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Special Issue "Molecules against Alzheimer II"

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

Deadline for manuscript submissions: 30 April 2019

Special Issue Editors

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, E-08028 Barcelona, Spain
Website | E-Mail
Phone: +34934024533
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds
Guest Editor
Prof. Dr. Michael Decker

Pharmaceutical and Medicinal Chemistry, Institute for Pharmacy and Food Chemistry, Julius-Maximilians University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Website | E-Mail
Interests: hybrid compounds; multifunctional cholinesterase inhibitors; cannabinoid and other GPCR ligands; natural products

Special Issue Information

Dear Colleagues,

The prevalence, mortality and economic figures associated with Alzheimer’s disease (AD) are continuously beating the most worrisome predictions. The ever-increasing impact of AD is leading to unbearable suffering for patients, relatives and caregivers, and will put health systems and national economies worldwide at unmanageable risk if drug development efforts are not successful. The social awareness of the huge burden of AD and the tremendous decades-long research efforts to delineate their pathogenic mechanisms and develop efficient therapies have not corresponded with the discovery of new drugs that have proven capable of halting or even just slowing down the neurodegenerative processes occurring in AD. Indeed, AD is one of the therapeutic areas with the highest attrition rates in clinical trials. However, this should not discourage us from maintaining our intensive research endeavors, rather the opposite. In this light, the best-established (but so far unproductive) working hypotheses on the pathogenic mechanisms of AD are being continuously revisited and new promising hypotheses are being drawn up, thereby providing very valuable clues for the development of the long-sought-after disease-modifying drugs.

Following the successful first edition, this Special Issue aims to gather recent medicinal chemistry works focused on the discovery of novel biological targets, diagnostic tools and drug candidates and the application of innovative CNS drug delivery systems and therapeutic approaches that can improve the early detection and treatment of AD. We welcome original articles and short communications as well as a limited number of review articles on these topics. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on the Special Issue website.

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

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 bimonthly 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
  • drug design
  • drug synthesis
  • disease-modifying agents
  • neuroprotective compounds
  • cognition enhancing agents
  • diagnostic agents (like PET or SPECT)

Published Papers (5 papers)

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Research

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Open AccessArticle Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors
Molecules 2018, 23(12), 3252; https://doi.org/10.3390/molecules23123252
Received: 25 October 2018 / Revised: 27 November 2018 / Accepted: 7 December 2018 / Published: 8 December 2018
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Abstract
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of
[...] Read more.
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of EeAChE (IC50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC50 = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against HsAChE and was found to be even more active than donepezil and inhibited HsAChE better than EeAChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme. Full article
(This article belongs to the Special Issue Molecules against Alzheimer II)
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Open AccessArticle Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-Target Agents for the Treatment of Alzheimer’s Disease
Molecules 2018, 23(12), 3100; https://doi.org/10.3390/molecules23123100
Received: 30 October 2018 / Revised: 23 November 2018 / Accepted: 24 November 2018 / Published: 27 November 2018
PDF Full-text (7138 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series
[...] Read more.
Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series of 4-flexible amino-2-arylethenylquinoline derivatives as multi-target agents was efficiently synthesized and evaluated for the treatment of AD. Among these synthesized derivatives, some compounds exhibited strong self-induced Aβ1–42 aggregation inhibition and antioxidant activity. The structure-activity relationship was summarized, which confirmed that the introduction of a flexible amino group featuring a N,N-dimethylaminoalkylamino moiety at the 4-position increased the Aβ1–42 aggregation inhibition activity, with an inhibition ratio of 95.3% at 20 μM concentration. Compound 6b1, the optimal compound, was able to selectively chelate copper (II), and inhibit Cu2+-induced Aβ aggregation effectively. It also could disassemble the self-induced Aβ1–42 aggregation fibrils with a ratio of 64.3% at 20 μM concentration. Moreover, compound 6b1 showed low toxicity and a good neuroprotective effect against Aβ1–42-induced toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated compound 6b1 significantly reversed scopolamine-induced memory deficit in mice. Taken together, these results suggested that compound 6b1 was a promising multi-target compound worthy of further study for AD. Full article
(This article belongs to the Special Issue Molecules against Alzheimer II)
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Graphical abstract

Open AccessArticle Design, Synthesis of N-phenethyl Cinnamide Derivatives and Their Biological Activities for the Treatment of Alzheimer’s Disease: Antioxidant, Beta-amyloid Disaggregating and Rescue Effects on Memory Loss
Molecules 2018, 23(10), 2663; https://doi.org/10.3390/molecules23102663
Received: 1 September 2018 / Revised: 3 October 2018 / Accepted: 10 October 2018 / Published: 16 October 2018
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Abstract
Gx-50 is a bioactive compound for the treatment of Alzheimer’s disease (AD) found in Sichuan pepper (Zanthoxylum bungeanum). In order to find a stronger anti-AD lead compound, 20 gx-50 (120) analogs have been designed and synthesized, and
[...] Read more.
Gx-50 is a bioactive compound for the treatment of Alzheimer’s disease (AD) found in Sichuan pepper (Zanthoxylum bungeanum). In order to find a stronger anti-AD lead compound, 20 gx-50 (120) analogs have been designed and synthesized, and their molecular structures were determined based on nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis, as well as comparison with literature data. Compounds 120 were evaluated for their anti-AD potential by using DPPH radical scavenging assay for considering their anti-oxidant activity, thioflavin T (ThT) fluorescence assay for considering the inhibitory or disaggregate potency of Aβ, and transgenic Drosophila model assay for evaluating their rescue effect on memory loss. Finally, compound 13 was determined as a promising anti-AD candidate. Full article
(This article belongs to the Special Issue Molecules against Alzheimer II)
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Open AccessArticle Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers
Molecules 2018, 23(10), 2523; https://doi.org/10.3390/molecules23102523
Received: 29 August 2018 / Revised: 20 September 2018 / Accepted: 28 September 2018 / Published: 2 October 2018
PDF Full-text (2598 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Alzheimer’s disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a
[...] Read more.
Alzheimer’s disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind Aβ oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to Aβ, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor Aβ toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for Aβ binding. Full article
(This article belongs to the Special Issue Molecules against Alzheimer II)
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Review

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Open AccessFeature PaperReview Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease
Molecules 2018, 23(12), 3230; https://doi.org/10.3390/molecules23123230
Received: 22 November 2018 / Revised: 4 December 2018 / Accepted: 5 December 2018 / Published: 7 December 2018
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Abstract
The cholinergic hypothesis has been reported first being the cause of memory dysfunction in the Alzheimer’s disease. Researchers around the globe have focused their attention on understanding the mechanisms of how this complicated system contributes to processes such as learning, memory, disorientation, linguistic
[...] Read more.
The cholinergic hypothesis has been reported first being the cause of memory dysfunction in the Alzheimer’s disease. Researchers around the globe have focused their attention on understanding the mechanisms of how this complicated system contributes to processes such as learning, memory, disorientation, linguistic problems, and behavioral issues in the indicated chronic neurodegenerative disease. The present review reports recent updates in hybrid molecule design as a strategy for selectively addressing multiple target proteins involved in Alzheimer’s disease (AD) and the study of their therapeutic relevance. The rationale and the design of the bifunctional compounds will be discussed in order to understand their potential as tools to investigate the role of the cholinergic system in AD. Full article
(This article belongs to the Special Issue Molecules against Alzheimer II)
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