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1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361017

RESUMO

Glycogen synthase kinase-3 beta (GSK-3ß) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3ß allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3ß allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3ß allosteric modulators.


Assuntos
Sítio Alostérico , Glicogênio Sintase Quinase 3 beta/química , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Regulação Alostérica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Fármacos Neuroprotetores/química , Ligação Proteica
2.
J Mol Model ; 27(2): 26, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33410998

RESUMO

Flavonoids are a big class of natural product and have a wide range of biological activities. Some of these applications depend on its antioxidant capacity. Nevertheless, another mechanism can be involved by means of alkylation reaction on α,ß-unsaturated carbonyl system. This study aimed to evaluate the antioxidant capacity and the chemical reactivity among simplified flavonoid derivatives and isoxazolone analogous as Michael system by using B3LYP functional and 6-311 g(d,p) basis set. Frontier molecular orbital, ionization potential (IP), spin density contributions, and Fukui index explain the antioxidant capacity and reactivity index on isoxazolone and its related derivatives. The best contribution at ß-alkene moiety is related to better reactivity of α,ß-unsaturated carbonyl group. A decrease in antioxidant capacity is related to an increase in the chemical reactivity index. The frontier molecular orbitals show that aurone is more reactive than isoxazolone. In accordance with Fukui index, isoxazolone can be better inhibitor as Michael system when compared to flavonoid derivatives. Graphical abstract.


Assuntos
Flavonoides/química , Oxazóis/química , Teoria da Densidade Funcional , Modelos Moleculares
3.
J Biomol Struct Dyn ; 39(9): 3115-3127, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32338151

RESUMO

Adenosine A2A receptor (A2AR) is the predominant receptor in immune cells, where its activation triggers cAMP-mediated immunosuppressive signaling and the underlying inhibition of T cells activation and T cells-induced effects mediated by cAMP-dependent kinase proteins mechanisms. In this study, were used ADME/Tox, molecular docking and molecular dynamics simulations to investigate selective adenosine A2AR agonists as potential anti-inflammatory drugs. As a result, we obtained two promising compounds (A and B) that have satisfactory pharmacokinetic and toxicological properties and were able to interact with important residues of the A2AR binding cavity and during the molecular dynamics simulations were able to keep the enzyme complexed.Communicated by Ramaswamy H. Sarma.

4.
J Mol Model ; 26(11): 318, 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-33099704

RESUMO

A hypothetical study by using molecular modeling for antioxidant capacity of kojic acid derivatives was performed using quantum chemistry calculations by DFT/B3LYP/6-311++G(3d,2p). Four modification approaches were considered namely simplification, functional modifications, ring regioisomerism, and hydroxylation. Molecular orbitals, single-electron transfers, hydrogen atom transfers, and spin density distributions were used for antioxidant prediction. In accordance with HOMO, LUMO, Gap, ionization potential, bond dissociation energy, and stabilization energy, the molecular simplifications of kojic acid show that enol moiety is more important for antioxidant capacity than alcohol group. Few molecular modifications on alcohol or enol position were more potent than kojic acid. The π conjugation system among ether, alkene, and hydroxyl moieties can be involved on resonance effects of better compounds. A different performance was observed on alcohol molecular modifications when compared to enol position. All lactone derivatives were more potent than kojic acid on both mechanisms, and their hydroxylated derivatives were more potent than ascorbic acid. In conclusion, the ring regioisomers and its hydroxylated derivatives have better antioxidant capacity than kojic acid. Graphical Abstract The theoretical study using molecular modeling for antioxidant capacity prediction of kojic acid was more related to enol moiety than alcohol. The regioisomerism and hybrid derivatives show that the lactone derivatives increase antioxidant capacity more than the pyrone derivatives.

5.
Pharmaceuticals (Basel) ; 13(9)2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32858871

RESUMO

The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = -11.0 kcal/mol), LMQC36 (∆G = -10.6 kcal/mol), and LMQC50 (∆G = -10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = -10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = -45.31 kcal/mol; LMQC72: ΔGbind = -38.58 kcal/mol; LMQC36: ΔGbind = -36.10 kcal/mol; and LMQC50: ΔGbind = -39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.

6.
Saudi Pharm J ; 28(7): 819-827, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32647483

RESUMO

Edaravone is a heterocyclic pyrazolone compound. It has pronounced effect against free radicals, however renal and hepatic disorders have been reported. Isoxazolones are considered bioisosteric analogues of pyrazolones and may have comparable properties. Thus, we investigated the structural and electronic influences for edaravone, isoxazolone, and their tautomers on antioxidant process. Structure and tautomerism study among edaravone, isoxazolone and their heterocycles derivatives were related to antioxidant mechanisms by using the hybrid DFT method B3LYP with the basis sets 6-31++G(2d,2p). The C-H tautomer was the most stable and energetically favored among them. Intramolecular N-H-N hydrogen bonds and polar medium were responsible for the low energy differences among all possible tautomers. N-H tautomers in both systems proved to be better antioxidant by SET (single electron transfer), while O-H tautomers were better antioxidant on HAT (homolytic hydrogen atom transfer) mechanism. Theoretical calculation showed that edaravone is more potent than phenylisoxazolone, however, both has similar antioxidant scavenging on experimental DPPH. The carbonyliminic system played a very important role in the antioxidant activity for both studied classes.

7.
Molecules ; 25(5)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32164183

RESUMO

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.


Assuntos
Receptores A2 de Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade
8.
Molecules ; 24(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991684

RESUMO

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.


Assuntos
Anti-Inflamatórios não Esteroides/química , Benzoatos/química , Simulação por Computador , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/química , Ibuprofeno/química , Simulação de Acoplamento Molecular , Propionatos/química , Animais , Humanos , Camundongos , Ratos
9.
Molecules ; 24(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609687

RESUMO

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13⁻15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13⁻15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.


Assuntos
Fenilbutazona/química , Fenilbutazona/farmacologia , Descoberta de Drogas/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fenilbutazona/efeitos adversos , Fenilbutazona/toxicidade , Relação Estrutura-Atividade
10.
J Nanosci Nanotechnol ; 18(7): 4987-4991, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29442683

RESUMO

The electronic structures and optical properties of triphenylamine-functionalized graphene (G-TPA) doped with transition metals, using water as a solvent, were theoretically investigated to verify the efficiency of photocatalytic hydrogen production with the use of transition metals. This study was performed by Density Functional Theory and Time-dependent Density Functional Theory through Gaussian 09W software, adopting the B3LYP functional for all structures. The 6-31g(d) basis set was used for H, C and N atoms, and the LANL2DZ basis set for transition metals using the Effective Core Potentials method. Two approaches were adopted: (1) using single metallic dopants (Ni, Pd, Fe, Os and Pt) and (2) using combinations of Ni with the other dopants (NiPd, NiPt, NiFe and NiOs). The DOS spectra reveal an increase of accessible states in the valence shell, in addition to a gap decrease for all dopants. This doping also increases the absorption in the visible region of solar radiation where sunlight is most intense (400 nm to 700 nm), with additional absorption peaks. The results lead us to propose the G-TPA structures doped with Ni, Pd, Pt, NiPt or NiPd to be novel catalysts for the conversion of solar energy for photocatalytic hydrogen production, since they improve the absorption of solar energy in the range of interest for solar radiation; and act as reaction centers, reducing the required overpotential for hydrogen production from water.

11.
J Mol Model ; 23(8): 224, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28710571

RESUMO

Density functional theory was performed for thermodynamic predictions on natural gas, whose B3LYP/6-311++G(d,p), B3LYP/6-31+G(d), CBS-QB3, G3, and G4 methods were applied. Additionally, we carried out thermodynamic predictions using G3/G4 averaged. The calculations were performed for each major component of seven kinds of natural gas and to their respective air + natural gas mixtures at a thermal equilibrium between room temperature and the initial temperature of a combustion chamber during the injection stage. The following thermodynamic properties were obtained: internal energy, enthalpy, Gibbs free energy and entropy, which enabled us to investigate the thermal resistance of fuels. Also, we estimated an important parameter, namely, the specific heat ratio of each natural gas; this allowed us to compare the results with the empirical functions of these parameters, where the B3LYP/6-311++G(d,p) and G3/G4 methods showed better agreements. In addition, relevant information on the thermal and mechanic resistance of natural gases were investigated, as well as the standard thermodynamic properties for the combustion of natural gas. Thus, we show that density functional theory can be useful for predicting the thermodynamic properties of natural gas, enabling the production of more efficient compositions for the investigated fuels. Graphical abstract Investigation of the thermodynamic properties of natural gas through the canonical ensemble model and the density functional theory.

12.
Bioorg Med Chem Lett ; 25(21): 4808-4811, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26183083

RESUMO

The synthesis and antioxidant evaluation by DPPH scavenging of a series of salicylic acid derivatives is described. Gentisic acid and its ester, amide, and amino analogs possess more radical scavenging capacity than salicylic acid and other salicylate derivatives. This property can possibly provide an additional pathway for anti-inflammatory activity through either single electron or hydrogen atom transfer, leading to a new strategy for the design of anti-inflammatory agents.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Ácido Salicílico/química , Anti-Inflamatórios não Esteroides/síntese química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Estrutura Molecular , Teoria Quântica , Ácido Salicílico/síntese química , Ácido Salicílico/farmacologia
13.
J Mol Model ; 21(7): 166, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26044360

RESUMO

An electronic study of nimesulide was performed by using density functional theory calculations. The activities of the six different derivatives were related with electron donating or accepting capacities. All compounds which had nitro moiety had low electron donating and high electron accepting capacities. However, the reduced derivative of nimesulide have more electron donating capacity than other compounds. The highest spin density contribution in nitro and lowest spin density contribution on phenoxyl moieties can be related with preferential metabolism by reduction when compared with the oxidation. The redox behavior between nitro and amino groups can be related with anti-inflammatory mechanism of nimesulide. These results explain the redox influence of nitro moiety on biological metabolism and mechanism of nimesulide.


Assuntos
Anti-Inflamatórios não Esteroides/química , Elétrons , Hidrogênio/química , Sulfonamidas/química , Humanos , Modelos Moleculares , Oxirredução , Teoria Quântica , Soluções , Relação Estrutura-Atividade
14.
J Mol Model ; 20(12): 2541, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25503701

RESUMO

Quinones represent an important class of biological compounds, but are also involved with toxicological intermediates and among their hazardous effects include cytotoxicity, immunotoxicity, and carcinogenesis. The structure-toxicity relationship for quinone derivatives has been used to cytotoxicity or cytoprotective effects by redox mechanism is determined using quantum chemical calculations through the density functional theory (DFT). According to our DFT study, the electron acceptance is related with LUMO, electron affinity, and stabilization energy values. The highest spin density distribution in the heteroatoms is more favored for the more cytotoxic compounds. The electrophilic capacities of these compounds have been related with LUMO values. The cytotoxic properties of quinones are related to the stabilization energy after electron accepting by redox mechanism. Electron affinity is the most relevant parameter related to toxicity mechanism. Regioisomers has different electrophilic capacity. The electrophilicity increases on molecules containing electron-withdrawing groups (EWG) and reduces on molecules containing electron-donating groups (EDG). These results explain the toxic difference between natural and synthetic quinone derivatives and can be used in the design and study of new drugs.


Assuntos
Quinonas/síntese química , Quinonas/toxicidade , Citoproteção , Estabilidade de Medicamentos , Elétrons , Transferência de Energia , Radicais Livres/química , Isomerismo , Modelos Moleculares , Estrutura Molecular , Oxirredução , Teoria Quântica , Relação Estrutura-Atividade
15.
Vascul Pharmacol ; 63(2): 55-62, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25131395

RESUMO

Previously, we showed that nitro-2-phenylethane is a vasorelaxant constituent of the essential oil of Aniba canelilla. Here, we investigated the mechanisms underlying the vascular effects of 1-nitro-2-phenylethene (NPe), a structural analog of 1-nitro-2-phenylethane obtained synthetically, in rat isolated thoracic aortic preparations. At 0.1-100 µg/mL, NPe similarly relaxed endothelium-intact or endothelium-denuded aortic preparations pre-contracted with 60mM KCl or with phenylephrine (PHE, 1 µM). Vasorelaxant effects of NPe against PHE-induced contractions remained unaffected following blockade of potassium channels by TEA, and inhibition of either nitric oxide synthase by l-NAME, cyclooxygenase by indomethacin or guanylate cyclase by ODQ. In preparations maintained under Ca(2+)-free conditions, NPe significantly reduced the contractions induced (i) by PHE, but not those evoked by caffeine, (ii) by CaCl2 in either PHE (in the presence of 1 µM verapamil)- or KCl-stimulated preparations, (iii) by extracellular Ca(2+) restoration in thapsigargin-treated aortic preparations, and (iv) by the activator of protein kinase C phorbol-12,13-dibutyrate or the inhibitor of protein tyrosine phosphatase sodium orthovanadate. It is concluded that NPe induced an endothelium-independent vasorelaxation with potency greater than its structural analog 1-nitro-2-phenylethane. Such action appears to occur intracellularly probably through inhibition of contractile events that are clearly independent of Ca(2+) influx from the extracellular milieu.


Assuntos
Aorta Torácica/efeitos dos fármacos , Derivados de Benzeno/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta Torácica/metabolismo , Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Guanilato Ciclase/metabolismo , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/metabolismo , Fenilefrina/farmacologia , Canais de Potássio/metabolismo , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar
16.
J Nanosci Nanotechnol ; 14(6): 4590-4, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24738434

RESUMO

The system proposed consists of a flagellum relaxing around a static carbon nanowire to mimics behavior of a natural flagellum moving with damped harmonic motion along a wire under van der Waals and electrostatic forces. This flagellum is composed of a C20 nanosphere with different sizes of his tail formed by hydrocarbons. The thermodynamic properties such as molar entropy variation, as well as molar heat dissipation, efficiency and speed were obtained to evaluate which system is most stable by using the variable temperature. This system has a number of carbon atoms ranging from 103-110, with a maximum of 300 ps for each simulation. We had simulated molar entropy variation, energies and efficiency changing with time and initial temperature. The results indicate that among the systems studied, the flagellum with five carbon atoms achieved greater stability and better results in this search.


Assuntos
Carbono/química , Flagelos/química , Flagelos/ultraestrutura , Modelos Químicos , Modelos Moleculares , Nanofios/química , Nanofios/ultraestrutura , Materiais Biomiméticos/química , Simulação por Computador , Movimento (Física) , Temperatura
17.
PLoS One ; 9(1): e85712, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24465659

RESUMO

This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.518±0.029 µg/mL) and paucibacillary (0.662±0.123 µg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software.


Assuntos
Clofazimina/uso terapêutico , Dapsona/uso terapêutico , Hanseníase/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Rifampina/uso terapêutico , Adulto , Análise de Variância , Catalase/sangue , Citocromo P-450 CYP2C19/metabolismo , Dapsona/sangue , Dapsona/metabolismo , Quimioterapia Combinada , Feminino , Glutationa/sangue , Corpos de Heinz/efeitos dos fármacos , Corpos de Heinz/metabolismo , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/sangue , Masculino , Metemoglobina/metabolismo , Pessoa de Meia-Idade , Oxirredução , Ligação Proteica , Espécies Reativas de Oxigênio/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
Molecules ; 18(10): 12663-74, 2013 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-24129275

RESUMO

An antioxidant mechanism of tetrahydrocannabinol (THC) and cannabidiol (CBD) were compared with a simplified model of α-tocopherol, butylhydroxytoluene and hydroxytoluene in order to understand the antioxidant nature of THC and CBD molecules using DFT. The following electronic properties were evaluated: frontier orbitals nature, ionization potential, O-H bond dissociation energy (BDEOH), stabilization energy, and spin density distribution. An important factor that shows an influence in the antioxidant property of THC is the electron abstraction at the phenol position. Our data indicate that the decrease of the HOMO values and the highest ionization potential values are related to phenol, ether, and alkyl moieties. On the other hand, BDEOH in molecules with the cyclohexenyl group at ortho position of phenol are formed from lower energies than the molecules with an ether group at the meta position. In the light of our results, the properties calculated here predict that THC has a sightly higher antioxidant potential than CBD.


Assuntos
Antioxidantes/química , Canabidiol/química , Dronabinol/química , Simulação por Computador , Eletroquímica , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Teoria Quântica
19.
Planta Med ; 79(8): 628-33, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23670627

RESUMO

In this study, 1-nitro-2-phenylethane was evaluated with respect to its effects in edema models of acute inflammation induced with carrageenan, dextran, and croton oil. 1-Nitro-2-phenylethane produced inhibition of rat paw edema induced by carrageenan and dextran at the doses of 25 and 50 mg/kg. The same doses caused an inhibition of croton oil-induced ear edema in mice. Our results suggest that 1-nitro-2-phenylethane has anti-inflammatory activity, probably of peripheral origin, acting in the synthesis and/or release of inflammatory mediators. A conformational study of 1-nitro-2-phenylethane was carried out using density functional theory calculations, showing three different groups of conformers corresponding to energy minimum geometries. The stereoelectronic repulsions are responsible for conformational preferences and the one most stable conformer. The prostaglandin endoperoxide synthase mechanism is related more to electrophilic than nucleophilic properties.


Assuntos
Anti-Inflamatórios/farmacologia , Derivados de Benzeno/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Derivados de Benzeno/uso terapêutico , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Masculino , Camundongos , Ratos , Ratos Wistar
20.
Chem Biol Drug Des ; 81(3): 414-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23405943

RESUMO

This theoretical and experimental study describes the design and evaluation of the free-radical scavenging effect for the molecular association of 4-aminophenol and salicylate derivatives. For this purpose, we employed theoretical methods for the selection of antioxidant drugs and the rapid methods of evaluation: the 1,1-diphenyl-2-picrylhydrazyl radical and the thiobarbituric acid reactive substances in the lipid peroxidation initiated by Fe(2+) and ascorbic acid in human erythrocytes. The associate derivatives exhibited a more potent inhibition than the salicylic acid, while the benzoyl compound exhibited a more potent inhibition than paracetamol. The molecular parameters related to the electron distribution and structure (ionization potential and energy of the highest occupied molecular orbital) correlated very well with the antioxidant action of the compounds studied here in different tests.


Assuntos
Aminofenóis/química , Desenho de Fármacos , Sequestradores de Radicais Livres/química , Salicilatos/química , Aminofenóis/síntese química , Aminofenóis/farmacologia , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Teoria Quântica , Salicilatos/síntese química , Salicilatos/farmacologia , Relação Estrutura-Atividade
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