1,720,974 research outputs found
4-Hydroxycoumarins as Michael donors in asymmetric routes to polycyclic coumarins (microreview)
No full textDifferent [3,4]-fused polycyclic 2H-chromen-2-ones can be prepared in a stereoselective fashion
starting from 4-hydroxycoumarins as nucleophilic synthones. Herein we report a brief overview of the
most recent methods including Pd-catalyzed [3+3] annulation processes, organocatalytic one-pot and
domino Michael addition/cyclization, tandem conjugate addition/hydroxyalkylation, and organocascade catalytic reaction
Monoamine Oxidase Inhibition for the Treatment of Neurodegenerative Diseases: Rationale, Assay Methodologies, and Reference Compounds
No full textMonoamine oxidases (MAOs) A and B are key enzymes involved in the metabolism of amine neurotransmitters as well as exogenous amine-containing substances. Since their characterization in the 1960s, they represent a pharmacological target for the discovery of small molecular inhibitors, especially as antidepressants and antiparkinsonian drugs. The development of in vitro/in vivo assays has paralleled such interest allowing the setup of fast and reliable screening methods herein described. Hence, a huge number of potent and selective inhibitors have been discovered, although only in some cases reaching the pharmaceutical market. A renewed interest has emerged with the so-called multitarget approach, combining multiple biological activities in a single molecular entity, speeding up the screening of MAO inhibitors endowed with additional activities for the treatment of neurodegenerative diseases
1,2,3,4-Tetrahydroisoquinoline/2H-chromen-2-one conjugates as nanomolar P-glycoprotein inhibitors: Molecular determinants for affinity and selectivity over multidrug resistance associated protein 1
Full text linkA series of coniugates bearing a 1,2,3,4-tetrahydroisoquinoline motif linked to substituted 7-hydroxy-2H-chromen-2-ones was synthesized and assayed through calcein-AM test in Madin-Darby Canine Kidney (MDCK) cells overexpressing P-glycoprotein (P-gp) and closely related multidrug resistance associated protein 1 (MRP1) to probe the interference with efflux mechanisms mediated by P-gp and MRP1, respectively. A number of substituents at C3 and C4 of coumarin nucleus along with differently sized and shaped spacers was enrolled to investigate the effects of focused structural modifications over affinity and selectivity. Linker length and flexibility played a key role in enhancing P-gp affinity as proved by the most potent P-gp modulator (3h, IC50 = 70 nM). A phenyl ring within the spacer (3k, 3l, 3o) and bulkier groups (Br in 3r, Ph in 3u) at coumarin C3 led to derivatives showing nanomolar activity (160 nM < IC50 < 280 nM) along with outstanding selectivity over MRP1 (SI > 350). Molecular docking calculations carried out on a human MDR1 homology model structure contributed to gain insights into the ligands’ binding modes. Some compounds (3d, 3h, 3l, 3r, 3t, 3u) reversed MDR thereby restoring doxorubicin cytotoxicity when co-administered with the drug into MDCK-MDR1 cells
Hansch-Type QSAR Models for the Rational Design of MAO Inhibitors: Basic Principles and Methodology
No full text: Hansch-type regression analysis enables the derivation of quantitative structure-activity relationship (QSAR) equations correlating bioactivity data with physicochemical parameters accounting for hydrophobicity, electronic properties, and steric effects of molecules or functional groups (substituents). Two datasets of MAO A and B inhibitors were enrolled in prototypical workflows employing multiparametric stepwise regression analysis, which includes linear and nonlinear (generally quadratic) terms. The optimal choice of variables (and/or combinations thereof) along with statistical validation yielded two robust equations describing MAO B potency and B/A selectivity, which included three and one parameter(s), respectively, and explained more than 80% of y-variance (r2) with low standard deviation (s) and good statistical significance (F, Fisher value)
Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors
Full text linkHerein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes’ inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule
A twenty-year journey exploring coumarin-based derivatives as bioactive molecules
Full text linkThe coumarin core (i.e., 1-benzopyran-2 (2H)-one) is a structural motif highly recurrent in both natural products and bioactive molecules. Indeed, depending on the substituents and branching positions around the byciclic core, coumarin-containing compounds have shown diverse pharmacological activities, ranging from anticoagulant activities to anti-inflammatory, antimicrobial, anti-HIV and antitumor effects. In this survey, we have reported the main scientific results of the 20-years investigation on the coumarin core, exploited by the research group headed by Prof. Angelo Carotti (Bari, Italy) either as a scaffold or a pharmacophore moiety in designing novel biologically active small molecules
Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones
Full text linkA series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes. © 2019 by the authors
Playing Around the Coumarin Core in the Discovery of Multimodal Compounds Directed at Alzheimer’s-Related Targets: A Recent Literature Overview
No full textAlzheimer’s disease (AD) causes a great socioeconomic burden because of its increasing prevalence and the lack of effective therapies. The multifactorial nature of AD prompts researchers to search for new strategies for discovering disease-modifying therapeutics. To this extent, the multitarget approach holds the potential of synergic or cooperative activities arising from compounds that are properly designed to address two or more pathogenetic mechanisms. As a privileged and nature-friendly scaffold, coumarin has successfully been enrolled as the heterocyclic core in the design of multipotent anti-Alzheimer’s agents. Herein, we comprehensively summarize the most recent literature (2018–2023), covering the rational design and the discovery of coumarin-containing multitarget directed ligands (MTDLs) whose anti-AD profile encompassed at least two different biological activities relevant for disease onset and progression. To enhance the clarity of presentation, synthetic coumarin-based MTDLs are categorized into four clusters based on their substitution pattern and reported bioactivities: (i) mono-, (ii) di-, and (iii) polysubstituted coumarins directed at protein targets, and (iv) coumarins directed at protein targets with additional metal-chelating features. Before discussing multimodal coumarins, the rationale for addressing each biological target is briefly presented
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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