Rosivaldo Borges | UFPA - Federal University of Pará (original) (raw)

Papers by Rosivaldo Borges

Research paper thumbnail of Estudo Teórico e Experimental De Estrutura e Reatividade Relacionado Ao Metabolismo e Toxicidade Do Paracetamol

Química Nova, 2022

Recebido em 21/04/2022; aceito em 19/05/2022; publicado na web em 21/07/2022 THEORETICAL AND EXPE... more Recebido em 21/04/2022; aceito em 19/05/2022; publicado na web em 21/07/2022 THEORETICAL AND EXPERIMENTAL STUDY OF STRUCTURE AND REACTIVITY RELATED TO METABOLISM AND TOXICITY OF PARACETAMOL. An experimental and theoretical approach on oxidative metabolism of paracetamol was applied for the pharmaceutical chemistry learning. Classical reactions, functional group identification, structural parameter, and chemical reactivity using frontier orbitals and Fukui index were used explaining the main products between N-acetyl-p-benzosemiquinone (NAPQI) and thiolic compounds. The chemoprotection mechanisms by N-acetyl-cysteine on high dosage of paracetamol are consistent with theoretical and experimental results. The methods also described the relationship between the chemical reactivity of quinone-imine system and the induced-toxicity of paracetamol by Michael reaction. These results can be applied in experimental pharmaceutical chemistry teaching.

Research paper thumbnail of In Vitro Protective Effect and Antioxidant Mechanism of Resveratrol Induced by Dapsone Hydroxylamine in Human Cells

PLOS ONE, 2015

Dapsone (DDS) hydroxylamine metabolites cause oxidative stress-linked adverse effects in patients... more Dapsone (DDS) hydroxylamine metabolites cause oxidative stress-linked adverse effects in patients, such as methemoglobin formation and DNA damage. This study evaluated the ameliorating effect of the antioxidant resveratrol (RSV) on DDS hydroxylamine (DDS-NHOH) mediated toxicity in vitro using human erythrocytes and lymphocytes. The antioxidant mechanism was also studied using in-silico methods. In addition, RSV provided intracellular protection by inhibiting DNA damage in human lymphocytes induced by DDS-NHOH. However, whilst pretreatment with RSV (10-1000 μM significantly attenuated DDS-NHOH-induced methemoglobinemia, but it was not only significantly less effective than methylene blue (MET), but also post-treatment with RSV did not reverse methemoglobin formation, contrarily to that observed with MET. DDS-NHOH inhibited catalase (CAT) activity and reactive oxygen species (ROS) generation, but did not alter superoxide dismutase (SOD) activity in erythrocytes. Pretreatment with RSV did not alter these antioxidant enzymes activities in erythrocytes treated with DDS-NHOH. Theoretical calculations using density functional theory methods showed that DDS-NHOH has a pro-oxidant effect, whereas RSV and MET have antioxidant effect on ROS. The effect on methemoglobinemia reversion for MET was significantly higher than that of RSV. These data suggest that the pretreatment with resveratrol may decrease heme-iron oxidation and DNA damage through reduction of ROS generated in cells during DDS therapy.

Research paper thumbnail of Involvement of electron and hydrogen transfers through redox metabolism on activity and toxicity of the nimesulide

Journal of Molecular Modeling, 2015

An electronic study of nimesulide was performed by using density functional theory calculations. ... more 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.

Research paper thumbnail of Antioxidant factors, nitric oxide levels, and cellular damage in leprosy patients

Revista da Sociedade Brasileira de Medicina Tropical, 2013

Introduction: The immune response caused by Mycobacterium leprae is a risk factor for the develop... more Introduction: The immune response caused by Mycobacterium leprae is a risk factor for the development of oxidative stress (OS) in leprosy patients. This study aimed to assess OS in leprosy patients before the use of a multidrug therapy. Methods: We evaluated the nitric oxide (NO) concentration; antioxidant capacity; levels of malondialdehyde, methemoglobin and reduced glutathione; and the activity of catalase and superoxide dismutase (SOD) in leprosy patients. Results: We observed lower SOD activity in these leprosy patients; however, the NO levels and antioxidant capacity were increased. Conclusions: The infectious process in response to M. leprae could primarily be responsible for the OS observed in these patients.

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

PLoS ONE, 2014

This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; ... more 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 (0.51860.029 mg/mL) and paucibacillary (0.66260.123 mg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDTsupervised 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.

Research paper thumbnail of Dihydroflavonols from the leaves of Derris urucu (Leguminosae): structural elucidation and DPPH radical-scavenging activity

Journal of the Brazilian Chemical Society, 2009

Derris urucu é uma planta da Amazônia com propriedades inseticida e ictiotóxica. Estudos com esta... more Derris urucu é uma planta da Amazônia com propriedades inseticida e ictiotóxica. Estudos com esta espécie reportam a presença de flavonóides, principalmente rotenóides, bem como de estilbenos. A partir do extrato etanólico das folhas de Derris urucu (Leguminosae), três novos diidroflavonóides, denominados urucuol A (1), B (2) e C (3) e o diidroflavonol isotirumalina (4), foram isolados e identificados. As estruturas destes compostos foram elucidadas por uma extensiva análise espectroscópica de RMN uni e bidimensional, UV, IV e dados de EM, além de comparação com dados da literatura. Os compostos isolados (1-4) foram avaliados quanto ao seu potencial sequestrador do radical DPPH • e apresentaram baixo poder antioxidante quando comparados ao antioxidante comercial trans-resveratrol. Derris urucu is an Amazonian plant with insecticide and ichthyotoxic properties. Studies with this species show the presence of flavonoids, mainly rotenoids, as well as stilbenes. The ethanol extract of the leaves of Derris urucu (Leguminosae) afforded three new dihydroflavonols named urucuol A (1), B (2) and C (3), and the dihydroflavonol isotirumalin (4). Their structures were elucidated by extensive analysis of 1D and 2D NMR, UV and IR spectra and MS data and comparison with literature data. The isolated compounds (1-4) were evaluated for DPPH • radical scavenging activity and showed a relatively lower antioxidant ability compared to the commercial antioxidant trans-resveratrol.

Research paper thumbnail of Stability and Reactivity of Benzopyranones Derivatives

Journal of Computational and Theoretical Nanoscience, 2011

The goal of this investigation is the stability and reactivity of benzopyranones derivatives usin... more The goal of this investigation is the stability and reactivity of benzopyranones derivatives using quantum chemistry calculations at the B3LYP level of theory, together with the 6-31G * basis set. Quantum chemistry was employed to obtain energy (E), HOMO and LUMO, ionization potential (IP), and spin-density distribution for benzopyranones derivatives. The gas phase structures are discussed based on thermodynamic values. Calculations of spin densities were performed for radical formed by electron abstraction. The results supported a relation between thermodynamic values and frequency of observation. The lowest HOMO and IP values are related with more reactive and minus stable compounds. These results are confirmed by spin densities distribution.

Research paper thumbnail of A Geometric and Electronic Study of Dapsone

Journal of Computational and Theoretical Nanoscience, 2011

Quantum mechanical calculations at the B3LYP theory level, together with the 6-31G * basis set, w... more Quantum mechanical calculations at the B3LYP theory level, together with the 6-31G * basis set, were employed to obtain the energy, HOMO, LUMO, MEPs, and charge of dapsone is compared with others derivatives. Conformational analysis using density functional calculations show that symmetric conformational isomer has low energy than asymmetric conformational isomer. The symmetry level was observed by molecular charge analysis. Its redox properties by electrons transfer are dependent of amine and sulphone moieties. Our results explain the oxidation mechanism of dapsone by electron transfer.

Research paper thumbnail of An Electronic Study for Metronidazole Metabolism

Journal of Computational and Theoretical Nanoscience, 2011

Page 1. Delivered by Ingenta to: ? IP : 93.91.26.12 Mon, 16 May 2011 16:03:40 RESEARCH AR TICLE C... more Page 1. Delivered by Ingenta to: ? IP : 93.91.26.12 Mon, 16 May 2011 16:03:40 RESEARCH AR TICLE Copyright © 2011 American Scientific Publishers All rights reserved Printed in the United States of America Journal of Computational and Theoretical Nanoscience Vol. ...

Research paper thumbnail of An Electronic Study of Tocopherol-Ring Regioisomers as Antioxidants

Journal of Computational and Theoretical Nanoscience, 2011

ABSTRACT The electronic structures study have been used in the classification of tocopherol-rings... more ABSTRACT The electronic structures study have been used in the classification of tocopherol-rings regiosiomers as antioxidants by quantum chemistry calculations using DFT methods at the B3LYP/6-31G* level of theory. The HOMO, ionization potential, stabilization energies, and spin density distribution calculations were performed for radical formed by electron or hydrogen abstraction from the phenolic hydroxyl groups at the pare-, meta- or ortho-positions. These values are related with HOMO and MEPs for antioxidant regioisomers classification. Our results shown that para-regioisomer is more nucleophilic compounds by electron transfer and more reactive molecule by hydrogen donating, followed by ortho-, and meta-regioisomers.

Research paper thumbnail of Vasorelaxant effect of trans‐4‐chloro‐β‐nitrostyrene, a synthetic nitroderivative, in rat thoracic aorta

Fundamental & Clinical Pharmacology

Previously, we showed that 1‐nitro‐2‐phenylethene, a nitrostyrene derivative of 1‐nitro‐2‐phenyle... more Previously, we showed that 1‐nitro‐2‐phenylethene, a nitrostyrene derivative of 1‐nitro‐2‐phenylethane, induced vasorelaxant effects in rat aorta preparations. Here, we studied mechanisms underlying the vasorelaxant effects of its structural analog, trans‐4‐chloro‐β‐nitrostyrene (T4CN), in rat aortic rings. Increasing concentrations of T4CN (0.54‐544.69 µm) fully and similarly relaxed contractions induced by phenylephrine (PHE, 1 µm) or KCl (60 mm) in endothelium‐intact aortic rings with IC50 values of 66.74 [59.66–89.04] and 79.41 [39.92–158.01] µm, respectively. In both electromechanical and pharmacomechanical couplings, the vasorelaxant effects of T4CN remained unaltered by endothelium removal, as evidenced by the IC50 values (108.35 [56.49–207.78] and 65.92 [39.72–109.40] µm, respectively). Pretreatment of endothelium‐intact preparations with L‐NAME, ODQ, glibenclamide, or TEA did not change the vasorelaxant effect of T4CN. Under Ca2+‐free conditions, T4CN significantly reduced the phasic contractions induced by caffeine or PHE, as well as the contractions due to exogenous CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil). These results suggest that in rat aortic rings, T4CN induced vasorelaxation independently from the activation of soluble guanylate cyclase/cGMP pathway, an effect that may be related to the electrophilicity of the substituted chloro‐nitrostyrene. This vasorelaxation seems to involve inhibition of both calcium influx from the extracellular milieu and calcium mobilization from intracellular stores mediated by IP3 receptors and by ryanodine‐sensitive Ca2+ channels.

Research paper thumbnail of Vasodilatory action of trans ‐4‐methoxy‐β‐nitrostyrene in rat isolated pulmonary artery

Clinical and Experimental Pharmacology and Physiology

Trans‐4‐methoxy‐β‐nitrostyrene (T4MN) induced more potent vasorelaxant effects in resistance arte... more Trans‐4‐methoxy‐β‐nitrostyrene (T4MN) induced more potent vasorelaxant effects in resistance arteries from hypertensive rats than its parent drug, β‐nitrostyrene 1‐nitro‐2‐phenylethene (NPe). To better understand the influence of insertion of the electron‐releasing methoxy group in the aromatic ring of NPe, we investigated vasorelaxant effects of T4MN in isolated pulmonary artery and compared them with those of NPe in view of the potential interest of T4MN in pulmonary arterial hypertension. T4MN and NPe both caused concentration‐dependent vasorelaxation in pulmonary artery rings pre‐contracted with either phenylephrine (1 µmol/L) or KCl (60 mmol/L), an effect unaffected by endothelium removal. In endothelium‐intact preparations pre‐contracted with phenylephrine, the vasorelaxant effect of T4MN was more potent than that of NPe. However, unlike NPe, this effect was significantly reduced following pretreatment with 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) (10 µmol/L, a guanylate cyclase inhibitor) or tetraethylammonium (5 mmol/L, a potassium channel blocker). T4MN abolished the CaCl2‐induced contractions in pulmonary artery preparations stimulated with phenylephrine (PHE) under Ca2+‐free conditions in the presence of verapamil , to preferentially activate receptor‐operated calcium channels. From these findings, we propose that T4MN evokes endothelium‐independent vasorelaxant effects in isolated rat pulmonary artery, partially by inhibiting Ca2+ influx through L‐type Ca2+ channels, as well as by activating soluble guanylate cyclase and potassium channels. The present results suggest the therapeutic potential of T4MN in treating pulmonary arterial hypertension.

Research paper thumbnail of A comparative study between kojic acid and its methylated derivatives as antioxidant related to maltol and alomaltol

Chemical Data Collections

Research paper thumbnail of N-Acetyl-cysteine Increases Chemical Stability of Hydroquinone in Pharmaceutical Formulations: a Theoretical and Experimental Approach

Journal of the Brazilian Chemical Society, 2017

In this study, the chemistry stability of hydroquinone (HQ) was evaluated according to its effect... more In this study, the chemistry stability of hydroquinone (HQ) was evaluated according to its effects in redox properties and compared to kojic acid (KA). The HQ oxidation was more inhibited by N-acetylcysteine (NAC) than ascorbic acid (AA). These results were elucidated using theoretical methods at the DFT/B3LYP level of theory. All electronic parameters were related between antioxidant performance and highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), HOMO-LUMO value gap (GAP), ionization potential (IP), and phenol or enol bond dissociation energy (BDE OH) values. However, the interactions between HQ and NAC cannot be related by changing of these electronic parameters. Therefore the high calculated values for electron transfer can be associated to NAC due to polarizability or chelation properties of sulfur moiety.

Research paper thumbnail of Avanços Químicos No Planejamento e Desenvolvimento De Derivados Do Paracetamol

Química Nova

CHEMICAL ADVANCES ON DESIGN AND DEVELOPMENT OF PARACETAMOL DERIVATIVES. Acetaminophen or paraceta... more CHEMICAL ADVANCES ON DESIGN AND DEVELOPMENT OF PARACETAMOL DERIVATIVES. Acetaminophen or paracetamol is a widely used analgesic and antipyretic drug and appears to be safe if used at normal therapeutic doses, but in large doses produce liver and / or kidney damage in humans and experimental animals. Prostaglandin endoperoxide synthase (PGES) and cytochrome P-450 are the key enzymes in humans as they are responsible for the analgesic and toxicity effects of paracetamol, respectively. At present, the development of new derivatives still has few impacts on clinical applications of safe compounds. Thus, in this work are discussed, a series of approaches on the design and development of acetaminophen derivatives. Some efforts were realized in our own research group.

Research paper thumbnail of Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

Molecules

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory... more 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 du...

Research paper thumbnail of Cardiovascular Effects of Trans-4-Methoxy-β-Nitrostyrene in Spontaneously Hypertensive Rats: Comparison With Its Parent Drug β-Nitrostyrene

Frontiers in Pharmacology

We previously reported that trans-4-methoxy-β-nitrostyrene (T4MN) evoked higher vasorelaxant effe... more We previously reported that trans-4-methoxy-β-nitrostyrene (T4MN) evoked higher vasorelaxant effects in small resistance arteries from spontaneously hypertensive rats (SHRs) in comparison with its parent drug, the β-nitrostyrene 1-nitro-2-phenylethene (NPe). To further our knowledge of the influence of insertion of an electron-releasing group such as methoxy in the aromatic ring of NPe, we investigated the cardiovascular responses to intravenous (i.v.) injection of T4MN in SHRs and compared with those of NPe. In anesthetized SHRs, i.v. treatment with T4MN (0.03-0.5 mg/kg) and NPe (0.03-3 mg/kg) induced dose-dependent bradycardia and hypotension, which were biphasic (named phases 1 and 2). Magnitude of these responses was significantly higher for T4MN compared with NPe. Phase 1 cardiovascular responses to both T4MN (0.3 mg/ kg) and NPe (3 mg/kg) were prevented by cervical bivagotomy or perineural treatment of both cervical vagus nerves with capsaicin, but was unchanged by i.v. pretreatment with capsazepine or ondansetron. After injection into the left ventricle, NPe and T4MN no longer evoked phase 1 responses. In conscious SHRs, NPe (3 mg/kg, i.v.), and T4MN (0.3 mg/kg, i.v.) evoked monophasic hypotensive and bradycardiac effects which were suppressed by i.v. pretreatment with methylatropine. It is concluded that i.v. administration of NPe and T4MN in SHRs induced a vago-vagal hypotensive and bradycardic reflex that did not involve the activation of vanilloid TRPV 1 or 5-HT 3 receptors located on vagal pulmonary sensory nerves. With respect to its parent drug, T4MN was more potent in inducing this reflex. Phase 2 hypotensive response to i.v. NPe and T4MN seems partially resulting from a direct vasodilatory action. It seems that insertion of a methoxy group into the aromatic ring stabilized NPe, which in turn increases its cardiovascular effects.

Research paper thumbnail of The role of regioselective hydroxylation on toxicity of diclofenac and related derivatives

Research paper thumbnail of In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity

Molecules

Inflammation is a complex reaction involving cellular and molecular components and an unspecific ... more 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 con...

Research paper thumbnail of Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

Molecules

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involv... more 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 ...

Research paper thumbnail of Estudo Teórico e Experimental De Estrutura e Reatividade Relacionado Ao Metabolismo e Toxicidade Do Paracetamol

Química Nova, 2022

Recebido em 21/04/2022; aceito em 19/05/2022; publicado na web em 21/07/2022 THEORETICAL AND EXPE... more Recebido em 21/04/2022; aceito em 19/05/2022; publicado na web em 21/07/2022 THEORETICAL AND EXPERIMENTAL STUDY OF STRUCTURE AND REACTIVITY RELATED TO METABOLISM AND TOXICITY OF PARACETAMOL. An experimental and theoretical approach on oxidative metabolism of paracetamol was applied for the pharmaceutical chemistry learning. Classical reactions, functional group identification, structural parameter, and chemical reactivity using frontier orbitals and Fukui index were used explaining the main products between N-acetyl-p-benzosemiquinone (NAPQI) and thiolic compounds. The chemoprotection mechanisms by N-acetyl-cysteine on high dosage of paracetamol are consistent with theoretical and experimental results. The methods also described the relationship between the chemical reactivity of quinone-imine system and the induced-toxicity of paracetamol by Michael reaction. These results can be applied in experimental pharmaceutical chemistry teaching.

Research paper thumbnail of In Vitro Protective Effect and Antioxidant Mechanism of Resveratrol Induced by Dapsone Hydroxylamine in Human Cells

PLOS ONE, 2015

Dapsone (DDS) hydroxylamine metabolites cause oxidative stress-linked adverse effects in patients... more Dapsone (DDS) hydroxylamine metabolites cause oxidative stress-linked adverse effects in patients, such as methemoglobin formation and DNA damage. This study evaluated the ameliorating effect of the antioxidant resveratrol (RSV) on DDS hydroxylamine (DDS-NHOH) mediated toxicity in vitro using human erythrocytes and lymphocytes. The antioxidant mechanism was also studied using in-silico methods. In addition, RSV provided intracellular protection by inhibiting DNA damage in human lymphocytes induced by DDS-NHOH. However, whilst pretreatment with RSV (10-1000 μM significantly attenuated DDS-NHOH-induced methemoglobinemia, but it was not only significantly less effective than methylene blue (MET), but also post-treatment with RSV did not reverse methemoglobin formation, contrarily to that observed with MET. DDS-NHOH inhibited catalase (CAT) activity and reactive oxygen species (ROS) generation, but did not alter superoxide dismutase (SOD) activity in erythrocytes. Pretreatment with RSV did not alter these antioxidant enzymes activities in erythrocytes treated with DDS-NHOH. Theoretical calculations using density functional theory methods showed that DDS-NHOH has a pro-oxidant effect, whereas RSV and MET have antioxidant effect on ROS. The effect on methemoglobinemia reversion for MET was significantly higher than that of RSV. These data suggest that the pretreatment with resveratrol may decrease heme-iron oxidation and DNA damage through reduction of ROS generated in cells during DDS therapy.

Research paper thumbnail of Involvement of electron and hydrogen transfers through redox metabolism on activity and toxicity of the nimesulide

Journal of Molecular Modeling, 2015

An electronic study of nimesulide was performed by using density functional theory calculations. ... more 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.

Research paper thumbnail of Antioxidant factors, nitric oxide levels, and cellular damage in leprosy patients

Revista da Sociedade Brasileira de Medicina Tropical, 2013

Introduction: The immune response caused by Mycobacterium leprae is a risk factor for the develop... more Introduction: The immune response caused by Mycobacterium leprae is a risk factor for the development of oxidative stress (OS) in leprosy patients. This study aimed to assess OS in leprosy patients before the use of a multidrug therapy. Methods: We evaluated the nitric oxide (NO) concentration; antioxidant capacity; levels of malondialdehyde, methemoglobin and reduced glutathione; and the activity of catalase and superoxide dismutase (SOD) in leprosy patients. Results: We observed lower SOD activity in these leprosy patients; however, the NO levels and antioxidant capacity were increased. Conclusions: The infectious process in response to M. leprae could primarily be responsible for the OS observed in these patients.

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

PLoS ONE, 2014

This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; ... more 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 (0.51860.029 mg/mL) and paucibacillary (0.66260.123 mg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDTsupervised 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.

Research paper thumbnail of Dihydroflavonols from the leaves of Derris urucu (Leguminosae): structural elucidation and DPPH radical-scavenging activity

Journal of the Brazilian Chemical Society, 2009

Derris urucu é uma planta da Amazônia com propriedades inseticida e ictiotóxica. Estudos com esta... more Derris urucu é uma planta da Amazônia com propriedades inseticida e ictiotóxica. Estudos com esta espécie reportam a presença de flavonóides, principalmente rotenóides, bem como de estilbenos. A partir do extrato etanólico das folhas de Derris urucu (Leguminosae), três novos diidroflavonóides, denominados urucuol A (1), B (2) e C (3) e o diidroflavonol isotirumalina (4), foram isolados e identificados. As estruturas destes compostos foram elucidadas por uma extensiva análise espectroscópica de RMN uni e bidimensional, UV, IV e dados de EM, além de comparação com dados da literatura. Os compostos isolados (1-4) foram avaliados quanto ao seu potencial sequestrador do radical DPPH • e apresentaram baixo poder antioxidante quando comparados ao antioxidante comercial trans-resveratrol. Derris urucu is an Amazonian plant with insecticide and ichthyotoxic properties. Studies with this species show the presence of flavonoids, mainly rotenoids, as well as stilbenes. The ethanol extract of the leaves of Derris urucu (Leguminosae) afforded three new dihydroflavonols named urucuol A (1), B (2) and C (3), and the dihydroflavonol isotirumalin (4). Their structures were elucidated by extensive analysis of 1D and 2D NMR, UV and IR spectra and MS data and comparison with literature data. The isolated compounds (1-4) were evaluated for DPPH • radical scavenging activity and showed a relatively lower antioxidant ability compared to the commercial antioxidant trans-resveratrol.

Research paper thumbnail of Stability and Reactivity of Benzopyranones Derivatives

Journal of Computational and Theoretical Nanoscience, 2011

The goal of this investigation is the stability and reactivity of benzopyranones derivatives usin... more The goal of this investigation is the stability and reactivity of benzopyranones derivatives using quantum chemistry calculations at the B3LYP level of theory, together with the 6-31G * basis set. Quantum chemistry was employed to obtain energy (E), HOMO and LUMO, ionization potential (IP), and spin-density distribution for benzopyranones derivatives. The gas phase structures are discussed based on thermodynamic values. Calculations of spin densities were performed for radical formed by electron abstraction. The results supported a relation between thermodynamic values and frequency of observation. The lowest HOMO and IP values are related with more reactive and minus stable compounds. These results are confirmed by spin densities distribution.

Research paper thumbnail of A Geometric and Electronic Study of Dapsone

Journal of Computational and Theoretical Nanoscience, 2011

Quantum mechanical calculations at the B3LYP theory level, together with the 6-31G * basis set, w... more Quantum mechanical calculations at the B3LYP theory level, together with the 6-31G * basis set, were employed to obtain the energy, HOMO, LUMO, MEPs, and charge of dapsone is compared with others derivatives. Conformational analysis using density functional calculations show that symmetric conformational isomer has low energy than asymmetric conformational isomer. The symmetry level was observed by molecular charge analysis. Its redox properties by electrons transfer are dependent of amine and sulphone moieties. Our results explain the oxidation mechanism of dapsone by electron transfer.

Research paper thumbnail of An Electronic Study for Metronidazole Metabolism

Journal of Computational and Theoretical Nanoscience, 2011

Page 1. Delivered by Ingenta to: ? IP : 93.91.26.12 Mon, 16 May 2011 16:03:40 RESEARCH AR TICLE C... more Page 1. Delivered by Ingenta to: ? IP : 93.91.26.12 Mon, 16 May 2011 16:03:40 RESEARCH AR TICLE Copyright © 2011 American Scientific Publishers All rights reserved Printed in the United States of America Journal of Computational and Theoretical Nanoscience Vol. ...

Research paper thumbnail of An Electronic Study of Tocopherol-Ring Regioisomers as Antioxidants

Journal of Computational and Theoretical Nanoscience, 2011

ABSTRACT The electronic structures study have been used in the classification of tocopherol-rings... more ABSTRACT The electronic structures study have been used in the classification of tocopherol-rings regiosiomers as antioxidants by quantum chemistry calculations using DFT methods at the B3LYP/6-31G* level of theory. The HOMO, ionization potential, stabilization energies, and spin density distribution calculations were performed for radical formed by electron or hydrogen abstraction from the phenolic hydroxyl groups at the pare-, meta- or ortho-positions. These values are related with HOMO and MEPs for antioxidant regioisomers classification. Our results shown that para-regioisomer is more nucleophilic compounds by electron transfer and more reactive molecule by hydrogen donating, followed by ortho-, and meta-regioisomers.

Research paper thumbnail of Vasorelaxant effect of trans‐4‐chloro‐β‐nitrostyrene, a synthetic nitroderivative, in rat thoracic aorta

Fundamental & Clinical Pharmacology

Previously, we showed that 1‐nitro‐2‐phenylethene, a nitrostyrene derivative of 1‐nitro‐2‐phenyle... more Previously, we showed that 1‐nitro‐2‐phenylethene, a nitrostyrene derivative of 1‐nitro‐2‐phenylethane, induced vasorelaxant effects in rat aorta preparations. Here, we studied mechanisms underlying the vasorelaxant effects of its structural analog, trans‐4‐chloro‐β‐nitrostyrene (T4CN), in rat aortic rings. Increasing concentrations of T4CN (0.54‐544.69 µm) fully and similarly relaxed contractions induced by phenylephrine (PHE, 1 µm) or KCl (60 mm) in endothelium‐intact aortic rings with IC50 values of 66.74 [59.66–89.04] and 79.41 [39.92–158.01] µm, respectively. In both electromechanical and pharmacomechanical couplings, the vasorelaxant effects of T4CN remained unaltered by endothelium removal, as evidenced by the IC50 values (108.35 [56.49–207.78] and 65.92 [39.72–109.40] µm, respectively). Pretreatment of endothelium‐intact preparations with L‐NAME, ODQ, glibenclamide, or TEA did not change the vasorelaxant effect of T4CN. Under Ca2+‐free conditions, T4CN significantly reduced the phasic contractions induced by caffeine or PHE, as well as the contractions due to exogenous CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil). These results suggest that in rat aortic rings, T4CN induced vasorelaxation independently from the activation of soluble guanylate cyclase/cGMP pathway, an effect that may be related to the electrophilicity of the substituted chloro‐nitrostyrene. This vasorelaxation seems to involve inhibition of both calcium influx from the extracellular milieu and calcium mobilization from intracellular stores mediated by IP3 receptors and by ryanodine‐sensitive Ca2+ channels.

Research paper thumbnail of Vasodilatory action of trans ‐4‐methoxy‐β‐nitrostyrene in rat isolated pulmonary artery

Clinical and Experimental Pharmacology and Physiology

Trans‐4‐methoxy‐β‐nitrostyrene (T4MN) induced more potent vasorelaxant effects in resistance arte... more Trans‐4‐methoxy‐β‐nitrostyrene (T4MN) induced more potent vasorelaxant effects in resistance arteries from hypertensive rats than its parent drug, β‐nitrostyrene 1‐nitro‐2‐phenylethene (NPe). To better understand the influence of insertion of the electron‐releasing methoxy group in the aromatic ring of NPe, we investigated vasorelaxant effects of T4MN in isolated pulmonary artery and compared them with those of NPe in view of the potential interest of T4MN in pulmonary arterial hypertension. T4MN and NPe both caused concentration‐dependent vasorelaxation in pulmonary artery rings pre‐contracted with either phenylephrine (1 µmol/L) or KCl (60 mmol/L), an effect unaffected by endothelium removal. In endothelium‐intact preparations pre‐contracted with phenylephrine, the vasorelaxant effect of T4MN was more potent than that of NPe. However, unlike NPe, this effect was significantly reduced following pretreatment with 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) (10 µmol/L, a guanylate cyclase inhibitor) or tetraethylammonium (5 mmol/L, a potassium channel blocker). T4MN abolished the CaCl2‐induced contractions in pulmonary artery preparations stimulated with phenylephrine (PHE) under Ca2+‐free conditions in the presence of verapamil , to preferentially activate receptor‐operated calcium channels. From these findings, we propose that T4MN evokes endothelium‐independent vasorelaxant effects in isolated rat pulmonary artery, partially by inhibiting Ca2+ influx through L‐type Ca2+ channels, as well as by activating soluble guanylate cyclase and potassium channels. The present results suggest the therapeutic potential of T4MN in treating pulmonary arterial hypertension.

Research paper thumbnail of A comparative study between kojic acid and its methylated derivatives as antioxidant related to maltol and alomaltol

Chemical Data Collections

Research paper thumbnail of N-Acetyl-cysteine Increases Chemical Stability of Hydroquinone in Pharmaceutical Formulations: a Theoretical and Experimental Approach

Journal of the Brazilian Chemical Society, 2017

In this study, the chemistry stability of hydroquinone (HQ) was evaluated according to its effect... more In this study, the chemistry stability of hydroquinone (HQ) was evaluated according to its effects in redox properties and compared to kojic acid (KA). The HQ oxidation was more inhibited by N-acetylcysteine (NAC) than ascorbic acid (AA). These results were elucidated using theoretical methods at the DFT/B3LYP level of theory. All electronic parameters were related between antioxidant performance and highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), HOMO-LUMO value gap (GAP), ionization potential (IP), and phenol or enol bond dissociation energy (BDE OH) values. However, the interactions between HQ and NAC cannot be related by changing of these electronic parameters. Therefore the high calculated values for electron transfer can be associated to NAC due to polarizability or chelation properties of sulfur moiety.

Research paper thumbnail of Avanços Químicos No Planejamento e Desenvolvimento De Derivados Do Paracetamol

Química Nova

CHEMICAL ADVANCES ON DESIGN AND DEVELOPMENT OF PARACETAMOL DERIVATIVES. Acetaminophen or paraceta... more CHEMICAL ADVANCES ON DESIGN AND DEVELOPMENT OF PARACETAMOL DERIVATIVES. Acetaminophen or paracetamol is a widely used analgesic and antipyretic drug and appears to be safe if used at normal therapeutic doses, but in large doses produce liver and / or kidney damage in humans and experimental animals. Prostaglandin endoperoxide synthase (PGES) and cytochrome P-450 are the key enzymes in humans as they are responsible for the analgesic and toxicity effects of paracetamol, respectively. At present, the development of new derivatives still has few impacts on clinical applications of safe compounds. Thus, in this work are discussed, a series of approaches on the design and development of acetaminophen derivatives. Some efforts were realized in our own research group.

Research paper thumbnail of Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

Molecules

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory... more 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 du...

Research paper thumbnail of Cardiovascular Effects of Trans-4-Methoxy-β-Nitrostyrene in Spontaneously Hypertensive Rats: Comparison With Its Parent Drug β-Nitrostyrene

Frontiers in Pharmacology

We previously reported that trans-4-methoxy-β-nitrostyrene (T4MN) evoked higher vasorelaxant effe... more We previously reported that trans-4-methoxy-β-nitrostyrene (T4MN) evoked higher vasorelaxant effects in small resistance arteries from spontaneously hypertensive rats (SHRs) in comparison with its parent drug, the β-nitrostyrene 1-nitro-2-phenylethene (NPe). To further our knowledge of the influence of insertion of an electron-releasing group such as methoxy in the aromatic ring of NPe, we investigated the cardiovascular responses to intravenous (i.v.) injection of T4MN in SHRs and compared with those of NPe. In anesthetized SHRs, i.v. treatment with T4MN (0.03-0.5 mg/kg) and NPe (0.03-3 mg/kg) induced dose-dependent bradycardia and hypotension, which were biphasic (named phases 1 and 2). Magnitude of these responses was significantly higher for T4MN compared with NPe. Phase 1 cardiovascular responses to both T4MN (0.3 mg/ kg) and NPe (3 mg/kg) were prevented by cervical bivagotomy or perineural treatment of both cervical vagus nerves with capsaicin, but was unchanged by i.v. pretreatment with capsazepine or ondansetron. After injection into the left ventricle, NPe and T4MN no longer evoked phase 1 responses. In conscious SHRs, NPe (3 mg/kg, i.v.), and T4MN (0.3 mg/kg, i.v.) evoked monophasic hypotensive and bradycardiac effects which were suppressed by i.v. pretreatment with methylatropine. It is concluded that i.v. administration of NPe and T4MN in SHRs induced a vago-vagal hypotensive and bradycardic reflex that did not involve the activation of vanilloid TRPV 1 or 5-HT 3 receptors located on vagal pulmonary sensory nerves. With respect to its parent drug, T4MN was more potent in inducing this reflex. Phase 2 hypotensive response to i.v. NPe and T4MN seems partially resulting from a direct vasodilatory action. It seems that insertion of a methoxy group into the aromatic ring stabilized NPe, which in turn increases its cardiovascular effects.

Research paper thumbnail of The role of regioselective hydroxylation on toxicity of diclofenac and related derivatives

Research paper thumbnail of In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity

Molecules

Inflammation is a complex reaction involving cellular and molecular components and an unspecific ... more 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 con...

Research paper thumbnail of Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

Molecules

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involv... more 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 ...