetic data to be lower than the spin-only value and electron paramagnetic resonance (EPR) spectra. The thermal properties of the complexes were investigated by thermogravimetric (TG) and differential thermal analysis (DTA) techniques.


Assuntos
Anti-Inflamatórios/química , Complexos de Coordenação/química , Cobre/química , Diclofenaco/análogos & derivados , Anti-Inflamatórios/síntese química , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Diclofenaco/síntese química , Ligações de Hidrogênio , Ligantes , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Eur J Pharm Sci ; 134: 102-115, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002986

RESUMO

A series of aryl 7-chloroquinolinyl hydrazone derivatives (3a-u) have been synthesized in 55-76% yield using simple reaction condition. The synthesized compounds were evaluated for their anti-inflammatory activities based on their ability to inhibit pro-inflammatory cytokine secretion from the macrophages after stimulation with lipopolysaccharide (LPS). Three compounds appeared as promising anti-inflammatory agents. The mechanism of inflammatory activity of the potent compound 3e was further investigated using a series of biochemical, molecular and microscopic techniques. Further structure activity relationship (SAR) study was carried out to validate the anti-inflammatory activities of the active compounds. Our experimental data revealed that the active moiety i.e. compound 3e majorly causes inhibition of TLR4 signaling pathway and this appears to be the novel functional attribute of this compound.


Assuntos
Anti-Inflamatórios/farmacologia , Hidrazonas/síntese química , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Hidrazonas/química , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
J Antibiot (Tokyo) ; 72(6): 498-506, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30988370

RESUMO

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a growing class of natural products found in organisms ranging from plants to humans. The roles these endogenous derivatives of fatty acids play in biology and their novel pathways for controlling inflammation have increased our understanding of basic human physiology. FAHFAs incorporate diverse fatty acids into their structures, however, given their recent discovery non-natural derivatives have not been a focus and as a result structure-activity relationships remain unknown. The importance of the long chain hydrocarbons extending from the ester linkage as they relate to anti-inflammatory activity is unknown. Herein the systematic removal of carbons from either the hydroxy fatty acid or fatty acid regions of the most studied FAHFA, palmitic acid ester of 9-hydroxystearic acid (9-PAHSA), was achieved and these synthetic, abridged analogs were tested for their ability to attenuate IL-6 production. Reduction of the carbon chain lengths of the 9-hydroxystearic acid portion or palmitic acid hydrocarbon chain resulted in lower molecular weight analogs that maintained anti-inflammatory activity or in one case enhanced activity.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ácido Palmítico/química , Ácido Palmítico/farmacologia , Ácidos Esteáricos/química , Ácidos Esteáricos/farmacologia , Animais , Anti-Inflamatórios/química , Camundongos , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade
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