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20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative...
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20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 20 October 2024 | Viewed by 10006

Special Issue Editors

Dr. Elena Cichero

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genoa, Viale Benedetto XV, 16132 Genoa, Italy
Interests: medicinal chemistry; GPCR; enzyme; neuroprotective agents; cystic fibrosis; cancer; molecular modeling; virtual screening; homology modeling; repositioning
Special Issues, Collections and Topics in MDPI journals
Dr. Michele Tonelli

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genoa Viale Benedetto XV, 3, 16132 Genoa, Italy
Interests: medicinal chemistry; neuroprotective drugs; anti-Alzheimer’s drug; multitarget-directed ligands; antiviral drugs; antiprotozoan drugs

Special Issue Information

Dear Colleagues,

Nowadays, human life expectancy is increasing, thus leading to population aging being inevitable and often accompanied by increased levels of patients developing neurodegenerative diseases. Neuroprotection represents an intriguing strategic approach to contrast neurodegeneration as shown in a variety of central nervous system (CNS) disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and drug misuse-induced neurotoxicity, among others. Recently, novel therapeutic agents for neurodegenerative diseases based on small molecules as well as unprecedented druggable targets mediating a neuroprotective effect have been investigated. This Special Issue invites both reviews and original articles that shed light on the state of the art and on the latest findings in the search for novel drug-like neuroprotective agents, and aims to elucidate future directions probing promising biological targets such as GPCRs or enzymes. The rational design and development of new neuroprotective compounds based on virtual screening applications and high-throughput screening (HTS) campaigns are also included in the scope of this Special Issue.

Dr. Elena Cichero
Dr. Michele Tonelli
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. Pharmaceuticals 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 2900 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

  • neurodegeneration
  • neuroprotective agents
  • chemical synthesis
  • drug design
  • GPCR
  • enzyme
  • screening

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Published Papers (6 papers)

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Research

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20 pages, 3588 KiB  
Article
Prominent Neuroprotective Potential of Indole-2-N-methylpropargylamine: High Affinity and Irreversible Inhibition Efficiency towards Monoamine Oxidase B Revealed by Computational Scaffold Analysis
by Lucija Vrban and Robert Vianello
Pharmaceuticals 2024, 17(10), 1292; https://doi.org/10.3390/ph17101292 - 28 Sep 2024
Viewed by 446
Abstract
Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than [...] Read more.
Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. Methods: Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. Results: We identified indole-2-propargylamine 4fH and indole-2-N-methylpropargylamine 4fMe as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted 4fMe as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔG‡ = −2.5 kcal mol−1) and an improved reaction exergonicity (ΔΔGR = −4.3 kcal mol−1), together with its higher binding affinity, consistently determined by docking (ΔΔGBIND = −0.1 kcal mol−1) and MM-PBSA analysis (ΔΔGBIND = −1.5 kcal mol−1). Conclusions: Our findings strongly advocate 4fMe as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases. Full article
(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)
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26 pages, 18326 KiB  
Article
Design and Synthesis of Novel N-Benzylidene Derivatives of 3-Amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine under Microwave, In Silico ADME Predictions, In Vitro Antitumoral Activities and In Vivo Toxicity
by Sirine Karoui, Marwa Dhiabi, Mehdi Fakhfakh, Souhir Abid, Emmanuelle Limanton, Rémy Le Guével, Thierry D. Charlier, Anthony Mainguy, Olivier Mignen, Ludovic Paquin, Houcine Ammar and Jean-Pierre Bazureau
Pharmaceuticals 2024, 17(4), 458; https://doi.org/10.3390/ph17040458 - 2 Apr 2024
Viewed by 1222
Abstract
The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully [...] Read more.
The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using 1H and 13C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski’s rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC50 < 0.3 μM) and no toxicity on fibroblasts (IC50 > 25 μM). A dose-dependent inhibition of Store-Operated Ca+2 Entry (SOCE) was observed in the HEK293 cell line with 10h. In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 μM at 72 hpf. Full article
(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)
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27 pages, 6281 KiB  
Article
Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays
by Elena Cichero, Valeria Francesconi, Beatrice Casini, Monica Casale, Evgeny Kanov, Andrey S. Gerasimov, Ilya Sukhanov, Artem Savchenko, Stefano Espinoza, Raul R. Gainetdinov and Michele Tonelli
Pharmaceuticals 2023, 16(11), 1632; https://doi.org/10.3390/ph16111632 - 20 Nov 2023
Cited by 3 | Viewed by 1941
Abstract
Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by [...] Read more.
Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by a low selectivity for TAAR1 with respect to other monoaminergic G protein-coupled receptors, like the adrenoreceptors. This study utilized comparative molecular docking studies and quantitative–structure activity relationship (QSAR) analyses to unveil key structural differences between TAAR1 and alpha2-adrenoreceptor (α2-ADR), with the aim to design novel TAAR1 agonists characterized by a higher selectivity profile and reduced off-target effects. While the presence of hydrophobic motives is encouraged towards both the two receptors, the introduction of polar/positively charged groups and the ligand conformation deeply affect the TAAR1 or α2-ADR putative selectivity. These computational methods allowed the identification of the α2A-ADR agonist guanfacine as an attractive TAAR1-targeting lead compound, demonstrating nanomolar activity in vitro. In vivo exploration of the efficacy of guanfacine showed that it is able to decrease the locomotor activity of dopamine transporter knockout (DAT-KO) rats. Therefore, guanfacine can be considered as an interesting template molecule worthy of structural optimization. The dual activity of guanfacine on both α2-ADR and TAAR1 signaling and the related crosstalk between the two pathways will deserve more in-depth investigation. Full article
(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)
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14 pages, 2095 KiB  
Article
Distinct and Dynamic Changes in the Temporal Profiles of Neurotransmitters in Drosophila melanogaster Brain following Volatilized Cocaine or Methamphetamine Administrations
by Ana Filošević Vujnović, Lara Saftić Martinović, Marta Medija and Rozi Andretić Waldowski
Pharmaceuticals 2023, 16(10), 1489; https://doi.org/10.3390/ph16101489 - 19 Oct 2023
Viewed by 1380
Abstract
Due to similarities in genetics, cellular response, and behavior, Drosophila is used as a model organism in addiction research. A well-described behavioral response examined in flies is the induced increase in locomotor activity after a single dose of volatilized cocaine (vCOC) and volatilized [...] Read more.
Due to similarities in genetics, cellular response, and behavior, Drosophila is used as a model organism in addiction research. A well-described behavioral response examined in flies is the induced increase in locomotor activity after a single dose of volatilized cocaine (vCOC) and volatilized methamphetamine (vMETH), the sensitivity, and the escalation of the locomotor response after the repeated dose, the locomotor sensitization. However, knowledge about how vCOC and vMETH affect different neurotransmitter systems over time is scarce. We used LC-MS/MS to systematically examine changes in the concentration of neurotransmitters, metabolites and non-metabolized COC and METH in the whole head homogenates of male flies one to seven hours after single and double vCOC or vMETH administrations. vMETH leads to complex changes in the levels of examined substances over time, while vCOC strongly and briefly increases concentrations of dopamine, tyramine and octopamine followed by a delayed degradation into N-acetyl dopamine and N-acetyl tyramine. The first exposure to psychostimulants leads to significant and dynamic changes in the concentrations relative to the second administration when they are more stable over several hours. Further investigations are needed to understand neurochemical and molecular changes post-psychostimulant administration. Full article
(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)
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18 pages, 4366 KiB  
Article
Vitamin E and Silymarin Reduce Oxidative Tissue Damage during Gentamycin-Induced Nephrotoxicity
by Tsvetelin Georgiev, Galina Nikolova, Viktoriya Dyakova, Yanka Karamalakova, Ekaterina Georgieva, Julian Ananiev, Veselin Ivanov and Petya Hadzhibozheva
Pharmaceuticals 2023, 16(10), 1365; https://doi.org/10.3390/ph16101365 - 27 Sep 2023
Cited by 5 | Viewed by 1371
Abstract
Aminoglycoside antibiotics and gentamicin (GN), in particular, are still widely used in clinical practice. It is a well-known fact that GN causes nephrotoxicity, and redox disturbances are discussed as a factor in its side effects. Recently, a new type of cell oxidative death, [...] Read more.
Aminoglycoside antibiotics and gentamicin (GN), in particular, are still widely used in clinical practice. It is a well-known fact that GN causes nephrotoxicity, and redox disturbances are discussed as a factor in its side effects. Recently, a new type of cell oxidative death, named ferroptosis, was discovered; it is associated with iron accumulation in the cell, glutathione (GSH) depletion and inactivation of glutathione peroxidase-4 (GPX4), reactive oxygen species (ROS) increment with concomitant lipid peroxidation. In this regard, a possible connection between GN-induced renal damage, ferroptosis and the overall antioxidant status of the organism could be investigated. Moreover, due to its beneficial effects, GN is still one of the main choices as a therapeutic agent for several diseases, and the possible reduction of its side effects with the application of certain antioxidants will be of important clinical significance. The study was conducted with adult male white mice divided into several groups (n = 6). GN nephrotoxicity was induced by the administration of GN 100–200 mg/kg i.p. for 10 days. The control group received only saline. The other groups received either Vitamin E (400 mg/kg p.o.) or Silymarin (200 mg/kg p.o.) applied alone or together with GN for the same period. After the end of the study, the animals were sacrificed, and blood and tissue samples were taken for the assessment of biochemical parameters and antioxidant status, as well as routine and specific for GPX4 histochemistry examination. The experimental results indicate that GN-induced nephrotoxicity negatively modulates GPX4 activity and is associated with increased production of ROS and lipid peroxidation. The groups treated with antioxidants demonstrated preserved antioxidant status and better GPX4 activity. In conclusion, the inhibition of ROS production and especially the suppression of ferroptosis, could be of clinical potential and can be applied as a means of reducing the toxic effects of GN application. Full article
(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)
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Review

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39 pages, 19372 KiB  
Review
Marine-Derived Bioactive Metabolites as a Potential Therapeutic Intervention in Managing Viral Diseases: Insights from the SARS-CoV-2 In Silico and Pre-Clinical Studies
by Queency N. Okechukwu, Feyisayo O. Adepoju, Osman N. Kanwugu, Parise Adadi, Ángel Serrano-Aroca, Vladimir N. Uversky and Charles Odilichukwu R. Okpala
Pharmaceuticals 2024, 17(3), 328; https://doi.org/10.3390/ph17030328 - 1 Mar 2024
Cited by 1 | Viewed by 2680
Abstract
Worldwide urbanization and subsequent migration have accelerated the emergence and spread of diverse novel human diseases. Among them, diseases caused by viruses could result in epidemics, typified by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which hit the globe towards the end [...] Read more.
Worldwide urbanization and subsequent migration have accelerated the emergence and spread of diverse novel human diseases. Among them, diseases caused by viruses could result in epidemics, typified by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which hit the globe towards the end of December 2019. The global battle against SARS-CoV-2 has reignited interest in finding alternative treatments for viral infections. The marine world offers a large repository of diverse and unique bioactive compounds. Over the years, many antiviral compounds from marine organisms have been isolated and tested in vitro and in vivo. However, given the increasing need for alternative treatment, in silico analysis appears to provide a time- and cost-effective approach to identifying the potential antiviral compounds from the vast pool of natural metabolites isolated from marine organisms. In this perspective review, we discuss marine-derived bioactive metabolites as potential therapeutics for all known disease-causing viruses including the SARS-CoV-2. We demonstrate the efficacy of marine-derived bioactive metabolites in the context of various antiviral activities and their in silico, in vitro, and in vivo capacities. Full article
(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)
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