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Synthesis and Identification of Small Compounds Active in Neurodegeneration

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

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 26138

Special Issue Editors


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Guest Editor
Department of Pharmacy, University “G. D’Annunzio”, Chieti, Italy
Interests: antioxidants; bioactive compounds; small molecules; polyphenols; antibacterial activity; anticancer activity; medicinal chemistry; synthesis
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Co-Guest Editor
Biomedical Research Center Seltersberg (BFS), Laboratory for Nutrition in Prevention and Therapy, Institute of Nutritional Sciences, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany
Interests: brain aging; neurodegenerative diseases; food-based prevention; pharmacological intervention; mitochondrial function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s Disease, affect millions of people worldwide and are increasingly recognized as one of the most prevalent disorders with high burden to the patients, their families, and society. Despite substantial effort to advance the understanding of the etiology and potential treatment of neurodegeneration, information is still incomplete because many potential mechanisms are implicated in neurodegenerative pathology such as neuroinflammation, mitochondrial dysfunction and disequilibrium in protein homeostasis, aging, genetic variants, traumatic injury, oxidative stress, inflammation, toxic exposure and stress. However, very few drugs have been successful for the treatment of CNS diseases, and the therapeutic efficacy is greatly limited by many factors such as ineffective transport of drugs across the Blood-Brain Barrier (BBB). Different molecular properties (molecular size, hydrophilicity, dissociation degree, etc.) are fundamental to cross the BBB, and optimization of these parameters still remains a significant challenge in the development of neurological therapeutics. Natural sources and chemical synthesis are two options for developing novel neuroprotective drug candidates. The aim of this Special Issue is to spot recent advances in “Synthesis and Identification of Small Compounds Active in Neurodegeneration”, including original research papers or up-to-date, comprehensive reviews, highlighting recent identification of synthetic as well as small, natural-based molecules regarding the use of nanomaterials as versatile drug transport systems across BBB. We believe this Special Issue is a relevant and timely one, and we look forward to receiving your contributions.

You may choose our Joint Special Issue in Chemistry.

Dr. Barbara De Filippis
Prof. Dr. Gunter P. Eckert
Guest Editors

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Keywords

  • small active compounds
  • food chemistry
  • neurodegenerative diseases
  • medicinal and pharmaceutical chemistry
  • BBB
  • synthesis
  • nanoformulations

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Published Papers (9 papers)

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Research

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13 pages, 588 KiB  
Article
Synthesis and Bioinformatic Characterization of New Schiff Bases with Possible Applicability in Brain Disorders
by Speranta Avram, Ana Maria Udrea, Diana Camelia Nuta, Carmen Limban, Adrian Cosmin Balea, Miron Teodor Caproiu, Florea Dumitrascu, Cătălin Buiu and Alexandra Teodora Bordei
Molecules 2021, 26(14), 4160; https://doi.org/10.3390/molecules26144160 - 08 Jul 2021
Cited by 6 | Viewed by 2315
Abstract
(1) Background: The research aims to find new treatments for neurodegenerative diseases, in particular, Alzheimer’s disease. (2) Methods: This article presents a bioinformatics and pathology study of new Schiff bases, (EZ)-N′-benzylidene-(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanehydrazide derivatives, and aims to evaluate the [...] Read more.
(1) Background: The research aims to find new treatments for neurodegenerative diseases, in particular, Alzheimer’s disease. (2) Methods: This article presents a bioinformatics and pathology study of new Schiff bases, (EZ)-N′-benzylidene-(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanehydrazide derivatives, and aims to evaluate the drug-like, pharmacokinetic, pharmacodynamic and pharmacogenomic properties, as well as to predict the binding to therapeutic targets by applying bioinformatics, cheminformatics and computational pharmacological methods. (3) Results: We obtained these Schiff bases by condensing (2RS)-2-(6-chloro-9H-carbazol-2-yl)propanehydrazide with aromatic aldehydes, using the advantages of microwave irradiation. The newly synthesized compounds were characterized spectrally, using FT-IR and NMR spectroscopy, which confirmed their structure. Using bioinformatics tools, we noticed that all new compounds are drug-likeness features and may be proposed as potentially neuropsychiatric drugs (4) Conclusions: Using bioinformatics tools, we determined that the new compound 1e had a high potential to be used as a good candidate in neurodegenerative disorders treatment. Full article
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11 pages, 2207 KiB  
Article
The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells
by Camila González, Constanza Cartagena, Leonardo Caballero, Francisco Melo, Carlos Areche and Alberto Cornejo
Molecules 2021, 26(12), 3760; https://doi.org/10.3390/molecules26123760 - 21 Jun 2021
Cited by 10 | Viewed by 2265
Abstract
Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael’s [...] Read more.
Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael’s addition appears as a feasible type of interaction involving an α, β unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish β sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael’s acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species. Full article
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17 pages, 4407 KiB  
Article
Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study
by Nicoletta di Leo, Stefania Moscato, Marco Borso', Simona Sestito, Beatrice Polini, Lavinia Bandini, Agostina Grillone, Matteo Battaglini, Alessandro Saba, Letizia Mattii, Gianni Ciofani and Grazia Chiellini
Molecules 2021, 26(6), 1616; https://doi.org/10.3390/molecules26061616 - 14 Mar 2021
Cited by 7 | Viewed by 2205
Abstract
Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological [...] Read more.
Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property. Full article
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19 pages, 8283 KiB  
Article
Combined Therapy of A1AR Agonists and A2AAR Antagonists in Neuroinflammation
by Gabriella Marucci, Diego Dal Ben, Catia Lambertucci, Aleix Martí Navia, Andrea Spinaci, Rosaria Volpini and Michela Buccioni
Molecules 2021, 26(4), 1188; https://doi.org/10.3390/molecules26041188 - 23 Feb 2021
Cited by 13 | Viewed by 2506
Abstract
Alzheimer’s, Parkinson’s, and multiple sclerosis are neurodegenerative diseases related by neuronal degeneration and death in specific areas of the central nervous system. These pathologies are associated with neuroinflammation, which is involved in disease progression, and halting this process represents a potential therapeutic strategy. [...] Read more.
Alzheimer’s, Parkinson’s, and multiple sclerosis are neurodegenerative diseases related by neuronal degeneration and death in specific areas of the central nervous system. These pathologies are associated with neuroinflammation, which is involved in disease progression, and halting this process represents a potential therapeutic strategy. Evidence suggests that microglia function is regulated by A1 and A2A adenosine receptors (AR), which are considered as neuroprotective and neurodegenerative receptors, respectively. The manuscript’s aim is to elucidate the role of these receptors in neuroinflammation modulation through potent and selective A1AR agonists (N6-cyclopentyl-2′- or 3′-deoxyadenosine substituted or unsubstituted in 2 position) and A2AAR antagonists (9-ethyl-adenine substituted in 8 and/or in 2 position), synthesized in house, using N13 microglial cells. In addition, the combined therapy of A1AR agonists and A2AAR antagonists to modulate neuroinflammation was evaluated. Results showed that A1AR agonists were able, to varying degrees, to prevent the inflammatory effect induced by cytokine cocktail (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ), while A2AAR antagonists showed a good ability to counteract neuroinflammation. Moreover, the effect achieved by combining the two most effective compounds (1 and 6) in doses previously found to be non-effective was greater than the treatment effect of each of the two compounds used separately at maximal dose. Full article
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25 pages, 5883 KiB  
Article
Parameters for Irreversible Inactivation of Monoamine Oxidase
by Rona R. Ramsay, Livia Basile, Antonin Maniquet, Stefanie Hagenow, Matteo Pappalardo, Maria Chiara Saija, Sharon D. Bryant, Alen Albreht and Salvatore Guccione
Molecules 2020, 25(24), 5908; https://doi.org/10.3390/molecules25245908 - 13 Dec 2020
Cited by 9 | Viewed by 3468
Abstract
The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have [...] Read more.
The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The Ki values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH influences the formation of the covalent adduct essential for effective inactivation of MAO. Full article
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17 pages, 3686 KiB  
Article
Synthesis and Biological Evaluation of Halogenated E-Stilbenols as Promising Antiaging Agents
by Ester Sara Di Filippo, Letizia Giampietro, Barbara De Filippis, Marwa Balaha, Vincenzo Ferrone, Marcello Locatelli, Tiziana Pietrangelo, Angela Tartaglia, Rosa Amoroso and Stefania Fulle
Molecules 2020, 25(23), 5770; https://doi.org/10.3390/molecules25235770 - 07 Dec 2020
Cited by 9 | Viewed by 2196
Abstract
The increased risk of illness and disability is related to the age inevitable biological changes. Oxidative stress is a proposed mechanism for many age-related diseases. The crucial importance of polyphenol pharmacophore for aging process is largely described thanks to its effects on concentrations [...] Read more.
The increased risk of illness and disability is related to the age inevitable biological changes. Oxidative stress is a proposed mechanism for many age-related diseases. The crucial importance of polyphenol pharmacophore for aging process is largely described thanks to its effects on concentrations of reactive oxygen species. Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RSV) plays a critical role in slowing the aging process but has a poor bioavailabity after oral intake. In this present work, a series of RSV derivatives was designed, synthesized, and evaluated as potential antioxidant agents. These derivatives contain substituents with different electronic and steric properties in different positions of aromatic rings. This kind of substituents affects the activity and the bioavailability of these compounds compared with RSV used as reference compound. Studies of Log P values demonstrated that the introduction of halogens gives the optimum lipophilicity to be considered promising active agents. Among them, compound 6 showed the higher antioxidant activity than RSV. The presence of trifluoromethyl group together with a chlorine atom increased the antioxidant activity compared to RSV. Full article
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14 pages, 3561 KiB  
Article
Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation
by Emanuela Colombo, Rosaria Pascente, Daniela Triolo, Claudia Bassani, Anthea De Angelis, Francesca Ruffini, Linda Ottoboni, Giancarlo Comi, Gianvito Martino and Cinthia Farina
Molecules 2020, 25(22), 5403; https://doi.org/10.3390/molecules25225403 - 18 Nov 2020
Cited by 12 | Viewed by 2298
Abstract
Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the compound Laquinimod and its [...] Read more.
Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the compound Laquinimod and its active metabolite de-Laquinimod on astrocyte functions and the astrocyte–neuron interaction. We show that human iAstrocytes expressed the receptor for the inflammatory mediator IL1 and responded to it via nuclear translocation of NFκB, an event that did not occur if cells were treated with Laquinimod, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Similarly, while exposure to IL1 downregulated glial glutamate transporters GLAST and GLT1, treatment with Laquinimod supported maintenance of physiological levels of these proteins despite the inflammatory milieu. Laquinimod also induced nuclear translocation of the aryl hydrocarbon receptor (AHR), suggesting that drug action was mediated by activation of the AHR pathway. However, the drug was effective despite AHR inhibition via CH223191, indicating that AHR signaling in the astrocyte is dispensable for drug responses. Finally, in vitro experiments with rat spinal neurons showed that laquinimod did not exert neuroprotection directly on the neuron but dampened astrocyte-induced neurodegeneration. Our findings indicate that fibroblast-derived human astrocytes represent a suitable model to study astrocyte–neuron crosstalk and demonstrate indirect, partial neuroprotective efficacy for laquinimod. Full article
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15 pages, 4563 KiB  
Article
Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors
by Muhammed Çeçen, Jong Min Oh, Zeynep Özdemir, Saliha Ebru Büyüktuncel, Mehtap Uysal, Mohamed A. Abdelgawad, Arafa Musa, Nicola Gambacorta, Orazio Nicolotti, Bijo Mathew and Hoon Kim
Molecules 2020, 25(22), 5371; https://doi.org/10.3390/molecules25225371 - 17 Nov 2020
Cited by 12 | Viewed by 2452
Abstract
Twelve pyridazinones (T1T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 [...] Read more.
Twelve pyridazinones (T1T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 (IC50 = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)2 (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with Ki values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer’s disease. Full article
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Review

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19 pages, 1205 KiB  
Review
Anti-aggregation Effects of Phenolic Compounds on α-synuclein
by Kenjiro Ono, Mayumi Tsuji, Tritia R. Yamasaki and Giulio M. Pasinetti
Molecules 2020, 25(10), 2444; https://doi.org/10.3390/molecules25102444 - 24 May 2020
Cited by 19 | Viewed by 5269
Abstract
The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson’s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there [...] Read more.
The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson’s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies. Full article
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