Rosivaldo S. Borges

A theoretical antioxidant pharmacophore for resveratrol.

The structure-activity relationship has been used to study the determination of antioxidant pharmacophore for resveratrol using quantum chemistry calculations by the Functional of Density Theory method. According to the geometry obtained by using a B3LYP/6-31G(*), the HOMO, ionization potential, bond dissociation energies, stabilization energies, and spin density distribution, the electron or hydrogen abstraction in para position is more favored than in meta positions for resveratrol and related derivatives because of the resonance effects. Comparison with structurally related compounds revealed that the antioxidant pharmacophore of resveratrol is 4-hydroxystilbene. Spin distribution showed that the pi-type electron system determines the stability of radicals and the unpaired electrons are mainly distributed to the O-atom in para position, double bond, and B-benzene ring. The antioxidant activity of resveratrol is related to the stabilization energy of 4-hydroxystilbene in resveratrol hydroxylated derivatives. Furthermore, the results explain the activity difference between resveratrol and its hydroxylated derivatives.

Structure of Dihydrochalcones and Related Derivatives and Their Scavenging and Antioxidant Activity against Oxygen and Nitrogen Radical Species

Quantum mechanical calculations at B3LYP/6-31G** level of theory were employed to obtain energy (E), ionization potential (IP), bond dissociation enthalpy (O-H BDE) and stabilization energies (ΔEiso) in order to infer the scavenging activity of dihydrochalcones (DHC) and structurally related compounds. Spin density calculations were also performed for the proposed antioxidant activity mechanism of 2,4,6-trihydroxyacetophenone (2,4,6-THA). The unpaired electron formed by the hydrogen abstraction from the phenolic hydroxyl group of 2,4,6-THA is localized on the phenolic oxygen at 2, 6, and 4 positions, the C3 and C6 carbon atoms at ortho positions, and the C5 carbon atom at para position. The lowest phenolic oxygen contribution corresponded to the highest scavenging activity value. It was found that antioxidant activity depends on the presence of a hydroxyl at the C2 and C4 positions and that there is a correlation between IP and O-H BDE and peroxynitrite scavenging activity and lipid peroxidation. These results identified the pharmacophore group for DHC.

The basic antioxidant structure for flavonoid derivatives.

AbstractAn antioxidant structure–activity study is carried out in this work with ten flavonoid compounds using quantum chemistry calculations with the functional of density theory method. According to the geometry obtained by using the B3LYP/6-31G(d) method, the HOMO, ionization potential, stabilization energies, and spin density distribution showed that the flavonol is the more antioxidant nucleus. The spin density contribution is determinant for the stability of the free radical. The number of resonance structures is related to the π-type electron system. 3-hydroxyflavone is the basic antioxidant structure for the simplified flavonoids studied here. The electron abstraction is more favored in the molecules where ether group and 3-hydroxyl are present, nonetheless 2,3-double bond and carbonyl moiety are facultative. FigureThe basic antioxidant structure for flavonoid derivatives

Density Functional Theory (DFT) Study of Edaravone Derivatives as Antioxidants

Quantum chemical calculations at the B3LYP/6–31G* level of theory were employed for the structure-activity relationship and prediction of the antioxidant activity of edaravone and structurally related derivatives using energy (E), ionization potential (IP), bond dissociation energy (BDE), and stabilization energies (ΔEiso). Spin density calculations were also performed for the proposed antioxidant activity mechanism. The electron abstraction is related to electron-donating groups (EDG) at position 3, decreasing the IP when compared to substitution at position 4. The hydrogen abstraction is related to electron-withdrawing groups (EDG) at position 4, decreasing the BDECH when compared to other substitutions, resulting in a better antioxidant activity. The unpaired electron formed by the hydrogen abstraction from the C–H group of the pyrazole ring is localized at 2, 4, and 6 positions. The highest scavenging activity prediction is related to the lowest contribution at the carbon atom. The likely mechanism is related to hydrogen transfer. It was found that antioxidant activity depends on the presence of EDG at the C2 and C4 positions and there is a correlation between IP and BDE. Our results identified three different classes of new derivatives more potent than edaravone.

Understanding the Molecular Aspects of Tetrahydrocannabinol and Cannabidiol as Antioxidants

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.

Clinical Oxidative Stress during Leprosy Multidrug Therapy: Impact of Dapsone Oxidation

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.

Design and evaluation of 4-aminophenol and salicylate derivatives as free-radical scavenger.

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 Fe2+ 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.

Evaluation and theoretical study on the anti-inflammatory mechanism of 1-nitro-2-phenylethane.

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.

Vasorelaxant effects of 1-nitro-2-phenylethene in rat isolated aortic rings

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.

Molecular Dynamics of Film Formation of Metal Tetrasulfonated Phthalocyanine and Poly Amidoamine Dendrimers

We performed molecular dynamics computer simulations to elucidate the behavior and properties of the metal tetrasulfonated phthalocyanine molecule and the poly(amidoamine) dendrimers in self-assembly depositions, respectively, on poly(allylamine hydrochloride) polymer and on film formed by metal tetrasulfonated phthalocyanine with poly(allylamine hydrochloride). Important physical properties of phthalocyanines were obtained such as the kinetic energy and temperature in situ. By the semiempirical model, we also obtained the UV-Vis absorption spectrum of the film formed by cobalt tetrasulfonated phthalocyanine deposited on poly(allylamine hydrochloride). We performed a study with poly(amidoamine) dendrimers on their deposition time on metal tetrasulfonated phthalocyanine, poly(allylamine hydrochloride) film, and we show the relationship of deposition time with the electrical charge and molecular mass of phthalocyanines. The deposition times of the dendrimers, as a function of their mass, were also elucidated.