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Special Issue "Molecules against Alzheimer"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (29 February 2016)

Special Issue Editors

Guest Editor
Prof. Dr. Michael Decker

Pharmazeutische and Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
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Interests: hybrid compounds; multifunctional cholinesterase inhibitors; cannabinoid and other GPCR ligands; natural products
Guest Editor
Prof. Dr. Diego Muñoz-Torrero

Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, Barcelona E-08028, Spain
Website | E-Mail
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is a devastating disease with regard to its ever-increasing global prevalence, as well to its effects on individual patients and caregivers. Currently, it can only be treated with acetylcholinesterase inhibitors or an NMDA antagonist, but these drugs only afford a symptomatic relief for a limited time. This very modest outcome of drug development is surprising due to the many research efforts and breakthroughs in AD biochemistry and pathophysiology. Obviously, AD’s highly complex interaction of multifactorial neurodegenerative disease processes challenges medicinal chemists and drug developers.

This Special Issue aims to highlight recent efforts on the early medicinal chemistry stage of anti-Alzheimer drug development, and wants to put a special focus on innovative applications of multifunctional and hybrid molecules, as well as the use of natural products for lead identification. In this Special Issue we intend to present the most interesting examples and applications of the following topics: the design and synthesis of multipotent lead structures, the chemical basis of the development of diagnostic imaging agents, the application of natural products and their derivatives for development of neuroprotectants, rational design and related innovative approaches to AD drugs.

We welcome original articles and short communications as well as a limited number of review articles on novel methods and approaches for AD drug development. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Prof. Dr. Michael Decker
Prof. Dr. Diego Muñoz-Torrero
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • drug discovery
  • rational design
  • hybrid molecules
  • multi-target-directed molecules
  • polypharmacology
  • biomarkers, imaging agents
  • neuroprotectants

Published Papers (17 papers)

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Editorial

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Open AccessEditorial Special Issue: “Molecules against Alzheimer”
Molecules 2016, 21(12), 1736; doi:10.3390/molecules21121736
Received: 9 December 2016 / Revised: 12 December 2016 / Accepted: 12 December 2016 / Published: 16 December 2016
Cited by 1 | PDF Full-text (169 KB) | HTML Full-text | XML Full-text
Abstract
This Special Issue, entitled “Molecules against Alzheimer”, gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder
[...] Read more.
This Special Issue, entitled “Molecules against Alzheimer”, gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, β-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)

Research

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Open AccessArticle Optimization and Biodistribution of [11C]-TKF, An Analog of Tau Protein Imaging Agent [18F]-THK523
Molecules 2016, 21(8), 1019; doi:10.3390/molecules21081019
Received: 27 May 2016 / Revised: 1 August 2016 / Accepted: 3 August 2016 / Published: 5 August 2016
Cited by 1 | PDF Full-text (2589 KB) | HTML Full-text | XML Full-text
Abstract
The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer’s disease (AD) and allow monitoring of disease progression and treatment efficacy. [18F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention
[...] Read more.
The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer’s disease (AD) and allow monitoring of disease progression and treatment efficacy. [18F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [11C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [11C]-TKF can be made by reaction precursor with [11C]MeOTf or 11CH3I, but [11C]MeOTf will give us higher labeling yields and specific activity. [11C]-TKF presented better brain uptake in normal mouse than [18F]-THK523 (3.23% ± 1.25% ID·g−1 vs. 2.62% ± 0.39% ID·g−1 at 2 min post-injection). The acute toxicity studies of [11C]-TKF were unremarkable. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment
Molecules 2016, 21(5), 643; doi:10.3390/molecules21050643
Received: 23 March 2016 / Revised: 27 April 2016 / Accepted: 11 May 2016 / Published: 16 May 2016
Cited by 4 | PDF Full-text (2084 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic
[...] Read more.
Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the “pharmacophores combination” strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu2+-induced ROS formation without any direct neurotoxic effect. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease
Molecules 2016, 21(5), 634; doi:10.3390/molecules21050634
Received: 18 February 2016 / Revised: 19 April 2016 / Accepted: 4 May 2016 / Published: 14 May 2016
Cited by 5 | PDF Full-text (1417 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and
[...] Read more.
We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
Open AccessCommunication Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer’s Disease
Molecules 2016, 21(4), 440; doi:10.3390/molecules21040440
Received: 2 March 2016 / Revised: 21 March 2016 / Accepted: 23 March 2016 / Published: 1 April 2016
Cited by 1 | PDF Full-text (735 KB) | HTML Full-text | XML Full-text
Abstract
Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid
[...] Read more.
Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid or lipoic acid groups producing potent selective inhibitors of butyrylcholinesterase (BuChE). The hybrid compounds were non-toxic to the murine hippocampal cell line HT-22 and lipoate esters were neuroprotective at 10 and 25 µM when the cells were challenged with glutamate (5 mM) in a similar manner to the positive control quercetin. The benzyl carbamate 7a was a potent inhibitor of BuChE (IC50 150 nM) and it was effective in reducing glutamate toxicity to neuronal cells at >5 µM. Representative compounds exhibited an antioxidant effect in the oxygen radical absorbance capacity assay as the lipoate 7d was not active, whereas the ferulate 8a showed a weak, but significant, activity with 0.635 ± 0.020 Trolox Equivalent. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta
Molecules 2016, 21(4), 410; doi:10.3390/molecules21040410
Received: 27 February 2016 / Revised: 17 March 2016 / Accepted: 23 March 2016 / Published: 26 March 2016
Cited by 5 | PDF Full-text (3807 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized
[...] Read more.
Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer’s Disease
Molecules 2016, 21(4), 412; doi:10.3390/molecules21040412
Received: 29 January 2016 / Revised: 18 March 2016 / Accepted: 23 March 2016 / Published: 25 March 2016
Cited by 2 | PDF Full-text (2426 KB) | HTML Full-text | XML Full-text
Abstract
We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer’s disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound
[...] Read more.
We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer’s disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca2+ levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca2+ level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca2+ in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer's Disease Therapy
Molecules 2016, 21(4), 400; doi:10.3390/molecules21040400
Received: 27 January 2016 / Revised: 11 March 2016 / Accepted: 15 March 2016 / Published: 24 March 2016
Cited by 2 | PDF Full-text (1053 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a
[...] Read more.
Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 μM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound). Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Searching for Multi-Targeting Neurotherapeutics against Alzheimer’s: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif
Molecules 2016, 21(3), 362; doi:10.3390/molecules21030362
Received: 15 February 2016 / Revised: 5 March 2016 / Accepted: 10 March 2016 / Published: 17 March 2016
Cited by 11 | PDF Full-text (1519 KB) | HTML Full-text | XML Full-text
Abstract
The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer’s disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel
[...] Read more.
The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer’s disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 µM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessCommunication Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates
Molecules 2016, 21(2), 191; doi:10.3390/molecules21020191
Received: 5 January 2016 / Revised: 28 January 2016 / Accepted: 29 January 2016 / Published: 11 February 2016
Cited by 5 | PDF Full-text (547 KB) | HTML Full-text | XML Full-text
Abstract
Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50
[...] Read more.
Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors
Molecules 2016, 21(2), 193; doi:10.3390/molecules21020193
Received: 10 December 2015 / Revised: 30 January 2016 / Accepted: 2 February 2016 / Published: 5 February 2016
Cited by 8 | PDF Full-text (1090 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with
[...] Read more.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessArticle Graveoline Analogs Exhibiting Selective Acetylcholinesterase Inhibitory Activity as Potential Lead Compounds for the Treatment of Alzheimer’s Disease
Molecules 2016, 21(2), 132; doi:10.3390/molecules21020132
Received: 11 December 2015 / Revised: 18 January 2016 / Accepted: 20 January 2016 / Published: 22 January 2016
Cited by 2 | PDF Full-text (2471 KB) | HTML Full-text | XML Full-text
Abstract
This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against
[...] Read more.
This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (Selectivity Index from 45 to 486). When the two sites in the graveoline parent ring substituting phenyl and amino terminal had six chemical bonds (n = 3) and the terminal amino was piperidine, compound 5c showed the best activity. Furthermore, the mechanism of action and binding mode were explored by enzyme kinetic simulation, molecular docking, and thioflavin T-based fluorometric assay. Cytotoxicity assay showed that the low concentration of the analogs did not affect the viability of the neurocyte SH-SY5Y. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
Open AccessArticle Long-Term Lithium Treatment Increases cPLA2 and iPLA2 Activity in Cultured Cortical and Hippocampal Neurons
Molecules 2015, 20(11), 19878-19885; doi:10.3390/molecules201119663
Received: 13 August 2015 / Revised: 12 October 2015 / Accepted: 19 October 2015 / Published: 4 November 2015
Cited by 5 | PDF Full-text (539 KB) | HTML Full-text | XML Full-text
Abstract
Background: Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium
[...] Read more.
Background: Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium may also affect membrane homeostasis. Objective: To investigate the effect of lithium on cytosolic phospholipase A2 (PLA2) activity, a key player on membrane phospholipid turnover which has been found to be reduced in blood and brain tissue of patients with Alzheimer’s disease (AD). Methods: Primary cultures of cortical and hippocampal neurons were treated for 7 days with different concentrations of lithium chloride (0.02 mM, 0.2 mM and 2 mM). A radio-enzymatic assay was used to determine the total activity of PLA2 and two PLA2 subtypes: cytosolic calcium-dependent (cPLA2); and calcium-independent (iPLA2). Results: cPLA2 activity increased by 82% (0.02 mM; p = 0.05) and 26% (0.2 mM; p = 0.04) in cortical neurons and by 61% (0.2 mM; p = 0.03) and 57% (2 mM; p = 0.04) in hippocampal neurons. iPLA2 activity was increased by 7% (0.2 mM; p = 0.04) and 13% (2 mM; p = 0.05) in cortical neurons and by 141% (0.02 mM; p = 0.0198) in hippocampal neurons. Conclusion: long-term lithium treatment increases membrane phospholipid metabolism in neurons through the activation of total, c- and iPLA2. This effect is more prominent at sub-therapeutic concentrations of lithium, and the activation of distinct cytosolic PLA2 subtypes is tissue specific, i.e., iPLA2 in hippocampal neurons, and cPLA2 in cortical neurons. Because PLA2 activities are reported to be reduced in Alzheimer’s disease (AD) and bipolar disorder (BD), the present findings provide a possible mechanism by which long-term lithium treatment may be useful in the prevention of the disease. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Review

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Open AccessReview Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases
Molecules 2016, 21(9), 1165; doi:10.3390/molecules21091165
Received: 9 June 2016 / Revised: 22 August 2016 / Accepted: 29 August 2016 / Published: 1 September 2016
Cited by 9 | PDF Full-text (1197 KB) | HTML Full-text | XML Full-text
Abstract
The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever
[...] Read more.
The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever since in many species, including humans. Aging, neurodegenerative, and some mental diseases are associated with an exponential decrease in brain neurogenesis. Therefore, the controlled pharmacological stimulation of the endogenous neural stem cells (NSCs) niches might counteract the neuronal loss in Alzheimer’s disease (AD) and other pathologies, opening an exciting new therapeutic avenue. In the last years, druggable molecular targets and signalling pathways involved in neurogenic processes have been identified, and as a consequence, different drug types have been developed and tested in neuronal plasticity. This review focuses on recent advances in neurogenic agents acting at serotonin and/or melatonin systems, Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase (NAMPT) and nuclear erythroid 2-related factor (Nrf2). Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessReview The Rationale for Insulin Therapy in Alzheimer’s Disease
Molecules 2016, 21(6), 689; doi:10.3390/molecules21060689
Received: 14 March 2016 / Revised: 14 May 2016 / Accepted: 19 May 2016 / Published: 26 May 2016
Cited by 4 | PDF Full-text (708 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss,
[...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, accompanied by a gradual decline in cognitive function and premature death. AD is the clinical manifestation of altered proteostasis. The initiating step of altered proteostasis in most AD patients is not known. The progression of AD is accelerated by several chronic disorders, among which the contribution of diabetes to AD is well understood at the cell biology level. The pathological mechanisms of AD and diabetes interact and tend to reinforce each other, thus accelerating cognitive impairment. At present, only symptomatic interventions are available for treating AD. To optimise symptomatic treatment, a personalised therapy approach has been suggested. Intranasal insulin administration seems to open the possibility for a safe, and at least in the short term, effective symptomatic intervention that delays loss of cognition in AD patients. This review summarizes the interactions of AD and diabetes from the cell biology to the patient level and the clinical results of intranasal insulin treatment of cognitive decline in AD. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
Open AccessReview Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease
Molecules 2016, 21(4), 466; doi:10.3390/molecules21040466
Received: 9 March 2016 / Revised: 3 April 2016 / Accepted: 5 April 2016 / Published: 8 April 2016
Cited by 13 | PDF Full-text (1238 KB) | HTML Full-text | XML Full-text
Abstract
Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer’s disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However,
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Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer’s disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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Open AccessConference Report Treatment with Akebia Saponin D Ameliorates Aβ1–42-Induced Memory Impairment and Neurotoxicity in Rats
Molecules 2016, 21(3), 323; doi:10.3390/molecules21030323
Received: 20 January 2016 / Revised: 1 March 2016 / Accepted: 2 March 2016 / Published: 8 March 2016
Cited by 2 | PDF Full-text (2666 KB) | HTML Full-text | XML Full-text
Abstract
Amyloid-β peptide (Aβ) is known to be directly associated with the progressive neuronal death observed in Alzheimer’s disease (AD). However, effective neuroprotective approaches against Aβ neurotoxicity are still unavailable. In the present study, we investigated the protective effects of Akebia saponin D (ASD),
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Amyloid-β peptide (Aβ) is known to be directly associated with the progressive neuronal death observed in Alzheimer’s disease (AD). However, effective neuroprotective approaches against Aβ neurotoxicity are still unavailable. In the present study, we investigated the protective effects of Akebia saponin D (ASD), a typical compound isolated from the rhizome of Dipsacus asper Wall, on Aβ1–42-induced impairment of learning and memory formation and explored the probable underlying molecular mechanisms. We found that treatment with ASD (30, 90 or 270 mg/kg) significantly ameliorated impaired spatial learning and memory in intracerebroventricularly (ICV) Aβ1–42-injected rats, as evidenced by a decrease tendency in escape latency during acquisition trials and improvement in exploratory activities in the probe trial in Morris water maze (MWM). Further study showed that ASD reversed Aβ1–42-induced accumulation of Aβ1–42 and Aβ1–40 in the hippocampus through down-regulating the expression of BACE and Presenilin 2 accompanied with increased the expression of TACE, IDE and LRP-1. Taken together, our findings suggested that ASD exerted therapeutic effects on Aβ-induced cognitive deficits via amyloidogenic pathway. Full article
(This article belongs to the Special Issue Molecules against Alzheimer)
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