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1.
Inorg Chem ; 58(21): 14626-14634, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31613591

RESUMO

The special linear dioxo cation structure of the uranyl cation, which relegates ligand coordination to an equatorial plane perpendicular to the O═U═O vector, poses an unusual challenge for the rational design of efficient chelating agents. Therefore, the planar hexadentate ligand rational design employed in this work incorporates two bidentate catecholamine (CAM) chelating moieties and a flexible linker with a ß-dicarbonyl chelating moiety (ß-dicarbonyl(CAM)2 ligands). The solution thermodynamics of ß-dicarbonyl(CAM)2 with a uranyl cation was investigated by potentiometric and spectrophotometric titrations. The results demonstrated that the pUO22+ values are significantly higher than for the previously reported TMA(2Li-1,2-HOPO)2, and efficient chelation of the uranyl cation was realized by the planar hexadentate ß-dicarbonyl(CAM)2. The efficient chelating ability of ß-dicarbonyl(CAM)2 was attributed to the presence of the more flexible ß-dicarbonyl chelating linker and planar hexadentate structure, which favors the geometric arrangement between ligand and uranyl coordinative preference. Meanwhile, ß-dicarbonyl(CAM)2 also exhibits higher antiradical efficiency in comparison to butylated hydroxyanisole. These results indicated that ß-dicarbonyl(CAM)2 has potential application prospects as a chelating agent for efficient chelation of a uranyl cation.


Assuntos
Antioxidantes/química , Catecolaminas/química , Quelantes/química , Termodinâmica , Urânio/química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Catecolaminas/síntese química , Catecolaminas/farmacologia , Cátions/química , Quelantes/síntese química , Quelantes/farmacologia , Ligantes , Estrutura Molecular , Picratos/antagonistas & inibidores
2.
Chem Biodivers ; 16(10): e1900362, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400187

RESUMO

A series of novel esters and amides was synthesized on the basis of para-coumaric acid containing isobornyl groups in ortho-positions relative to the phenolic hydroxy group. Antioxidant properties of the obtained compounds were evaluated and compared on in vitro models: radical-scavenging ability, antioxidant activity on a substrate containing the lipids of animal brain, cytotoxicity of red blood cells, antioxidant and membrane-protective properties on the model of oxidative red blood cells hemolysis. Statistically significant relationship was established between the antioxidant activity of the studied compounds in model system containing animal lipids and the parameters reflecting their antioxidant properties on the model of H2 O2 -induced hemolysis of red blood cells. It was determined that an amide with a morpholine fragment has the highest antioxidant activity. The specified derivative significantly surpassed the reference substances (parent acid, BHT) and was not inferior to the effective antioxidant 2,6-diisobornyl-4-methylphenol in terms of its properties.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , /farmacologia , Eritrócitos/efeitos dos fármacos , Propionatos/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Hidroxitolueno Butilado/química , /química , Hemólise/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Camundongos , Estrutura Molecular , Propionatos/síntese química , Propionatos/química
3.
Eur J Med Chem ; 182: 111601, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445233

RESUMO

The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Compostos Heterocíclicos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Carragenina , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
4.
J Agric Food Chem ; 67(38): 10653-10659, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31464427

RESUMO

Quercetin, a polyphenolic compound, is widely distributed in plants and has numerous health benefits. However, its hydrophilicity can compromise its use in lipophilic systems. For this reason, quercetin was esterified with 12 different fatty acids as their acyl chlorides with varying chain lengths and degrees of unsaturation. Two monoesters (Q-3'-O-monoester and Q-3-O-monoester) and four diesters (Q-7,3'-O-diester, Q-3',4'-O-diester, Q-3,3'-O-diester, and Q-3,4'-O-diester) were the major products as was shown by HPLC-MS and 1H-NMR data. The lipophilicity of quercetin derivatives was calculated; this was found to increase with fatty acid chain length. The antioxidant potential of quercetin and its derivatives was evaluated by using DPPH radical and ABTS radical cation scavenging activity; quercetin showed the highest radical scavenging activity among all tested samples. Despite the decrease of antioxidant activity in this study, the derivatives may show better antioxidant activity in lipophilic media and display improved absorption and bioavailability in the body once consumed.


Assuntos
Antioxidantes/química , Ésteres/química , Quercetina/química , Antioxidantes/síntese química , Cromatografia Líquida de Alta Pressão , Esterificação , Ácidos Graxos/química , Espectrometria de Massas , Estrutura Molecular
5.
Eur J Med Chem ; 182: 111596, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419776

RESUMO

Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aß protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells. Such MTDL were obtained by linking on a central piperidine two scaffolds of interest: a typical aminochlorobenzophenone present in numerous 5-HT4R agonists, and diverse antioxidant chemotypes. Interestingly, the most active compound 9g possesses a Ki of 12.7 nM towards 5-HT4R and an antioxidant activity in vitro and in cellulo.


Assuntos
Antioxidantes/farmacologia , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/metabolismo , Células COS , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Picratos/antagonistas & inibidores , Picratos/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/síntese química , Agonistas do Receptor 5-HT4 de Serotonina/química , Relação Estrutura-Atividade
6.
J Photochem Photobiol B ; 198: 111579, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401316

RESUMO

The sol-gel/ultrasonically rout produced the novel MnS2-SiO2 nano-hetero-photocatalysts with the various ratio of MnS2. Prepared nano-catalyst were investigated in the photo-degradation of methylene blue under UV light illumination. Structural and optical attributes of as-prepared nano-catalysts were evaluated by X-ray diffraction and photoelectron spectroscopy. The morphological were studied by scanning electron microscopy-EDS, and dynamic light scattering. The diffuse reflectance spectroscopy was applied to examine the band gap energy. The Eg values of SiO2, MnS2-SiO2-0, MnS2-SiO2-1, and MnS2-SiO2-2 nanocomposites are 6.51, 3.85, 3.17, and 2.67 eV, respectively. The particle size of the SiO2 and MnS2-SiO2-1 nanocomposites were 100.0, and 65.0 nm, respectively. The crystallite size values of MnS2-SiO2-1 were 52.21 nm, and 2.9 eV, respectively. MnS2-SiO2 nano-photocatalyst was recognized as the optimum sample by degrading 96.1% of methylene blue from water. Moreover, the influence of pH of the solution, and contact time as decisive factors on the photo-degradation activity were investigated in this project. The optimum data for pH and time were found 9 and 60 min, respectively. The photo-degradation capacity of MnS2-SiO2-2 is improved (96.1%) due to the low band gap was found from UV-vis DRS. The antimicrobial data of MnS2-SiO2 were studied and demonstrated that the MnS2-SiO2 has fungicidal and bactericidal attributes.


Assuntos
Anti-Infecciosos/química , Antioxidantes/química , Compostos de Manganês/química , Nanocompostos/química , Óxidos/química , Dióxido de Silício/química , Raios Ultravioleta , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antioxidantes/síntese química , Catálise , Escherichia coli/efeitos dos fármacos , Fungos/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Azul de Metileno/química , Tamanho da Partícula , Streptococcus pyogenes/efeitos dos fármacos
7.
Eur J Med Chem ; 180: 62-71, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301564

RESUMO

Oxidative stress and inflammation are major causes of numerous life-threatening human diseases. In the present study, we synthesized a series of phenylacrylamide derivatives as novel anti-oxidant and anti-inflammatory agents. Biological evaluation showed that compound 6a could more potently protect HBZY-1 mesangial cells from H2O2-caused oxidative stress than positive controls resveratrol and sulforaphane by dose- and time-dependently impairing the ROS accumulation. Preliminary anti-oxidant mechanism studies indicated that compound 6a could activate Nrf2 and increase the protein and mRNA expression of downstream anti-oxidant enzymes, ie. NQO-1, HO-1, GCLM and GCLC. Notably, 6a could inhibit the production of NO and the activity of NF-κB in LPS-stimulated HBZY-1 mesangial cells, indicating its potential anti-inflammatory activity. Interestingly, both effects could be significantly attenuated by Nrf2 inhibitor TRG, HO-1 inhibitor ZnPP or GCL inhibitor BSO at non-toxic concentrations, confirming that the anti-oxidant and anti-inflammatory activity of 6a is related to the activation of Nrf2 signaling pathway. These results, together with the relatively safety profile, indicated that compound 6a could be a promising lead to develop novel anti-oxidant and anti-inflammatory agents, thus preventing diseases induced by oxidative stress and inflammation.


Assuntos
Acrilamida/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Acrilamida/síntese química , Acrilamida/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 179: 515-526, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276896

RESUMO

Nineteen organoselenides were synthesized and tested for their intrinsic cytotoxicity in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines and their corresponding selective cytotoxicity (SI) was estimated using normal lung fibroblast (WI-38) cells. Most of the organic selenides exhibited good anticancer activity, and this was more pronounced in HepG2 cells. Interestingly, the naphthoquinone- (5), thiazol- (12), and the azo-based (13) organic selenides demonstrated promising SI (up to 76). Furthermore, the amine 4c, naphthoquinone 5, and azo-based 13 and 15 organic selenides were able to down-regulate the expression of Bcl-2 and up-regulate the expression levels of IL-2, IL-6 and CD40 in HepG2 cells compared to untreated cells. Moreover, most of the synthesized candidates manifested good free radical-scavenging and GPx-like activities comparable to vitamin C and ebselen. The obtained results suggested that some of the presented organoselenium candidates have promising anti-HepG2 and antioxidant activities.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células MCF-7 , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Picratos/antagonistas & inibidores , Picratos/metabolismo , Relação Estrutura-Atividade
9.
Molecules ; 24(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151176

RESUMO

Oxidative stress has been incriminated in the physiopathology of many diseases, such as diabetes, cancer, atherosclerosis, and cardiovascular and neurodegenerative diseases. There is a great interest in developing new antioxidants that could be useful for preventing and treating conditions for which oxidative stress is suggested as the root cause. The thiazolidine-2,4-dione derivatives have been reported to possess various pharmacological activities and the phenol moiety is known as a pharmacophore in many naturally occurring and synthetic antioxidants. Twelve new phenolic derivatives of thiazolidine-2,4-dione were synthesized and physicochemically characterized. The antioxidant capacity of the synthesized compounds was assessed through several in vitro antiradical, electron transfer, and Fe2+ chelation assays. The top polyphenolic compounds 5f and 5l acted as potent antiradical and electron donors, with activity comparable to the reference antioxidants used. The ferrous ion chelation capacity of the newly synthesized compounds was modest. Several quantum descriptors were calculated in order to evaluate their influence on the antioxidant and antiradical properties of the compounds and the chemoselectivity of the radical generation reactions has been evaluated. The correlation with the energetic level of the frontier orbitals partially explained the antioxidant activity, whereas a better correlation was found while evaluating the O-H bond dissociation energy of the phenolic groups.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Antioxidantes/síntese química , Quelantes/síntese química , Quelantes/química , Quelantes/farmacologia , Técnicas de Química Sintética , Transporte de Elétrons , Depuradores de Radicais Livres/síntese química , Radicais Livres/antagonistas & inibidores , Humanos , Estrutura Molecular , Fenóis/química , Teoria Quântica , Tiazolidinedionas/síntese química
10.
Appl Microbiol Biotechnol ; 103(15): 5957-5974, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177312

RESUMO

Hydroxytyrosol (HT) is a polyphenol of interest to the food, feed, supplements and pharmaceutical sectors. It is one of the strongest known natural antioxidants and has been shown to confer other benefits such as anti-inflammatory and anti-carcinogenic properties, and it has the potential to act as a cardio- and neuroprotectant. It is known to be one of the compounds responsible for the health benefits of the Mediterranean diet. In nature, HT is found in the olive plant (Olea europaea) as part of the secoiridoid compound oleuropein, in its leaves, fruit, oil and oil production waste products. HT can be extracted from these olive sources, but it can also be produced by chemical synthesis or through the use of microorganisms. This review looks at the production of HT using plant extraction, chemical synthesis and biotechnological approaches.


Assuntos
Antioxidantes/isolamento & purificação , Biotecnologia/métodos , Álcool Feniletílico/análogos & derivados , Tecnologia Farmacêutica/métodos , Antioxidantes/síntese química , Antioxidantes/metabolismo , Olea/química , Álcool Feniletílico/síntese química , Álcool Feniletílico/isolamento & purificação , Álcool Feniletílico/metabolismo
11.
Molecules ; 24(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075868

RESUMO

The valorization of lignins as renewable aromatic feedstock is of utmost importance in terms of the use of sustainable resources. This study provides a deductive approach towards market-oriented lignin-derived antioxidants by ascertaining the direct effect of different structural features of lignin on the reactivity of its phenolic OH groups in the radical scavenging reactions. The antioxidant activity of a series of compounds, modeling lignin structural units, was experimentally characterized and rationalized, using thermodynamic descriptors. The calculated O-H bond dissociation enthalpies (BDE) of characteristic lignin subunits were used to predict the modification pathways of technical lignins. The last ones were isolated by soda delignification from different biomass sources and their oligomeric fractions were studied as a raw material for modification and production of optimized antioxidants. These were characterized in terms of chemical structure, molecular weight distribution, content of the functional groups, and the antioxidant activity. The developed approach for the targeted modification of lignins allowed the products competitive with two commercial synthetic phenolic antioxidants in both free radical scavenging and stabilization of thermooxidative destruction of polyurethane films.


Assuntos
Antioxidantes/síntese química , Teoria da Densidade Funcional , Lignina/química , Modelos Teóricos , Dimerização , Elétrons , Hidrogênio/química , Cinética , Polifenóis/química , Poliuretanos/química , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura Ambiente
12.
Arch Pharm (Weinheim) ; 352(6): e1800354, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081964

RESUMO

Nineteen antioxidant pseudopeptides were designed and synthesized. They were confirmed as mild antioxidants, in which L1-11 was the most active antioxidant with a cellular antioxidant activity (CAA) value of 5.65 ± 0.64 µmol QE/g, and L1-12 was the second most active one (5.58 ± 0.66 µmol QE/g). The existence of nonnatural amino acids in L1-12 increased its stability. Pretreatment with L1-12 dose-dependently extended the lifespan of Caenorhabditis elegans. L1-12 improved resistance against UVB irradiation, oxidative stress induced by paraquat, and thermal shock. It decreased the reactive oxygen species level and upregulated the superoxide dismutase activity inside C. elegans. This pseudopeptide sensitively enhanced the expressions of the Cat-1 and Nhr-8 genes to reduce oxidative damage, leading to an extension of the lifespan. All the evidence support that L1-12 may probably be a potential antiageing agent.


Assuntos
Aminoácidos/síntese química , Antioxidantes/síntese química , Caenorhabditis elegans/efeitos dos fármacos , Desenho de Drogas , Longevidade/efeitos dos fármacos , Peptídeos/síntese química , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/efeitos da radiação , Proteínas de Caenorhabditis elegans/genética , Transportador 1 de Aminoácidos Catiônicos/genética , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Expressão Gênica/efeitos dos fármacos , Longevidade/genética , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Peptídeos/química , Peptídeos/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Relação Estrutura-Atividade
13.
IET Nanobiotechnol ; 13(2): 124-133, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31051442

RESUMO

For the first time, through a fast, eco-friendly and economic method, the aqueous extract of the leaf of Euphorbia corollate was used to the green synthesis of the highly stable CuO@Magnetite@Hen Bone nanocomposites (NCs) as a potent antioxidant and antibacterial agent against Pseudomonas aureus, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae pathogenic bacteria. The biosynthesised NCs were identified using the scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy, elemental mapping, X-ray diffraction (XRD), Fourier transforms infrared spectroscopy and UV-vis analytical techniques. Also, the radical scavenging activity using (2,2-diphenyl-1-picrylhydrazyl) method was used to evaluate the antioxidant activity of the NCs. The stability of nanocatalyst was monitored using the XRD and SEM analyses after 30 days from its synthesis. Furthermore, its excellent catalytic activity, recycling stability, and high substrate applicability were demonstrated to the adsorption of the polycyclic aromatic hydrocarbons of the light crude oil from Shiwashok oil fields and destruction of methylene blue and methyl orange as harmful organic dyes at ambient temperature using UV-vis spectroscopy. Moreover, the green CuO@Magnetite@Hen Bone NCs were recovered and reused several times without considerable loss of its catalytic activity.


Assuntos
Antibacterianos/síntese química , Antioxidantes/síntese química , Corantes/isolamento & purificação , Cobre/química , Nanopartículas de Magnetita/química , Hidrocarbonetos Policíclicos Aromáticos/isolamento & purificação , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Osso e Ossos/química , Galinhas , Corantes/metabolismo , Reutilização de Equipamento , Euphorbia/química , Feminino , Química Verde/métodos , Oxirredução , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Folhas de Planta/química , Hidrocarbonetos Policíclicos Aromáticos/metabolismo
14.
J Enzyme Inhib Med Chem ; 34(1): 898-908, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30938216

RESUMO

The rapid emergence of bacterial resistance to antibiotics currently available for treating infectious diseases requires effective antimicrobial agents with new structural profiles and mechanisms of action. Twenty-three thiazolin-4-one derivatives were evaluated for their antibacterial activity by determining the growth inhibition zone diameter, the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC), against gram-positive and gram-negative bacteria. Compounds 3a-c, 3e-h, 6b-c and 9a-c expressed better MIC values than moxifloxacin, against Staphylococcus aureus. Compounds 3h and 9b displayed similar effect to indolmycin, a tryptophanyl-tRNA ligase inhibitor. Due to their structural analogy to indolmycin, all compounds were subjected to molecular docking on tryptophanyl-tRNA synthetase. Compounds 3a-e, 6a-e, 8 and 9a-e exhibited better binding affinities towards the target enzymes than indolmycin. The antioxidant potential of the compounds was evaluated by four spectrophotometric methods. Thiazolin-4-ones 3e, 6e and 9e presented better antiradical activity than ascorbic acid, trolox and BHT, used as references.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Tiazóis/farmacologia , Triptofano-tRNA Ligase/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Triptofano-tRNA Ligase/metabolismo
15.
Carbohydr Polym ; 215: 108-118, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981335

RESUMO

In the current study, five novel urea-functionalized chitosan derivatives were synthesized via condensation reactions of chloroacetyl chitosan (CTCS) with urea groups bearing nitrogen-containing heterocycles. In order to identify the structure characteristics of chitosan derivatives, FT-IR, 1H NMR spectroscopy, and elemental analysis were carried out. The antifungal activity of the derivatives against four species of phytopathogen (Fusarium oxysporum f. sp. niveum, Phomopsis asparagus, Fusarium oxysporum f. sp. cucumebrium Owen, and Botrytis cinerea) was evaluated. Furthermore, the antioxidant activity of chitosan derivatives was tested by hydroxyl-radical scavenging and superoxide-radical scavenging assays. The results indicated that chitosan derivatives bearing urea groups displayed superior bioactivity compared with chitosan. Besides, L929 cells were adopted for cytotoxicity test of chitosan and synthesized samples by CCK-8 assay and all samples showed decreased cytotoxicity. These results suggested that the novel urea-functionalized chitosan derivatives could be an ideal biomaterial for antifungal and antioxidant applications.


Assuntos
Antifúngicos , Antioxidantes , Quitosana , Animais , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Quitosana/análogos & derivados , Quitosana/síntese química , Quitosana/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Camundongos , Ureia/química
16.
Artigo em Inglês | MEDLINE | ID: mdl-30961430

RESUMO

This study reports a novel and efficient method for the synthesis of the first reported novel class of pyrazole thioglycosides 6a-h. These series of compounds were designed through the reaction of sodium 2-cyano-3-oxo-3-(4-substitutedphenylamino)prop-1-ene-1,1-bis(thiolate) salts 2 with hydrazine hydrate in ethanol at room temperature to give the corresponding sodium 5-amino-4-(substitutedphenylcarbamoyl)-1H-pyrazole-3-thiolates 3a-d. The latter compounds were treated with protected α-D-gluco- and galacto-pyranosyl bromides 4a,b in DMF at ambient temperature to give in a high yields the corresponding pyrazole thioglycosides 6a-h. Treatment of pyrazole salts 3a-d with hydrochloric acid at amobient temperature afforded the corresponding 3-mercaptopyrazole derivatives 5. The latter compounds were treated with peracetylated sugars 4 in sodium hydride in ethanol at ambient temperature to tolerate the S-glycosyl 6a-h compounds. Ammonolysis of the pyrazole thioglycosides 6a-h afforded the corresponding free thioglycosides 7a-h. The toxicity and antitumor activities of the synthesized compounds were studied.


Assuntos
Antioxidantes/síntese química , Pirazóis/síntese química , Ribonucleosídeos/química , Tioglicosídeos/síntese química , Animais , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Desenho de Drogas , Masculino , Camundongos , Estrutura Molecular , Pirazóis/farmacologia , Pirazóis/toxicidade , Relação Estrutura-Atividade , Tioglicosídeos/farmacologia , Tioglicosídeos/toxicidade
17.
Eur J Med Chem ; 174: 142-158, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31035237

RESUMO

Recent clinical reports have highlighted the increasing occurrence of drug resistance of known therapeutics. Particularly, antibiotic resistant microorganisms and multidrug resistance have posed a serious threat to health of the people. Since ages, metals and metal complexes have played key role in the development of contemporary chemotherapy. Many organic compounds used in medicine do not have a purely organic mode of action and require traces of metal ions directly or indirectly for activation or biotransformation. For decades, the metallopharmaceuticals have attracted researchers across the globe due to their amplified therapeutic/modulatory effect by altering the pharmacokinetic and pharmacodynamic properties of the complexes towards biological receptors. Medicinally privileged natural and (semi)-synthetic chalcones have already been reported to possess a wide variety of pharmacological effects by modulating diverse molecular targets. The presence of carbonyl, hydroxyl, phenolic oxygen and/or heteroatom(s) in heterocyclic ring system makes them excellent chelating ligand for metal coordination. Particularly, the metal complexes of bidentate chalcone/Schiff base analogs and ferrocenyl chalcones have shown great potential. In this review, the chelating/coordinating property of substituted chalcones, the therapeutic, catalytic, chemosensing and photosensitizing potential of various metal-chalcone complexes, their structural features and structure activity relationships (SARs) have been highlighted. Further, the understanding of coordination mode, their stoichiometric characteristics, and mode of action(s), this review may be helpful for medicinal and bioinorganic chemists to design and develop novel, more potent, safe, selective and cost-effective chalcone-based coordination compounds for diverse biomedical applications.


Assuntos
Chalconas/farmacologia , Complexos de Coordenação/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Fungos/efeitos dos fármacos , Humanos , Metais Pesados/química , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Relação Estrutura-Atividade
18.
Bull Exp Biol Med ; 166(6): 779-784, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028582

RESUMO

The cytotoxicity and antioxidant effects of chitosan-(poly)nitoxides of different molecular weights containing a nitroxide radical of the piperidine structure were studied on tumor (HeLa, A172, and HepG2) and normal (Vero) cell lines. The chitosan-(poly)nitroxides exhibited low cytotoxicity. Under conditions of oxidative stress induced with tert-butyl hydroperoxide, the most pronounced decrease in ROS levels in the presence of chitosan-(poly)nitroxides was observed in normal cells. In cell homogenates, the decrease in malondialdehyde levels was observed only in the presence of low-molecular-weight chitosan-(poly)nitroxide irrespective of the cell line. Our data demonstrate that the cell-specific antioxidant properties of chitosan-(poly)nitroxides are related to their penetration into cells and interaction with intracellular membranes.


Assuntos
Antioxidantes/farmacologia , Quitosana/farmacologia , Óxidos de Nitrogênio/química , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Antioxidantes/síntese química , Linhagem Celular Tumoral , Quitosana/análogos & derivados , Quitosana/síntese química , Células HeLa , Células Hep G2 , Humanos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Especificidade de Órgãos , Piperidinas/síntese química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Células Vero , terc-Butil Hidroperóxido/antagonistas & inibidores , terc-Butil Hidroperóxido/farmacologia
19.
Molecules ; 24(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018515

RESUMO

At the present time, scientists place a great deal of effort worldwide trying to improve the therapeutic potential of metal complexes of curcumin and curcuminoids. Herein, the synthesis of four homoleptic metal complexes with diacetylcurcumin (DAC), using a ligand designed to prevent the interaction of phenolic groups, rendering metal complexes through the ß-diketone functionality, is reported. Due to their physiological relevance, we used bivalent magnesium, zinc, copper, and manganese for complexation with DAC. The resulting products were characterized by ultraviolet-visible (UV-Vis), fluorescence spectroscopy, infrared spectroscopy (IR), liquid and solid-state nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), magnetic moment, mass spectrometry (MS), single crystal, and powder X-ray diffraction (SCXRD and PXRD). Crystallization was achieved in dimethylsulfoxide (DMSO) or N,N-dimethylformamide (DMF) as triclinic systems with space group P-1, showing the metal bound to the ß-diketone function, while the 1H-NMR confirmed the preference of the enolic form of the ligand. Single crystal data demonstrated a 1:2 metal:ligand ratio. The inhibition of lipid peroxidation was evaluated using the thiobarbituric acid reactive substance assay (TBARS). All four metal complexes (Mg, Zn, Cu, and Mn) exhibited good antioxidant effect (IC50 = 2.03 ± 0.27, 1.58 ± 0.07, 1.58 ± 0.15 and 1.24 ± 0.10 µM respectively) compared with butylated hydroxytoluene (BHT) and α-tocopherol. The cytotoxic activity in human cancer cell lines against colon adenocarcinoma (HCT-15), mammary adenocarcinoma (MCF-7), and lung adenocarcinoma (SKLU-1) was found comparable ((DAC)2Mg), or ca. 2-fold higher ((DAC)2Zn) than cisplatin. The acute toxicity assays indicate class 5 toxicity, according to the Organization for Economic Co-operation and Development (OECD) guidelines at doses of 3 g/kg for all complexes. No mortality or changes in the behavior of animals in any of the treated groups was observed. A therapeutic potential can be envisaged from the relevant cytotoxic activity upon human cancer cell lines in vitro and the undetected in vivo acute toxicity of these compounds.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Curcumina/análogos & derivados , Magnésio/química , Manganês/química , Zinco/química , Animais , Antineoplásicos Fitogênicos/síntese química , Antioxidantes/síntese química , Hidroxitolueno Butilado/farmacologia , Cátions Bivalentes , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Curcumina/química , Células Epiteliais , Humanos , Concentração Inibidora 50 , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Células MCF-7 , Masculino , Camundongos , Modelos Moleculares , Testes de Toxicidade Aguda , alfa-Tocoferol/farmacologia
20.
Eur J Med Chem ; 171: 420-433, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928712

RESUMO

(E)-3,4-dihydroxystyryl alkyl sulfones, as new analogues of neurodegenerative agents, were designed and synthesized. The biological results demonstrated that most of the target compounds preserved antioxidant and anti-inflammatory potency in scavenging reactive free radicals, protecting neuronal cells against neurotoxins such as H2O2, 6-hydroxydopamine and inhibiting lipopolysaccharide (LPS)-induced over-production of NO. Among these compounds, 6.22 with cyclopentyl propyl exhibited prominent antioxidant activity at low concentration (2.5 µM) in H2O2 model (cell viability = 94.5%). In addition, 6.22 (IC50 = 1.6 µM) displayed better anti-inflammatory activity than that of lead compound 1 (IC50 = 13.4 µM). In view of the outstanding performance of 6.22, the apoptotic rates of H2O2-damaged PC12 cells were detected by Annexin V-FITC/PI assay. 6.22 showed higher potency in inhibition of apoptosis than 1 at low concentration (2.5 µM), consisting with the antioxidant and anti-inflammatory models. Furthermore, with the predicted CNS (+) blood-brain barrier (BBB) permeability (Pe = 6.84 × 10-6 cm s-1), low cytotoxicity and favorable physiochemical properties based on calculation, compound 6.22 can be further developed as a potential multifunctional neuroprotective agent.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/farmacologia , Camundongos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Permeabilidade/efeitos dos fármacos , Picratos/antagonistas & inibidores , Ratos , Relação Estrutura-Atividade
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