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Diversity-oriented synthesis of highly-functionalized amino-pyrazoles as pharmaceutically relevant compounds
No full textThe pyrazole ring represents a valuable heterocycle in medicinal chemistry, being shared by several effective molecules with a broad range of activity. In particular, amino-pyrazoles constitute a versatile framework in drug discovery.
By taking advantage of our expertise on the condensation of active methylene reagents and heterocumulenes, we developed new synthetic strategies for the preparation of highly-functionalized amino-pyrazoles through the formation of ketene N,S- or S,S-acetals. A One-pot synthetic procedure led to the formation of a series of pyrazole compounds endowed with promising antiproliferative activity in cell-based assay. Docking simulations carried out on the most active molecules indicated estrogen receptors as a potential target inside the cell.
Alongside, a stepwise synthetic protocol was used to prepare novel antioxidant pyrazole hydrazones that efficiently inhibited reactive oxygen species (ROS) formation and platelet aggregation. The same synthetic approach allowed the preparation of amino-pyrazoles with interesting antiangiogenetic properties as assessed in wound healing and tube formation assays on human fibroblasts and endothelial cells. Furthermore, these compounds displayed good Akt phosphorylation inhibition in Western Blot analyses.
Based on literature data, a set of pyrazoles was tested as antimalarial agents against D10 Chloroquine(CQ)-sensitive and W2 CQ-resistant P. falciparum strains. Selected derivatives showed micromolar IC50 values against the two considered protozoa strains and further SAR extension studies led to the identification of novel amino-pyrazole and pyrazolopyrimidine derivatives with improved antimalarial properties especially against the CQ-resistant W2 strain.
Overall, the development of diversity-oriented procedures for the preparation of highly substituted pyrazoles allowed the identification of unreported hit compounds as antiproliferative, antiangiogenic, antioxidant and antimalarial agents and provide further support to the pharmaceutical potential of pyrazole nucleus and heterocyclic system thereof derived in different therapeutic areas
HIGHLY-FUNCTIONALIZED AMINO PYRAZOLES AS ANTIOXIDANT AGENTS: A PRELIMINARY SYNTHETIC ACCESSIBILITY STUDY
No full text5-pyrazolyl urea derivatives showed interesting pharmaceutical properties. In particular, compounds 1
(Figure 1) showed promising antioxidant activity by inhibiting ROS formation in platelet. The free amino
group on the pyrazole ring appear to be essential for the antioxidant activity whereas the substitution of
the catechol moiety (X group, Figure 1) modulate the ability of the compound to block ROS formation. To further extend the SARs of derivatives 1 and evaluate the effect on the activity of the introduction of a
N-phenyl substituent on the pyrazole scaffold, we planned the synthesis of new amino pyrazoles 2 (Figure
1). In order to assess the chemical accessibility to the desired compounds, synthetic path A and B (Scheme
1) were considered. Methylhydrazine and p-anisaldehyde were selected as template reagents. Despite literature data, path A proved to be ineffective as the cyclization reaction could not occur in a
number of different experimental conditions. Path B led to the isolation of the desired compound as a
mixture of the two possible N-methyl isomers in good yields. In the poster, the different synthetic
conditions as well as the characterization of the obtained pyrazole isomers will be presented
PDE4D: A Multipurpose Pharmacological Target
No full textPhosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties
Novel tetrasubstituted 5-Arylamino pyrazoles able to interfere with angiogenesis and Ca2+ mobilization
No full textIn the last years, 5-pyrazolyl ureas and 5-aminopyrazoles have been investigated for their antiangiogenetic properties and their potential interaction with the ubiquitous Ca2+ binding protein Calreticulin. Based on the structure of the active compounds I and GeGe-3, novel 5-arylamino pyrazoles 2 and 3 were synthesized through a stepwise procedure. In MTT assays, all the new derivatives proved to be non-cytotoxic against eight different tumor cell lines, normal fibroblasts, and endothelial cells. Furthermore, selected derivatives showed relevant antiangiogenetic properties, resulting more effective than reference molecules I and GeGe-3 in inhibiting HUVEC endothelial tube formation. 5-Arylamino pyrazoles 2a and 2d were identified as the most interesting compounds and significantly prevented tube formation of tumor secretome-stimulated HUVEC. Furthermore, the two compounds inhibited HUVEC migration in wound healing assay and altered cell invasion capability. Additionally, 2a and 2d strongly affected Ca2+ mobilization and cytoskeletal organization of HUVEC cells, being as active as the reference compound GeGe-3. Differently from previous studies, molecular docking simulations suggested a poor affinity of 2a towards Calreticulin, one of the interacting partners of the lead compound GeGe-3. Collectively, this new amino-pyrazole library further extends the structure-activity relationships of the previously prepared derivatives and confirmed the biological attractiveness of this chemical scaffold as antiangiogenetic agents
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Antimalarial Activity of Tri- and Tetra-Substituted Anilino Pyrazoles
Full text linkPyrazole core represents a privilege scaffold in medicinal chemistry; a number of pyrazole compounds are endowed with various pharmacological activities in different therapeutic areas including antimalarial treatment. Supported by this evidence, a series of 5-anilino-3-(hetero)arylpyrazoles were evaluated for their antiplasmodial activity in in vitro assays. The compounds were synthesized according to regioselective and versatile protocols that combine active methylene reagents, aryl isothiocyanates and (substituted)hydrazines. The considered derivatives 2 allowed the definition of consistent structure–activity relationships and compounds 2b,e,k,l were identified as the most interesting derivatives of the series showing micromolar IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium strains. Additionally, the most active anilino-pyrazoles did not show any cytotoxicity against tumor and normal cells and were predicted to have favorable drug-like and pharmacokinetic properties
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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