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New Biologically Active Molecules for Combating Neurodegeneration and Viral Infection

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 13174

Special Issue Editors

Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia
Interests: drug discovery; medicinal chemistry; molecular pharmacology; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
1. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, S. Kovalevskaya Str., 22, 620108 Ekaterinburg, Russia
2. Department of Organic and Biomolecular Chemistry, Chemical Engineering Institute, Ural Federal University, Mira St. 19, 620002 Ekaterinburg, Russia
Interests: heterocyclic and medicinal chemistry; antivirals; antibacterials; drugs for therapy of neurogenerative diseases

Special Issue Information

Dear Colleagues,

According to the date of FDA approved pharmaceutical agents by therapy area in 2010−2019 (D. Brown and H. Wobst J. Med. Chem. 2021, 64, 2312), drugs for infections and CNS diseases treatment are among the three most “productive” and correspondingly most drug-requested areas (after oncology). In recent years, especially due to the sharp social demand for antiviral agents stimulated by thSARS-CoV-2 pandemic, a wide number of approaches have been developed for revealing novel effective and specific agents that could prevent or mitigate the issues caused by virus penetration in human cells. In the area of neurodegenerative CNS diseases, the general situation is much worse. For Alzheimer’s disease, for example, after 18 years of extremely hard experimental work, only one agent was approved in June 2021. To date, the urgent need for disease-modifying agents for such pathologies as AD, Parkinsonism, and ALS (amyotrophic lateral sclerosis) has not yet been satisfied.

This Special Issue of Molecules is focused on recent approaches in developing innovative and “reincarnative” pharmaceutical agents for cure and prevention of viral infection and neurogeneration. Notwithstanding big differences in these diseases, some chemical approaches in the design of novel, efficient drug-like agents could be quite similar.

In conclusion, we welcome submissions that cover, but are not limited to, the following topics:

  • Synthesis and study of novel agents for Alzheimer’s disease;
  • Synthesis and study of novel agents for Parkinson’s disease;
  • Synthesis and study of novel agents for ALS;
  • Multi- and mono target approaches for development novel neuroprotectors and cognition enhancers;
  • Old drugs for new approaches;
  • Targeting coronavirus diseases by synthetic chemical entities and natural products;
  • Antiviral properties of natural compounds and their synthetic derivatives;
  • Target-oriented search for antiviral agents against emergent viruses;
  • Development of surrogate systems to search for new antiviral agents

Prof. Dr. Sergey O. Bachurin
Prof. Dr. Valery N. Charushin
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 submissions that pass pre-check are 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 semimonthly 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 2700 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

  • neuroprotectors
  • cognition enhancers
  • Alzheimer's disease
  • ALS
  • Parkinson's disease
  • drug repositioning
  • multitarget drugs
  • coronavirus diseases
  • natural products and their synthetic derivatives
  • target-oriented search for antiviral agents
  • screening for new antiviral agents

Published Papers (6 papers)

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Research

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17 pages, 2033 KiB  
Article
2,5-Diketopiperazine Derivatives as Potential Anti-Influenza (H5N2) Agents: Synthesis, Biological Evaluation, and Molecular Docking Study
by Chanakan Winyakul, Weerachai Phutdhawong, Poomipat Tamdee, Jitnapa Sirirak, Thongchai Taechowisan and Waya S. Phutdhawong
Molecules 2022, 27(13), 4200; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27134200 - 29 Jun 2022
Cited by 6 | Viewed by 1829
Abstract
2,5-Diketopiperazine derivatives, consisting of benzylidene and alkylidene substituents at 3 and 6 positions, have been considered as a core structure for their antiviral activities. Herein, the novel N-substituted 2,5-Diketopiperazine derivatives were successfully prepared and their antiviral activities against influenza virus were evaluated [...] Read more.
2,5-Diketopiperazine derivatives, consisting of benzylidene and alkylidene substituents at 3 and 6 positions, have been considered as a core structure for their antiviral activities. Herein, the novel N-substituted 2,5-Diketopiperazine derivatives were successfully prepared and their antiviral activities against influenza virus were evaluated by monitoring viral propagation in embryonated chicken eggs. It was found that (3Z,6Z)-3-benzylidene-6-(2-methyl propylidene)-4-substituted-2,5-Diketopiperazines (13b–d), (3Z,6E)-3-benzylidene-6-(2-methylpropyli dene)-1-(1-ethyl pyrrolidine)-2,5-Diketopiperazine (14c), and Lansai-C exhibited negative results in influenza virus propagation at a concentration of 25 µg/mL. Additionally, molecular docking study revealed that 13bd and 14c bound in 430-cavity of neuraminidase from H5N2 avian influenza virus and the synthesized derivatives also strongly interacted with the key amino acid residues, including Arg371, Pro326, Ile427, and Thr439. Full article
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14 pages, 4803 KiB  
Article
3D Neuronal Cell Culture Modeling Based on Highly Porous Ultra-High Molecular Weight Polyethylene
by Aleksey A. Ustyugov, Nataliya A. Sipyagina, Alena N. Malkova, Elena A. Straumal, Lyudmila L. Yurkova, Anastasiya A. Globa, Maria A. Lapshina, Maria M. Chicheva, Kirill D. Chaprov, Aleksey V. Maksimkin and Sergey A. Lermontov
Molecules 2022, 27(7), 2087; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072087 - 24 Mar 2022
Cited by 5 | Viewed by 1607
Abstract
Cell culturing methods in its classical 2D approach have limitations associated with altered cell morphology, gene expression patterns, migration, cell cycle and proliferation. Moreover, high throughput drug screening is mainly performed on 2D cell cultures which are physiologically far from proper cell functions [...] Read more.
Cell culturing methods in its classical 2D approach have limitations associated with altered cell morphology, gene expression patterns, migration, cell cycle and proliferation. Moreover, high throughput drug screening is mainly performed on 2D cell cultures which are physiologically far from proper cell functions resulting in inadequate hit-compounds which subsequently fail. A shift to 3D culturing protocols could solve issues with altered cell biochemistry and signaling which would lead to a proper recapitulation of physiological conditions in test systems. Here, we examined porous ultra-high molecular weight polyethylene (UHMWPE) as an inexpensive and robust material with varying pore sizes for cell culturing. We tested and developed culturing protocols for immortalized human neuroblastoma and primary mice hippocampal cells which resulted in high rate of cell penetration within one week of cultivation. UHMWPE was additionally functionalized with gelatin, poly-L-lysine, BSA and chitosan, resulting in increased cell penetrations of the material. We have also successfully traced GFP-tagged cells which were grown on a UHMWPE sample after one week from implantation into mice brain. Our findings highlight the importance of UHMWPE use as a 3D matrix and show new possibilities arising from the use of cheap and chemically homogeneous material for studying various types of cell-surface interactions further improving cell adhesion, viability and biocompatibility. Full article
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23 pages, 6312 KiB  
Article
Discovery of New Ginsenol-Like Compounds with High Antiviral Activity
by Aleksandrina S. Volobueva, Olga I. Yarovaya, Marina V. Kireeva, Sophia S. Borisevich, Kseniya S. Kovaleva, Iliya Ya. Mainagashev, Yuri V. Gatilov, Margarita G. Ilyina, Vladimir V. Zarubaev and Nariman F. Salakhutdinov
Molecules 2021, 26(22), 6794; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26226794 - 10 Nov 2021
Cited by 7 | Viewed by 2037
Abstract
A number of framework amides with a ginsenol backbone have been synthesized using the Ritter reaction. We named the acetamide as Ginsamide. A method was developed for the synthesis of the corresponding amine and thioacetamide. The new compounds revealed a high activity against [...] Read more.
A number of framework amides with a ginsenol backbone have been synthesized using the Ritter reaction. We named the acetamide as Ginsamide. A method was developed for the synthesis of the corresponding amine and thioacetamide. The new compounds revealed a high activity against H1N1 influenza, which was confirmed using an animal model. Biological experiments were performed to determine the mechanism of action of the new agents, a ginsamide-resistant strain of influenza virus was obtained, and the pathogenicity of the resistant strain and the control strain was studied. It was shown that the emergence of resistance to Ginsamide was accompanied by a reduction in the pathogenicity of the influenza virus. Full article
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19 pages, 4321 KiB  
Article
Design and Antioxidant Properties of Bifunctional 2H-Imidazole-Derived Phenolic Compounds—A New Family of Effective Inhibitors for Oxidative Stress-Associated Destructive Processes
by Elena L. Gerasimova, Elena R. Gazizullina, Maria V. Borisova, Dinara I. Igdisanova, Egor A. Nikiforov, Timofey D. Moseev, Mikhail V. Varaksin, Oleg N. Chupakhin, Valery N. Charushin and Alla V. Ivanova
Molecules 2021, 26(21), 6534; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216534 - 29 Oct 2021
Cited by 8 | Viewed by 1766
Abstract
The synthesis of inhibitors for oxidative stress-associated destructive processes based on 2H-imidazole-derived phenolic compounds affording the bifunctional 2H-imidazole-derived phenolic compounds in good-to-excellent yields was reported. In particular, a series of bifunctional organic molecules of the 5-aryl-2H-imidazole family [...] Read more.
The synthesis of inhibitors for oxidative stress-associated destructive processes based on 2H-imidazole-derived phenolic compounds affording the bifunctional 2H-imidazole-derived phenolic compounds in good-to-excellent yields was reported. In particular, a series of bifunctional organic molecules of the 5-aryl-2H-imidazole family of various architectures bearing both electron-donating and electron-withdrawing substituents in the aryl fragment along with the different arrangements of the hydroxy groups in the polyphenol moiety, namely derivatives of phloroglucinol, pyrogallol, hydroxyquinol, including previously unknown water-soluble molecules, were studied. The structural and antioxidant properties of these bifunctional 5-aryl-2H-imidazoles were comprehensively studied. The redox transformations of the synthesized compounds were carried out. The integrated approach based on single and mixed mechanisms of antioxidant action, namely the AOC, ARC, Folin, and DPPH assays, were applied to estimate antioxidant activities. The relationship “structure-antioxidant properties” was established for each of the antioxidant action mechanisms. The conjugation effect was shown to result in a decrease in the mobility of the hydrogen atom, thus complicating the process of electron transfer in nearly all cases. On the contrary, the conjugation in imidazolyl substituted phloroglucinols was found to enhance their activity through the hydrogen transfer mechanism. Imidazole-derived polyphenolic compounds bearing the most electron-withdrawing functionality, namely the nitro group, were established to possess the higher values for both antioxidant and antiradical capacities. It was demonstrated that in the case of phloroglucinol derivatives, the conjugation effect resulted in a significant increase in the antiradical capacity (ARC) for a whole family of the considered 2H-imidazole-derived phenolic compounds in comparison with the corresponding unsubstituted phenols. Particularly, conjugation of the polyphenolic subunit with 2,2-dimethyl-5-(4-nitrophenyl)-2H-imidazol-4-yl fragment was shown to increase ARC from 2.26 to 5.16 (104 mol-eq/L). This means that the considered family of compounds is capable of exhibiting an antioxidant activity via transferring a hydrogen atom, exceeding the activity of known natural polyphenolic compounds. Full article
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26 pages, 9795 KiB  
Article
Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands
by Sergey O. Bachurin, Galina F. Makhaeva, Elena F. Shevtsova, Alexey Yu. Aksinenko, Vladimir V. Grigoriev, Pavel N. Shevtsov, Tatiana V. Goreva, Tatiana A. Epishina, Nadezhda V. Kovaleva, Elena A. Pushkareva, Natalia P. Boltneva, Sofya V. Lushchekina, Alexey V. Gabrelyan, Vladimir L. Zamoyski, Lyudmila G. Dubova, Elena V. Rudakova, Vladimir P. Fisenko, Elena V. Bovina and Rudy J. Richardson
Molecules 2021, 26(18), 5527; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185527 - 11 Sep 2021
Cited by 14 | Viewed by 2232
Abstract
A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and [...] Read more.
A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action. Full article
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Review

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20 pages, 1087 KiB  
Review
Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight
by Matthew Upcott, Kirill D. Chaprov and Vladimir L. Buchman
Molecules 2021, 26(23), 7351; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26237351 - 03 Dec 2021
Cited by 6 | Viewed by 2729
Abstract
The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that [...] Read more.
The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB. Full article
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