1,720,978 research outputs found
6-to-8 and 7-to-9 membered ring expansion in annulated tetrahydropyridines and azepines – novel approach toward azocine and azonine derivatives with substantial bioactivity
No full textThe 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
Investigation on pyrrolo[3,2-c]pyridine derivatives as inhibitors of platelet aggregation
No full textThe exploration of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole derivatives as selective butyrylcholinesterase inhibitors
No full textSynthesis of pyrrolo[2,3-d]pyridazines and pyrrolo[2,3-c]pyridines (6-azaindoles). Experimental and theoretical study
No full textA new synthetic route towards 6-azaindoles (pyrrolo[2,3-c]pyridines) and pyrrolo[2,3-d]pyridazines starting from 4-aroyl pyrroles is described. This overall protocol involves: (i) the Vilsmeier-Haack reaction to obtain pyrrolo-2,3-dicarbonyles and (ii) condensation with hydrazines or glycine methyl ester. The reaction mechanism between pyrrolo-2,3-dicarbonyl with phenyl hydrazine and glycine methyl ester has been modelled using DFT calculations to prove the formation of one from two possible isomers of condensation
Pyrrolo[2,1-a]isoquinoline scaffold in drug discovery: Advances in synthesis and medicinal chemistry
No full textPyrrolo[2,1-a]isoquinoline (PIq) is a nitrogen heterocyclic scaffold of diverse alkaloids endowed with several biological activities, including antiretroviral and antitumor activities. Several 5,6-dihydro-PIq (DHPIq) alkaloids, belonging to the lamellarins' family, have proved to be cytotoxic to tumor cells, as well as reversers of multidrug resistance. In this review, we provide an overview of the main achievements over the last decade in the synthetic approaches to access libraries of PIq compounds along with a survey, as comprehensive as possible, of bioactivity, mechanism of action, pharmacophore and structure-activity relationships of synthetic analogs of DHPIq-based alkaloids. The focus is mainly on the potential exploitation of the (DH)PIq scaffold in design and development of novel antitumor drugs
Annelated medium-sized azaheterocycles as attractive scaffolds for CNS targeted leads.
Full text linkMedium-sized nitrogen heterocycles (7-to-15-membered) have widespread interest in organic synthesis and medicinal chemistry. Indeed, such heterocyclic rings are found as subunits or core structures in natural and bioactive molecules, including pharmaceutical products, whereas on the other hand they often can serve as key intermediates in the synthesis of bicyclic compounds by selective transformations (e.g., transannular ring-contractions, cycloadditions). These molecular frameworks, particularly annelated 7-to-10-membered aza-heterocycles, have long drawn our attention as potential scaffolds for developing new multitarget- directed ligands (MTDLs) for treating Alzheimer's disease (AD) and other neurodegenerative syndromes.AD, the most common form of dementia affecting people worldwide, is a progressive neurodegenerative disorder, whose multifactorial pathogenesis is still not completely understood. The main histopathological changes include synaptic dysfunction and neuronal loss resulting from intracellular and extracellular fibrillar aggregates of Beta-amyloid (Abeta),hyperphosphorilated and beta-folded tau proteins, cholinergic impairment, oxidative stress, neuroinflammation, metal dys-homeostasis and mitochondrial damage. Among others, N- methyl-D-aspartate receptors (NMDARs) play a major role in learning and memory, and their overactivation causes excessive calcium influx and consequent excitotoxicity, which is associated with CNS diseases, including Parkinson's disease.
Starting from our old1,2 and recent 3 findings on the suitability of partially hydrogenated benzo-, chromane-4- one- and indole-fused azepine and azocine derivatives targeted at enzymes, receptors and biochemical pathways involved in the pathogenesis of AD, we extended the investigation to novel derivatives of annelated azonines and azecines.
Herein, our recent advances of benzo- and indol-fused 7-to-10-membered nitrogen heterocycles as molecular tools for AD-associated targets (e.g., butyryl- and acetylcholinesterase, monoamine oxidases A and B, Abeta aggregation, ROS insult, NMDAR antagonist), along with the results from investigation on cell and ex vivo/in vivo animal models, will be presented and discussed in an effort of rationalizing structure-activity relationships and progressing drug optimization of the examined CNS-targeted lead compounds
Investigation on the antiplatelet activity of pyrrolo[3,2-c]pyridine-containing compounds
No full textA series of 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines (THPPs), mostly C(2)-substituted derivatives, and some 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles (THPIs) were synthesized and tested in-vitro for their ability to inhibit aggregation of human platelet-rich plasma (PRP) induced by adenosine 5'-diphosphate (ADP) and adrenaline (epinephrine). 5-Benzyl THPP (3), 2-(benzylamino)methyl THPP (5f) and 2-ethyl THPI (6) moderately and dose-dependently inhibited platelet aggregation induced by adrenaline and, to a lesser extent, by ADP. These compounds inhibited the second phase of the PRP aggregation triggered by adrenaline, which largely depends upon thromboxane A(2) production and ADP release. In the adrenaline stimulated aggregation, the THPI derivative 6 was found to be nearly equipotent with aspirin, their IC50 values (concentration effecting 50% inhibition of aggregation) being 90 and 60 microM, respectively. A relation between activity and calculated octanol-water partition coefficient suggested that a log P value around 2.5 should be the optimal lipophilicity value for the activity of THPP-containing compounds
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
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