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1.
J Ethnopharmacol ; 247: 112259, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31577938

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ximenia americana L. is popularly known as yellow plum, brave plum or tallow wood. All the parts of this plant are used in popular medicine. Its reddish and smooth bark are used to treat skin infections, inflammation of the mucous membranes and in the wound healing process. OBJECTIVE: Verification of phytochemical profile, the molecular interaction between flavonoid, (-) epi-catechin and 5-LOX enzyme, by means of in silico study, the genotoxic effect and to investigate the pharmacological action of the aqueous extract of the stem bark of X. americana in pulmonary alterations caused by experimental COPD in Rattus norvegicus. MATERIALS AND METHODS: The identification of secondary metabolites was carried out by TLC and HPLC chromatographic methods, molecular anchoring tests were applied to analyze the interaction of flavonoid present in the extract with the enzyme involved in pulmonary inflammation process and the genotoxic effect was assessed by comet assay and micronucleus test. For induction of COPD, male rats were distributed in seven groups. The control group was exposed only to ambient air and six were subjected to passive smoke inhalations for 20 min/day for 60 days. One of the groups exposed to cigarette smoke did not receive treatment. The others were treated by inhalation with beclomethasone dipropionate (400 mcg/kg) and aqueous and lyophilized extracts of X. americana (500 mg/kg) separately or in combination for a period of 15 days. The structural and inflammatory pulmonary alterations were evaluated by histological examination. Additional morphometric analyses were performed, including the alveolar diameter and the thickness of the right ventricle wall. RESULTS: The results showed that the aqueous extract of the bark of X. americana possesses (-) epi -catechin, in silico studies with 5-LOX indicate that the EpiC ligand showed better affinity parameters than the AracA ligand, which is in accordance with the results obtained in vivo studies. Genotoxity was not observed at the dose tested and the extract was able to stagnate the alveolar enlargement caused by the destruction of the interalveolar septa, attenuation of mucus production and decrease the presence of collagen fibers in the bronchi of animals submitted to cigarette smoke. CONCLUSION: Altogether, the results proved that the aqueous extract of X. americana presents itself as a new option of therapeutic approach in the treatment of COPD.


Assuntos
Dano ao DNA/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Olacaceae/química , Extratos Vegetais/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/farmacologia , Brasil , Modelos Animais de Doenças , Etnofarmacologia , Feminino , Humanos , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/isolamento & purificação , Inibidores de Lipoxigenase/uso terapêutico , Masculino , Simulação de Acoplamento Molecular , Testes de Mutagenicidade , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Caules de Planta/química , Doença Pulmonar Obstrutiva Crônica/etiologia , Ratos , Ratos Wistar , Poluição por Fumaça de Tabaco/efeitos adversos , Resultado do Tratamento
2.
Pak J Pharm Sci ; 32(4): 1703-1708, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608893

RESUMO

Zanthoxylum armatum (DC) is a traditional spice and important herb used in Asia as a part of food and household medicine for the treatment of various conditions. The present study was designed to investigate in vitro for phenolic/flavonoid contents, antioxidant activities, lipoxygenase inhibitory activity, minerals and heavy-metal contents. The leaves, bark and fruit of Zanthoxylum armatum were extracted with organic solvent and evaluated for phenolic contents (Folin-Chiocalteu method), for flavonoids contents (colorimetric method), for in vitro antioxidant assays (DPPH and FRAP), lipoxygenase inhibitory activity (5-LOX assay), mineral contents (atomic absorption), and for heavy-metal contaminants (atomic absorption). The fruit contained the highest phenolic (25.6±1.2mg GAE/g) and flavonoid (26.3±1.4mg QE/g) contents and therefore, exhibited the most effective antioxidant properties in DPPH (88.5±0.9% inhibition) and FRAP (94.21±3.2% inhibition) assays. The extracts also inhibited the LOX enzyme, and the fruit showed more inhibition (63.8±1.2 %) as compared with the leaves and bark. Z. armatum contain valuable minerals and fortified with magnesium (4.948±0.2, 3.07±0.03 and 3.53±0.12) and potassium (0.19±0.011, 1.91±0.003, and 1.90±0.05) for leaves, fruit, and bark, respectively. The chemical profiling for heavy metals showed that their concentrations were within permissible limits. The data suggest that Z. armatum is a safe and valuable natural agent with functional properties for food and pharmaceutical industries.


Assuntos
Antioxidantes/farmacologia , Inibidores de Lipoxigenase/farmacologia , Fenóis/análise , Extratos Vegetais/farmacologia , Zanthoxylum/química , Antioxidantes/química , Avaliação Pré-Clínica de Medicamentos , Flavonoides/análise , Frutas/química , Inibidores de Lipoxigenase/química , Metais Pesados/análise , Casca de Planta/química , Extratos Vegetais/química , Folhas de Planta/química , Oligoelementos/análise
3.
Pak J Pharm Sci ; 32(3 Special): 1285-1291, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551205

RESUMO

Synthesis of new antioxidants and enzyme inhibitors is an active area of research in pharmaceutical sciences. This can be used for development of new active product ingredients which can prevent body from different diseases. This study comprises of preparation of transition metal complexes using 4-(4-bromophenyl)-2,2'-bipyridine (BPBP) and their screening for antioxidant and lipoxygenase inhibition properties. 4-(4-bromophenyl)-[2,2'-bipyridine]-6-carboxylic acid was used as starting material and its decarboxylation resulted in BPBP. Decarboxylation by conventional heating method was compared with microwave decarboxylation method. Selected metal complexes of the ligand were synthesized with Ruthenium (II), Iron (II) and Cobalt (II) ions. The complexes were characterized using UV, IR, 1H-NMR, ESI-MS and CHNS techniques. It was observed that BPBP acted as a bidentate ligand. The metal to ligand stoichiometry was 1:3 for all the synthesized complexes. The complexes had octahedral structure with C3 symmetry. The antioxidant activity was evaluated using free radical scavenging assay. BPBP showed insignificant antioxidant and lipoxygenase activities while its transition metal complexes showed promising activities. Antioxidant activity of Fe and Co-complexes was found significantly higher than the reference drug used in this study.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Complexos de Coordenação/química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , 2,2'-Dipiridil/química , Antioxidantes/síntese química , Cobalto/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ferro/química , Ligantes , Inibidores de Lipoxigenase/síntese química , Espectroscopia de Ressonância Magnética , Micro-Ondas , Estrutura Molecular , Rutênio/química
4.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
5.
Eur J Med Chem ; 180: 41-50, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31299586

RESUMO

In this work, a series of novel indole-2-amide compounds were designed, synthesized, characterized and the anti-inflammatory activity in vivo were evaluated. Compounds 8a, 10b, 12h, and 12l exhibited marked anti-inflammatory activity in 2,4-Dinitrofluorobenzenethe (DNFB) - induced mice auricle edema model. Further, compounds 8a, 10b and 12h exhibited potential in vitro COX-2 inhibitory activity (IC50 = 21.86, 23.3 and 23.21 nM, respectively), while the reference drug celecoxib was 11.20 nM. The most promising compound 10b was exhibited the highest selectivity for COX-2 (selectivity index (COX-1/COX-2) = 17.45) and moderate 5-LOX inhibitory activity (IC50 = 66 nM), which comparable to positive controlled zileuton (IC50 = 38.91 nM). In addition, the test results showed compounds 10b and 12h no significant cytotoxic activity on normal cells (RAW264.7). Further, at the active sites of the COX-1, COX-2 co-crystals, 3b and 4l showed higher binding forces in the molecular docking study, which consistent with the results of in vitro experiments. These results demonstrated that these compounds had dual inhibitory activity of COX/5-LOX, providing clues for further searching for safer and more effective anti-inflammatory drugs.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Indóis/farmacologia , Inibidores de Lipoxigenase/farmacologia , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Araquidonato 5-Lipoxigenase/metabolismo , Sobrevivência Celular/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 , Indóis/síntese química , Indóis/química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade
6.
Pak J Pharm Sci ; 32(3): 911-917, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278699

RESUMO

Flavonoids are phenolic compounds that have always attracted pharmaceutical researchers and food manufacturers. Nature has indirectly provided us flavones in our daily diet i.e. tea, fruits, juices and vegetables. Flavones have got special position in research field of natural and synthetic organic chemistry due to their biological capabilities. Three substituted flavone derivatives have been synthesized from substituted O-hydroxy acetophenones and 4-trifluoromethyl benzaldehyde in good yield. The structures have been established by different spectroscopic techniques like 1HNMR 13CNMR, IR spectroscopy. The compounds were then screened for their enzyme inhibition potential and antinociceptive response in mice models with writhings induced by acetic acid, tail immersion and formalin-induced nociception assay procedures and structure activity relationship was established. The effects following pretreatment with naloxone were also studied to reveal the involvement of opioid receptors in the antinociceptive action. The flavone derivatives showed moderate to weak inhibition against LOX. Moreover, significant to moderate decrease in the number of abdominal constrictions, increase in paw-licking response time in both phases and a significant raise in latency time in nociception models. Moreover, the antinociceptive response was significantly attenuated by pretreatment with opioid receptor antagonist suggesting the involvement of opioidergic system in the analgesic action. The flavone derivatives showed analgesic response in all models of nociception suggesting the possible involvement of opioidergic system in the antinociceptive action.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Dor/tratamento farmacológico , Analgésicos/síntese química , Animais , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Flavonoides/síntese química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Estrutura Molecular , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/etiologia , Espectrofotometria Infravermelho , Testes de Toxicidade Aguda
7.
Eur J Med Chem ; 179: 347-357, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260889

RESUMO

The inhibition of 5-lipoxygenase (5-LO), the key enzyme for the biosynthesis of leukotrienes (LTs), has generated increasing enthusiasm as anti-inflammatory and antitumor strategies in recent years. Based on our previous studies, we synthesized a series of dihydroxycinnamic acid-based analogs that might be 5-LO inhibitors. LTs biosynthesis inhibition in HEK293 cells and polymorphonuclear leukocytes (PMNL) was measured and antitumor activities were investigated in Renal Cell Carcinoma (RCC). Results showed that the 2,5-dihydroxycinnamic acid phenethyl ester (10b) was the best 5-LO inhibitor and was 7-fold more potent than Zileuton (1), the only clinically approved 5-LO inhibitor. 2,5-Dihydroxy substitution was more favorable to 5-LO inhibition since compound 10b is twice as active as CAPE (2) which is a 3,4-dihydroxylcinnamic acid ester. Meanwhile, 10b reduced the cell viability of renal cancer cells  and was more selective toward RCC4 and 786.0 cells which are deficient for the Von Hippel-Lindau (VHL) tumor suppressor gene. As to the underlying cell-death mechanisms, 10b induced apoptosis in VHL-deficient RCC4 cells. Also, increases in LC3B and p62 expression suggest a blockage of the autophagic flux in RCC in response to 10b.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Descoberta de Drogas , Neoplasias Renais/tratamento farmacológico , Inibidores de Lipoxigenase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Araquidonato 5-Lipoxigenase/biossíntese , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Relação Estrutura-Atividade
8.
Molecules ; 24(13)2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277326

RESUMO

Zanthoxylum mezoneurispinosum Ake Assi and Zanthoxylum psammophilum Ake Assi are species endemic to Côte d'Ivoire. In this study, we determined, for the first time, the composition and biological activities of essential oils obtained from each of these plants. Essential oils were obtained by hydrodistillation from different organs of each plant with a Clevenger-type apparatus and analyzed by gas chromatography-mass spectrometry (GC-MS). Thirty-four components, accounting for more than 99.9% of the overall composition, were identified in the oils. The Z. psammophilum leaf and trunk bark oils exhibited two unusual methylketones, undecan-2-one and tridecan-2-one, whereas the root oil was rich in thymol and sesquiterpenoids. The Z. mezoneurispinosum leaf and trunk bark oils were rich in monoterpenoids, whereas sesquiterpenoids were predominant in the root oil. These samples produced, for the first time, some new chemical profiles of essential oils. The oils' antioxidant activities were determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity and ferric reducing antioxidant power (FRAP) assays. The results showed that the essential oil isolated from roots of Z. mezoneurispinosum had the highest antioxidant activity, which is in accordance with the high thymol content of that oil. We also determined the lipoxygenase inhibitory activities of the essential oils. The results showed that all of the tested oils displayed high and close lipoxygenase inhibitory activities.


Assuntos
Antioxidantes/farmacologia , Inibidores de Lipoxigenase/farmacologia , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Zanthoxylum/química , Antioxidantes/química , Inibidores de Lipoxigenase/química , Óleos Voláteis/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Óleos Vegetais/química
9.
Eur J Med Chem ; 180: 637-647, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351395

RESUMO

Stilbenes with well-known antioxidant and antiradical properties are beneficial in different pathologies including cardiovascular diseases. The present research was performed to investigate the potential protective effect of resveratrol (1) and piceatannol (2), against hypoxia-induced oxidative stress in the H9c2 cardiomyoblast cell line, and the underlying mechanisms. Compounds 1 and 2 significantly inhibited the release of peroxynitrite and thiobarbituric acid levels at na no- or submicromolar concentrations, and this effect was more evident in piceatannol-treated cells, that significantly increased MnSOD protein level in a concentration dependent manner. Furthermore, since piceatannol, which is far less abundant in natural sources, displayed a higher bioactivity than the parent compound, we hereby report on a very fast synthesis and detailed structure-based design of a focused stilbene library. Finally, taking into account that hypoxia-induced ROS accumulation also increases expression and activity of 5-lipoxygenase (5-LOX) with production of leukotrienes, we have disclosed structural key factors crucial for 5-LOX activity. Among the synthesized analogues ( 3-7), compound 7 was the most effective in improving cardiomyocytes viability and in 5-LOX inhibition. In conclusion, modeling and experimental studies provided the basis for further optimization of stilbene analogues as multi-target inhibitors of the inflammatory and oxidative pathway.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Hipóxia , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Ratos , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade
10.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1253-1259, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303598

RESUMO

In this study, a range of oxamide ligands were synthesized by the reaction of amines with oxalyl chloride in basic medium. Spectroscopic and analytical techniques such as IR, 1H-NMR and ESI-MS techniques were used for characterization of the synthesized oxamides. The synthesized oxamides were screened for Lipoxygenase inhibition. Biological screening revealed that the oxamides possessed good lipoxygenase inhibition activities, whereas, the unsubstituted oxamide did not show any distinct lipoxygenase inhibition activity. Molecular docking studies of the oxamides were also carried out for lipoxygenase inhibition. The results obtained from molecular docking were well correlated with the empirical data.


Assuntos
Araquidonato 5-Lipoxigenase/química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Ácido Oxâmico/análogos & derivados , Aminas/química , Araquidonato 5-Lipoxigenase/metabolismo , Cloretos/química , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Oxalatos/química , Ácido Oxâmico/química , Conformação Proteica , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 175: 215-233, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082765

RESUMO

α-Santonin, a sesquiterpene lactone isolated from Artemisia Santonica, possesses diverse bioactivities including antioxidant, anti-inflammation, immunosuppressive, anti-roundworm, anti-malaria, etc. However, its bioactivities are not satisfactory and need to be further optimized. Thus, many α-santonin derivatives were synthesized on the basis of rings A, B and C for the discovery of new analogues with prominent bioactivities. Herein, we reviewed and discussed the related synthetic methodologies, diverse bioactivities and structure-activity relationships (SAR) of α-santonin derivatives.


Assuntos
Santonina/química , Santonina/farmacologia , Adjuvantes Imunológicos/farmacologia , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Herbicidas/farmacologia , Humanos , Inibidores de Lipoxigenase/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Plantas/efeitos dos fármacos , Santonina/síntese química , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacos , Tripanossomicidas/farmacologia
12.
Molecules ; 24(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30979087

RESUMO

The effect of elicitation with jasmonic acids (JA) and yeast extract (YE) on the production of phenolic compounds as well as the antioxidant and anti-inflammatory properties of phenolic extracts of lovage was evaluated. The analysis of phenolic compounds carried out with the UPLC-MS technique indicated that rutin was the dominant flavonoid, while 5-caffeoylquinic acid was the main component in the phenolic acid fraction in the lovage leaves. The application of 10 µM JA increased the content of most of the identified phenolic compounds. The highest antioxidant activities estimated as free radical scavenging activity against ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) and reducing power were determined for the sample elicited with 10 µM JA, while this value determined as iron chelating ability was the highest for the 0.1% YE-elicited lovage. The 0.1% and 1% YE elicitation also caused significant elevation of the lipoxygenase (LOX) inhibition ability, while all the concentrations of the tested elicitors significantly improved the ability to inhibit cyclooxygenase 2 (COX2) (best results were detected for the 10 µM JA and 0.1% YE2 sample). Thus, 0.1% yeast extract and 10 µM jasmonic acid proved to be most effective in elevation of the biological activity of lovage.


Assuntos
Anti-Inflamatórios/química , Antioxidantes/química , Levisticum/química , Fenóis/química , Benzotiazóis/química , Cromatografia Líquida de Alta Pressão , Ciclopentanos/química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Humanos , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Oxilipinas/química , Fenóis/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Rutina/química , Ácidos Sulfônicos/química , Espectrometria de Massas em Tandem , Leveduras/química
13.
Eur J Med Chem ; 169: 168-184, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877972

RESUMO

In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50 = 6.43-10.97 µM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50 = 194.01 µM vs.celecoxib: IC50 = 97.87 µM for 293T cells), and excellent inhibitory activities on COX-2 (IC50 = 0.17 µM) and 5-LOX (IC50 = 0.68 µM). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Azóis/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Lipoxigenase/farmacologia , Morfolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azóis/síntese química , Azóis/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Relação Estrutura-Atividade
14.
Bioorg Chem ; 85: 577-584, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30878890

RESUMO

A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC50 range of 6.4 - 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC50 = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC50 range of 1.77-4.91 nM comparing to meclofenamate sodium (IC50 = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Lipoxigenase/farmacologia , Naproxeno/análogos & derivados , Naproxeno/farmacologia , Oxidiazóis/farmacologia , Animais , Bovinos , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Desenho de Fármacos , Humanos , Inibidores de Lipoxigenase/síntese química , Linfócitos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Naproxeno/síntese química , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/farmacologia , Oxidiazóis/síntese química , Soja/enzimologia
15.
Pak J Pharm Sci ; 32(1): 217-220, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30772812

RESUMO

Millettia ovalifolia is traditionally used in variety of diseases including inflammation. In our investigation in to the phytochemical constituents of Millettia ovalifolia an effort was made to find out bioactive constituent from medicinal Plant M. ovalifolia to scientifically validate its use in inflammatory disorders. The compound 7-hydroxy-6-methoxy-2H-chromen-2-one was isolated from the bark of M. ovalifolia and was found to exhibited significant lipoxygenase (LOX) inhibitory activity with (IC50 value: 116.83±0.02µM). The Standard compounds Baicalein and Tenidap sodium revealed IC50 value being 22.1±0.03µM and 41.6±0.02µM. Molecular docking study further displayed significant molecular interactions between 7-hydroxy-6-methoxy-2H-chromen-2-one and LOX showed potential for further optimization as a possible anti-inflammatory lead compound.


Assuntos
Benzopiranos/farmacocinética , Descoberta de Drogas/métodos , Inibidores de Lipoxigenase/farmacologia , Lipoxigenases/metabolismo , Millettia , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Benzopiranos/química , Benzopiranos/isolamento & purificação , Flavanonas/farmacologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/isolamento & purificação , Lipoxigenases/química , Millettia/química , Oxindois/farmacologia , Casca de Planta , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Conformação Proteica , Relação Estrutura-Atividade
16.
Int J Toxicol ; 38(2): 121-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30739549

RESUMO

Metabolic activation of indirect-acting carcinogens in the target organ is an effective mechanism of carcinogenesis. Lipoxygenase (LOX) can co-oxidize the bladder carcinogen benzidine (BZ). However, it is not entirely clear whether BZ is activated and which enzyme is involved in its activation in bladder epithelial cells. Our results showed that BZ induced 5-LOX protein expression but had no significant influence on the expression of 15-LOX-2, CYP1B1, and CYP2E1 in SV-40 immortalized human uroepithelial SV-HUC-1 cells. BZ induced oxidative stress in SV-HUC-1 cells by increasing reactive oxygen species (ROS) and malondialdehyde levels significantly in the 100 and 200 µmol/L-BZ-treated groups and decreased the level of the antioxidant reduced glutathione significantly at 200 µmol/L BZ. Concurrently, the activity of catalase was increased, while the activity of superoxide dismutase was increased at 50 µmol/L BZ but gradually decreased with increasing concentrations of BZ ( P < 0.05). However, the oxidative stress and damage in SV-HUC-1 cells caused by BZ were effectively inhibited by the 5-LOX-specific inhibitor AA861 at 10 µmol/L. Thus, 5-LOX is probably the major LOX isozyme to co-oxidize exogenous chemicals in SV-HUC-1 cells. AA861 has a protective effect on the oxidative stress and damage induced by BZ in SV-HUC-1 cells. We conclude that BZ can be activated by 5-LOX to produce ROS and oxidative stress, which may be associated with bladder cancer caused by BZ.


Assuntos
Benzidinas/toxicidade , Carcinógenos/toxicidade , Lipoxigenase/metabolismo , Benzoquinonas/farmacologia , Catalase/metabolismo , Linhagem Celular , Humanos , Inibidores de Lipoxigenase/farmacologia , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Urotélio/citologia
17.
Food Chem ; 285: 431-440, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30797367

RESUMO

Stilbenoids represent a large group of bioactive compounds, which occur in food and medicinal plants. Twenty-five stilbenoids were screened in vitro for their ability to inhibit COX-1, COX-2 and 5-LOX. Piceatannol and pinostilbene showed activity comparable to the zileuton and ibuprofen, respectively. The anti-inflammatory potential of stilbenoids was further evaluated using THP-1 human monocytic leukemia cell line. Tests of the cytotoxicity on the THP-1 and HCT116 cell lines showed very low toxic effects. The tested stilbenoids were evaluated for their ability to attenuate the LPS-stimulated activation of NF-κB/AP-1. Most of the tested substances reduced the activity of NF-κB/AP-1 and later attenuated the expression of TNF-α. The effects of selected stilbenoids were further investigated on inflammatory signaling pathways. Non-prenylated stilbenoids regulated attenuation of NF-ĸB/AP-1 activity upstream by inhibiting the phosphorylation of MAPKs. A docking study used to in silico analyze the tested compounds confirmed their interaction with NF-ĸB, COX-2 and 5-LOX.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Anti-Inflamatórios não Esteroides/química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Células HCT116 , Humanos , Lipopolissacarídeos/farmacologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Prenilação , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Stroke ; 50(2): 520-523, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30602353

RESUMO

Background and Purpose- Subarachnoid hemorrhage (SAH) is a devastating form of stroke. Oxidative stress contributes to brain injury, but the mechanisms have been poorly studied. Here, we evaluated the role of 12/15-lipoxygenase (12/15-LOX), an enzyme known to cause cell death in ischemic stroke, on brain injury in a mouse model of SAH. Methods- C57Bl6 wild-type mice and Alox15 knockout mice were subjected to SAH using a direct blood injection technique. In SAH wild-type mice, half received the 12/15-LOX inhibitor ML351 and half received vehicle. Immunohistochemistry, brain edema, blood-brain barrier leakage and functional outcomes were assessed 1 and 3 days after SAH induction. Results- SAH led to increased 12/15-LOX in macrophages of the brain parenchyma, adjacent to the subarachnoid blood. Neuronal cell death after SAH was reduced by ML351 and in Alox15 knockout mice. Similarly, SAH induced brain edema, which was 12/15-LOX dependent. Finally, Alox15 gene knockout and inhibitor treatment in wild-type mice with SAH led to an improved behavioral outcome. Conclusions- 12/15-LOX is overexpressed in macrophages after SAH in mice, and inhibition of the 12/15-LOX pathway decreases brain injury and improves neurological outcome. This study suggests 12/15-LOX as a novel therapeutic target to limit brain injury after SAH.


Assuntos
Araquidonato 12-Lipoxigenase , Araquidonato 15-Lipoxigenase , Lesões Encefálicas , Isoxazóis/farmacologia , Inibidores de Lipoxigenase/farmacologia , Macrófagos , Naftalenos/farmacologia , Estresse Oxidativo , Hemorragia Subaracnóidea , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/metabolismo , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/enzimologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Macrófagos/enzimologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/enzimologia , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/patologia
19.
Molecules ; 24(2)2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650646

RESUMO

We have previously found two novel monoterpene glycosides, liguroside A and liguroside B, with an inhibitory effect on the catalytic activity of the enzyme leukocyte-type 12-lipoxygenase in the Qing Shan Lu Shui tea. Here, two new monoterpene glycosides, liguroside C and liguroside D which inhibit this enzyme, were isolated from the same tea. The spectral and chemical evidence characterized the structures of these compounds as (5E)-7-hydroperoxy-3,7-dimethyl-1,5-octadienyl-3-O-(α-l-rhamnopyranosyl)-(1''→3')-(4'''-O-trans-p-coumaroyl)-ß-d-glucopyranoside and (2E)-6-hydroxy-3,7-dimethyl-2,7-octadienyl-3-O-(α-l-rhamnopyranosyl)-(1''→3')-(4'''-O-trans-p-coumaroyl)-ß-d-glucopyranoside, respectively. These ligurosides, which irreversibly inhibited leukocyte-type 12-lipoxygenase, have a hydroperoxy group in the monoterpene moiety. Additionally, monoterpene glycosides had the same backbone structure but did not have a hydroperoxy group, such as kudingoside A and lipedoside B-III, contained in the tea did not inhibit the enzyme. When a hydroperoxy group in liguroside A was reduced by using triphenylphosphine, the resultant compound, kudingoside B, showed a lower inhibitory effect on the enzyme. These results strongly suggest the involvement of the hydroperoxy group in the irreversible inhibition of the catalytic activity of leukocyte-type 12-lipoxygenase by the monoterpene glycosides contained in the Qing Shan Lu Shui tea.


Assuntos
Leucócitos/efeitos dos fármacos , Leucócitos/enzimologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Chá/química , Araquidonato 12-Lipoxigenase/química , Relação Dose-Resposta a Droga , Glicosídeos/química , Glicosídeos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Monoterpenos/química , Monoterpenos/farmacologia
20.
Bioorg Med Chem ; 27(4): 604-619, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30638966

RESUMO

5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC50 values are 2.1 ±â€¯0.2 µM and 2.3 ±â€¯0.2 µM respectively, and are comparable to zileuton, IC50 = 1.4 ±â€¯0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.


Assuntos
Antioxidantes/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Piperidinas/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacocinética , Araquidonato 5-Lipoxigenase/química , Domínio Catalítico , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Peroxidases/química , Piperidinas/síntese química , Piperidinas/farmacocinética , Relação Estrutura-Atividade
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