Márcia Inês Goettert

Pyridinylquinoxalines and Pyridinylpyridopyrazines as Lead Compounds for Novel p38α Mitogen-Activated Protein Kinase Inhibitors

Various substituted 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines and 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)pyridopyrazines were synthesized as novel p38 alpha MAP kinase inhibitors via different short synthetic strategies with high variation possibilities. The formation of the quinoxaline/pyridopyrazine core was achieved from alpha-diketones and o-phenylenediamines/alpha-diaminopyridines under microwave irradiation. Introduction of an amino moiety at the pyridine C2 position of the 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines led to compounds showing potent enzyme inhibition down to the double-digit nanomolar range (6f; IC(50) = 81 nM). Replacement of the quinoxaline core with pyrido[2,3-b]pyrazine gave compound 9e with superior p38 alpha MAP kinase inhibition (IC(50) = 38 nM).

A Frozen Analogue Approach to Aminopyridinylimidazoles Leading to Novel and Promising p38 MAP Kinase Inhibitors

In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on the pyridinyl unit, using purine bioisosteres as constrained structure analogues. The identification of the most potent bioisostere was followed by a further derivatization to address hydrophobic region II. In combination with C-2 modifications of the imidazole core, we were able to design highly active inhibitors on the p38α MAP kinase. The inhibitor design presented herein represents a promising and highly efficient advancement of recent stages of development in this class of p38 MAP kinase inhibitors. In combination with the highly flexible synthetic strategy, directions toward further investigations of complex C-5 modifications of diarylimidazoles are indicated.

Gallic acid reduces the effect of LPS on apoptosis and inhibits the formation of neutrophil extracellular traps

Apoptosis and NETosis of neutrophils are two major mechanisms of programmed cell death that differ in their morphological characteristics and effects on the immune system. Apoptosis can be delayed by the presence of pathogens or chemical components such as lipopolysaccharide (LPS). Neutrophils have other antimicrobial strategy, called neutrophil extracellular traps (NETs), which contributes to the elimination and control of the pathogen. NETosis is induced by infection, inflammation or trauma and represents an innate immune activation mechanism. The objective of this study was to evaluate the effect of gallic acid (GA) in the modulation of apoptosis and NETs release. The results show that GA decreased the anti-apoptotic effect of LPS, blocked the induction of NETs and prevented the formation of free radicals induced by LPS. These findings demonstrate that the GA is a novel therapeutic agent for decreasing the exacerbated response of the body against an infectious agent.

Metabolically Stable Dibenzo[b,e]oxepin-11(6H)-ones as Highly Selective p38 MAP Kinase Inhibitors: Optimizing Anti-Cytokine Activity in Human Whole Blood

Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H)-ones were synthesized and tested in a p38α enzyme assay for their inhibition of tumor necrosis factor-α (TNF-α) release in human whole blood. Compared to the monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown that the additional introduction of hydrophilic residues at position 9 leads to a substantial improvement of the inhibitory potency and metabolic stability. Using protein X-ray crystallography, the binding mode of the disubstituted dibenzoxepinones and the induction of a glyince flip in the hinge region were confirmed. The most potent compound of this series, 32e, shows an outstanding biological activity on isolated p38α, with an IC50 value of 1.6 nM, extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and low ATP competitiveness. The ability to inhibit the release of TNF-α from human whole blood was optimized down to an IC50 value of 125 nM. With the promising dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.

Chiral Sulfoxides as Metabolites of 2-Thioimidazole-Based p38α Mitogen-Activated Protein Kinase Inhibitors: Enantioselective Synthesis and Biological Evaluation

A number of pharmaceutically important drugs contain asymmetric sulfinyl moieties, so the biological evaluation of chiral sulfoxides as human drug metabolites is important for the development of safe and effective pharmaceuticals. Asymmetric oxidation is one of the most attractive ways to prepare chiral sulfoxides. In combination with different chiral ligands, the iron- and titanium-catalyzed asymmetric oxidations of tri- and tetrasubstituted 2-thioimidazoles afford the corresponding sulfoxides with enantiomeric excesses up to 99% as novel p38α mitogen-activated protein kinase (p38α MAPK) inhibitors. The enantiomerically pure sulfoxides were evaluated on their inhibitory potency against p38α MAPK compared to the respective sulfides and sulfoxide racemates and showed differences in their affinities for the enzyme with IC(50) in the low nanomolar range. In addition, the ability to inhibit the release of tumor necrosis factor-α (TNF-α) from human whole blood (HWB) was examined. Some pyridinylimidazole derivatives showed excellent HWB activity with IC(50) as low as 52 nM.

Conformational effects on potency of thioimidazoles and dihydrothiazolines

We investigated the effect of steric restriction and hindrance on inhibitors directed against the biological activity of p38α MAP kinase. The structural reduction of the early lead compound SKF86002 into three structural classes of optimized SKF86002-like inhibitors produced a strong effect on inhibitory potency. This effect was investigated by conformational analysis and docking experiments.

Neuromodulatory effects of Calyptranthes grandifolia extracts against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells.

Alzheimers and Parkinsons diseases are neurodegenerative disorders characterized by progressive neuronal dysfunction. Previous studies revealed that some natural products have neuroprotective properties, including species of the Myrtaceae family. However, the neuromodulatory potential of Calyptranthes grandifolia is not clear. In the present study, we examined the ability of the ethanol and hexane leaf extracts of C. grandifolia to prevent 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Initially, we investigated the potential of the extracts to inhibit the neurodegenerative-related enzymes c-Jun N-terminal kinase 3 (JNK3) and acetylcholinesterase (AChE). In addition, SH-SY5Y cell viability was assessed by MTT assay after 100μM 6-OHDA-induced cell damage. In order to verify the possible effects of both extracts on 6-OHDA-induced cell death, hydrogen peroxide generation, mitochondrial potential and caspases-3 activity were assessed. Our findings revealed that ethanol extract exhibited inhibitory activity against JNK3 and AChE. In addition, when co-treating SH-SY5Y cells with 6-OHDA and the extracts, oxidative stress was inhibited by both extracts through a decrease of mitochondrial depolarization and caspases-3 activity. In summary, ethanol and hexane extracts of C. grandifolia have some suppressive property against neurotoxicity induced by 6-OHDA.

Plantas Medicinais da RENISUS Com Potencial Anti-inflamatório: Revisão Sistemática Em Três Bases de Dados Científicas

The inflammation is a response to acute tissue injury responsible for producing characteristic symptoms that lead to changes in tissue homeostasis and blood flow, as a defense mechanism of the immune system. However, chronic inflammation is a cause of many diseases like cancer, arteriosclerosis, diabetes and neurodegenerative diseases. Most anti-inflammatory drugs exert significant side effects that may limit their use. An alternative to such drugs are the medicinal plants, which provide an important approach for the identification of bioactive compounds. This systematic review aimed to quantify the clinical studies that relate therapeutic potential for inflammatory diseases from the study of plants RENISUS, published between 2010 and February 2013 in three scientific databases (SciELO, Science Direct and Springer). Of the 21 357 articles found in databases, analysis of articles was originally made from the title of journal reading, the chosen articles were subsequently assessed for Abstract. Finally, Articles chosen at this stage, the full text was analyzed. This analysis resulted in the selection of 44 studies of interest, which dealt with 20 different plants RENISUS.

ANÁLISE SISTEMÁTICA DA PRODUÇÃO CIENTÍFICA DO ZINGIBER OFFICINALE ROSCOE APÓS A CRIAÇÃO DA RELAÇÃO NACIONAL DE PLANTAS MEDICINAIS DE INTERESSE AO SISTEMA ÚNICO DE SAÚDE

Introduction: Ginger (Zingiber officinale Roscoe) is a native plant from Asia that has been used as a spice and medicinal compound for thousands of years. Many of its compounds have been isolated, identified, and studied due to their pharmacological effects. Objectives: Quantify clinical trials reporting some form of therapeutic action from the use of Z. officinale plant, which are listed on the National Medicinal Plants of Interest to the Unified Health System published between 2010 and 2013 in three scientific databases (SciELO, Science Direct and Springer). Material and Methods: We searched databases using the key search term “Zingiber officinale Roscoe.” A total of 757 articles were retrieved. We selected the studies dealing specifically with the term “Zingiber officinale ” or related terms such as “ginger,” “gingerol,” “gingerols,” “ginger,” and “ginger”. Reading the Abstract, we selected those that reported some kind of therapeutic treatment. In the last phase, the selected articles were fully read to search those proving therapeutic potentials from the study of Z. offic inale. Results: Thirty articles were included in this review. Six studies reported the antioxidant activity representing the most cited therapy. Conclusion: With the results, it is expected to be possible to guide further research on the species in question, including other diseases not yet explored.

In vitro activities of Ceiba speciosa (A.St.-Hil) Ravenna aqueous stem bark extract

Abstract Several species of the genus Ceiba (Malvaceae) are ethnopharmacologically used. Thus, this study aimed to investigate the in vitro beneficial properties of the aqueous stem bark extract of Ceiba speciosa. The extract presented a great amount of phenolic compounds (117.4 ± 6.2 mg GAE/g). The antioxidant activity was assessed by DPPH (IC50 = 42.87 μg/mL), ORAC (2351.17 μmol TE/g) and FRAP (235.94 μM FeSO4/g) methods. In addition, the extract reduced MCF-7 cell viability as assessed by MTT. However, it prevented mitochondrial membrane depolarization and reduced caspase-9 activity induced by hydrogen peroxide. In conclusion, these findings indicate the extract is an excellent source of natural antioxidants and is able to protect ROS-induced cell death. Therefore, C. speciosa extract may possess beneficial properties for application in pharmaceutical industry as an antioxidant. However, further studies to better elucidate its mechanisms and to isolate its active compounds are required.