1,720,978 research outputs found
New Azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity
Full text linkSeveral 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives were synthesized and evaluated for their activity as cholinesterase (ChE) inhibitors. The most potent inhibitors were identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be very active against human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships highlighted critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i.e., optimal position, size and lipophilicity of phenyl substituents). The effects of a number of compounds against NMDA-induced SH-SY5Y neuronal cell injury were also evaluated. Treatment with 12b increased cell viability in SH-SY5Y cells pretreated with 250 Î1⁄4M NMDA, with significant effects (P 
A second life for MAO inhibitors? From CNS diseases to anticancer therapy
Full text linkMonoamine oxidases A and B (MAO A, B) are ubiquitous enzymes responsible for oxidative deamination of amine neurotransmitters and xenobiotics. Despite decades of studies, MAO inhibitors (MAOIs) find today limited therapeutic space as second-line drugs for the treatment of depression and Parkinson's disease. In recent years, a renewed interest in MAOIs has been raised up by several studies investigating the role of MAOs, particularly MAO A, in tumor insurgence and progression, and the efficacy of MAOIs as coadjutants in the therapy of chemoresistant tumors. In this survey, we highlight the implication of MAOs in the biochemical pathways of tumorigenesis and review the state-of-the-art of preclinical and clinical studies of MAOIs as anticancer agents used in monotherapy or in combination with antitumor chemotherapeutics
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)
Synthesis and biological evaluation of Mannich base derivatives of the neuroprotective 6-(2-phenylethyl)-3,4,5,6-tetrahydroazepino[4,3- b]indol-1(2H)-one
No full textAlzheimer’s disease (AD) is a devastating disorder accounting for the majority of the dementias.1 Due to its multifactorial cause, and despite the advances achieved over the last two decades in the understanding of the AD pathogenic mechanisms, there are no effective therapies. So far, only few drugs are available, which include AChE inhibitors (rivastigmine, galantamine, and donepezil), for the symptomatic relief of mild to moderate AD, and the N-methyl-D-aspartate receptor antagonist memantine.2 Recently, we reported the inhibitory activities of cholinesterases (ChEs) by a number of 6- substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives.3 Among them, 6-(2-phenylethyl)-THAI 1, proved to be highly potent inhibitors of human BChE (IC50 = 13 nM), with 1000-fold selectivity over AChE. It showed additional neuroprotective effects on the SH-SY5Y cells viability, against NMDA- induced neurotoxicity. To overcome some drawbacks, such as a very low aqueous solubility (0.05 mg/mL) and a strong interaction with human serum albumin, which limit its use in vivo, compound 1 was chemically modified following the classical Mannich base approach.4 A number of derivatives (2), as potential prodrugs, were synthesized and tested. Herein, stability in physiological media, physicochemical properties, biological activities and preliminary biodistribution studies in animal models of type-2 derivatives are presented and discussed.Alzheimer’s disease (AD) is a devastating disorder accounting for the majority of the dementias.1 Due to its multifactorial cause, and despite the advances achieved over the last two decades in the understanding of the AD pathogenic mechanisms, there are no effective therapies. So far, only few drugs are available, which include AChE inhibitors (rivastigmine, galantamine, and donepezil), for the symptomatic relief of mild to moderate AD, and the N-methyl-D-aspartate receptor antagonist memantine.2 Recently, we reported the inhibitory activities of cholinesterases (ChEs) by a number of 6- substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives.3 Among them, 6-(2-phenylethyl)-THAI 1, proved to be highly potent inhibitors of human BChE (IC50 = 13 nM), with 1000-fold selectivity over AChE. It showed additional neuroprotective effects on the SH-SY5Y cells viability, against NMDA- induced neurotoxicity. To overcome some drawbacks, such as a very low aqueous solubility (0.05 mg/mL) and a strong interaction with human serum albumin, which limit its use in vivo, compound 1 was chemically modified following the classical Mannich base approach.4 A number of derivatives (2), as potential prodrugs, were synthesized and tested. Herein, stability in physiological media, physicochemical properties, biological activities and preliminary biodistribution studies in animal models of type-2 derivatives are presented and discussed
Bombyx Mori Silk Fibroin as a Sustainable Organocatalyst for Diastereoselective Michael Additions
No full textPowdered silk fibroin (PSF) extracted from Bombyx mori cocoons is reported as a heterogeneous organocatalyst in the selective Michael 1,4 addition of nitromethane to α,β-unsaturated carbonyl compounds, affording Michael adducts in almost quantitative yields, with complete antidiastereoselectivity and in mild conditions. PSF proved to be reusable for more than 50 recycles without any loss of catalytic activity. In silico studies suggest the presence of an enzyme-like pocket as the active catalytic site, pointing out fibroin fibers as a heterogeneous biological organocatalyst
Structure-property relationship study of the HPLC enantio-selective retention of neuroprotective 7-[(1-alkylpiperidin-3-yl)methoxy]coumarin derivatives on an amylose-based chiral stationary phase
Full text linkThe enantiomer separation of a number of racemic 7-[(1-alkylpiperidin-3-yl)methoxy]coumarin derivatives, some of which show outstanding in vitro multitarget neuroprotective activities, was successfully achieved on a polysaccharide-based chiral stationary phase, bearing amylose tris(3,5-dimethylphenylcarbamate) as chiral selector, in normal polar mode (methanol and acetonitrile as the mobile phases). The majority of the screened selectands, especially those bearing 1-(3-X-benzyl)piperidin-3-yl moieties, showed baseline enantiomer separations, and compound 8 (X = NO2) was the best resolved (α = 2.01; RS = 4.27). Linear free-energy relationships, usefully complemented by molecular docking calculations, proved the key role in enantioselective retention of aromatic interactions between π-donor moieties in the chiral selector and π-acceptor moieties in selectand, strengthened by hydrogen bond interaction between a hydrogen bond donor in the chiral selector and the hydrogen bond acceptor group(s) in the selectand. Statistically reliable equations highlighted the importance of the substituent's size and substitution pattern (meta better than para) to affect the enantiorecognition of the title compounds. The chromatographic data support the scalability of the optimized experimental conditions for preparative purposes. This article is protected by copyright. All rights reserved
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
Anticancer potential of novel α,β-unsaturated γ-lactam derivatives targeting the PI3K/AKT signaling pathway
Full text linkSix recently synthesized alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates were evaluated for their potential as cytotoxic and anticancer agents. All compounds were tested in the ERα positive MCF-7, triple negative MDA-MB-231, and Her2+ SKBR-3 breast cancer cell lines. The most lipophilic derivatives, bearing the 4-isopropylphenyl (2) or 4-tert-butylphenyl (3) group at the γ-lactam nitrogen, proved to be cytotoxic against all the cancer cell lines tested (IC50 values ranging from 18 to 63 μM), exerting their greatest activity in SKBR-3 cells, with IC50 values of 33 and 18 μM, respectively. Biological studies showed that the cytotoxic effects of 2 and 3 are accompanied by apoptotic death in breast cancer cells, and both compounds showed no significant toxicity on healthy cells (e.g., MCF-10A) and red blood cells. An in-depth mechanistic study based on molecular biology, immunoblotting analysis and in silico docking calculations suggested that α,β-unsaturated γ-lactam derivatives could interfere with the functioning of PI3K and PDK-1, two key enzymes in the PI3K/AKT signaling pathway, whose overactivation is related to the regulation of cell growth and survival in several malignancies
Advances in synthesis of novel annulated azecines and their unique pharmacological properties
Full text linkAnnulated azecines, mostly partially saturated benzo[d]azecine and dibenzo[c,g]azecine fusion isomers, constitute a unique class of alkaloids and nature-inspired azaheterocyclic compounds with interesting reactivity, physicochemical and biological properties. Due to difficulties associated with the synthesis of the benzazecine (or bioisosteric) scaffold they are not the focus of organic and medicinal chemists' consideration, whereas it is worth noting the range of their pharmacological activities and their potential application in medicinal chemistry. Herein, we reviewed the synthetic methodologies of arene-fused azecine derivatives known up to date and reported about the progress in disclosing their potential in drug discovery. Indeed, their conformational restriction or liberation drives their selectivity towards diverse biological targets, making them versatile scaffolds for developing drugs, including antipsychotic and anticancer drugs, but also small molecules with potential for anti-neurodegenerative treatments, as the recent literature shows
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