1,720,960 research outputs found
New azepino[4,3-b]indole derivatives, as selective butyrylcholinesterase inhibitors with potential for neurodegenerative disorders
No full textStarting from the cholinergic hypothesis, which originally implied a major role of acetylcholinesterase (AChE) in the cognitive impairment of the Alzheimer’s disease (AD), the role of butyrylcholinesterase (BChE) has progressively become more crucial in the AD development and progression. Indeed, it has been shown that the levels of AChE in the AD brain decrease by as much as 90%, whilst the levels of BChE, mainly in the G1 form (i.e., globular form of monomer structure), increase, suggesting that inhibition of BChE may represent a privileged target to develop new drugs for treating neurodegenerative diseases. As a matter of fact, in the last years several efforts have been made to identify selective BChE inhibitors, such as tricyclic cymserine analogs, which proved beneficial in vivo in animal models, most likely by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain.
Previously, we reported the ChE inhibition activity of novel medium-sized nitrogen-containing heterocycles (e.g., tetrahydroazocines) fused on indole, which showed ChE inhibition activity. Herein, we explore the ChE inhibition activity of a series of 3,4,5,6-tetrahydroazepino[4,3-b]indole derivatives, some of which proved to be highly potent and selective BChE inhibitors, with low toxicity as assessed in vitro on neuroblastoma cell cultures. Among the newly synthesized compounds, the lactam derivative 2 showed the highest BChE inhibition potency (IC50 = 1.5 nM), whereas further investigation showed that the above tricyclic system could provide a promising scaffold for new multimodal derivatives with potential in the treatment of neurodegenerative disorders
The exploration of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole derivatives as selective butyrylcholinesterase inhibitors
No full text
Fragment deconstruction study and human thrombin-bound crystal structures of new β-d-glucose-containing anticoagulants
No full textWe recently synthesized novel glucose-conjugated dual factor Xa (fXa) and thrombin (fIIa) inhibitors 3, bearing 5-chlorothien-2-yl and 1-isopropylpiperidine moieties as binders of the S1 and S3/S4 enzymes’ pockets, respectively, which showed potential for use in the treatment of thrombotic diseases. In particular, the β-d-glucosyl-bearing derivative proved to be a competitive inhibitor with high potency against fXa (Ki = 0.09 nM) and fIIa (Ki = 100 nM), and in vitro/ex vivo micromolar anticoagulant potency.1 Despite the narrower binding site groove of fIIa, the inhibitory potency of the glucosyl derivative, compared to the parent glucosyl-lacking compound 1, increases against fIIa (110-fold) much more than against fXa (7-fold). Experimental deconstruction of the most potent inhibitor molecule into smaller fragments, synthesized and tested, provided us with significant insights into the enzymes’ affinity contributions of the P1 and P3/P4 moieties, and a C3-alkyl-linked -d-glucose fragment (PG). To understand the inhibitors’ binding modes to fIIa, the crystal structures of human thrombin in complex with two glucose-based compounds were solved (pdb codes: 4NZE and 4N3L), and the crystallographic results will be presented and discussed
The exploration of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole derivatives as selective butyrylcholinesterase inhibitors
No full textThe role of butyrylcholinesterase (BChE) in the progression of Alzheimer’s disease (AD) has recently become more crucial (1). It is known that in healthy human brain acetylcholinesterase (AChE) predominates over BChE activity, but, as AD progresses, The levels of AChE in the brain decrease by as much as 90%, whilst the levels of BChE, Mainly in the G1 form (i.e., globular form of monomer structure), increase (2,3). This suggests that the inhibition of BChE may be useful in ameliorating the cholinergic
transmission, which likely worsen in AD due to the BChE increased activity (4). As a matter of fact, in the AD brain, selective BChE inhibitors, such as tricyclic cymserine Analogs (1,5), have been demonstrated to have beneficial effects in vivo, probably by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain. Some years ago, we reported the ChE inhibition activity of novel annulated (e.g., pyrrole- and indole-fused) tetrahydroazocines, which showed AChE selectivity (6). Herein, we explore the ChE inhibition activity of a large series of 1,2,3,4,5,6-hexahydroazepino[4,3-b]ndole
derivatives, some of which proved to be potent and selective BChE inhibitors. In particular, the lactam
derivative 2 was highly active against BChE, with a subnanomolar IC50 Value. Synthesis, enzyme inhibition
data and SARs are presented and discussed
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
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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