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Pharmaceutics
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The Therapy of Alzheimer’s Disease: Towards a New Generation of...
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The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 September 2024) | Viewed by 8458

Special Issue Editors

Prof. Dr. M. Amelia Santos

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Guest Editor
Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal
Interests: medicinal chemistry; biochemistry and molecular biology; development and biochemical evaluation of new AD therapeutics; multitarget approaches conjugated with drug repositioning
Special Issues, Collections and Topics in MDPI journals
Dr. Sílvia Chaves

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Guest Editor
Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal
Interests: chelating agents; anti-neurodegeneratives; molecular modelling; bioinorganic chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability development and interrupts neurocognitive function. Although it is the world's leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been successful in more than a decade. In the field of biomedicine, effective treatment for Alzheimer's disease is a severe obstacle. There is no treatment to cure Alzheimer's disease, with the available drugs showing only symptomatic relief.

At the current stage, stem cell-based therapy has been positioned as an effective, secure, and creative therapeutic solution to overcoming AD because of AD's multifactorial nature and inadequate care. In addition, nano drug delivery systems are promising vehicles for targeting several therapeutic moieties by enhancing drug molecules' penetration across the CNS and improving their bioavailability.

Herein, based on the already recognized multiple etiological factors that contribute to AD, we focus on the most recent developments for AD treatment achieved by different approaches. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but not limited to) the following:

  1. Novel biomarkers for targeted AD therapy;
  2. New approaches to AD therapy;
  3. Multifunctional drugs for multitargeting strategies;
  4. Drug repurposing and repositioning strategies;
  5. Controlled delivery of drugs with nanocarriers (polymeric nanoparticles (NP), inorganic NPs and lipid-based NPs);
  6. Other emergent therapy strategies.

I/We look forward to receiving your contributions. 

Prof. Dr. M. Amelia Santos
Dr. Sílvia Chaves
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. Pharmaceutics 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

  • Alzheimer's disease
  • AD
  • biomarker
  • pharmacological therapy
  • drug development
  • multi-target drugs
  • drug repositioning
  • nanomedicine
  • clinical trials

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Published Papers (5 papers)

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Research

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20 pages, 823 KiB  
Article
Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties
by Caterina Pont, Anna Sampietro, F. Javier Pérez-Areales, Nunzia Cristiano, Agustí Albalat, Belén Pérez, Manuela Bartolini, Angela De Simone, Vincenza Andrisano, Marta Barenys, Elisabet Teixidó, Raimon Sabaté, M. Isabel Loza, José Brea and Diego Muñoz-Torrero
Pharmaceutics 2024, 16(8), 982; https://doi.org/10.3390/pharmaceutics16080982 - 25 Jul 2024
Viewed by 830
Abstract
Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer’s disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful [...] Read more.
Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer’s disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein–huprine hybrid lead by hydroxy group removal—ring contraction—ring opening—ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC50 >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification. Full article
(This article belongs to the Special Issue The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs)
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20 pages, 3000 KiB  
Article
New Multitarget Rivastigmine–Indole Hybrids as Potential Drug Candidates for Alzheimer’s Disease
by Leo Bon, Angelika Banaś, Inês Dias, Inês Melo-Marques, Sandra M. Cardoso, Sílvia Chaves and M. Amélia Santos
Pharmaceutics 2024, 16(2), 281; https://doi.org/10.3390/pharmaceutics16020281 - 16 Feb 2024
Cited by 2 | Viewed by 1714
Abstract
Alzheimer’s disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search for new multitarget drugs. Therefore, following a multitarget approach, nine rivastigmine–indole (RIV-IND) hybrids (5a1-3, 5b1-3, 5c1-3) were designed, synthesized and evaluated for their multiple biological properties and free radical scavenging activity, as potential multitarget anti-AD drugs. The molecular docking studies of these hybrids on the active center of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) suggest their capacity to act as dual enzyme inhibitors with probable greater disease-modifying impact relative to AChE-selective FDA-approved drugs. Compounds 5a3 (IC50 = 10.9 µM) and 5c3 (IC50 = 26.8 µM) revealed higher AChE inhibition than the parent RIV drug. Radical scavenging assays demonstrated that all the hybrids containing a hydroxyl substituent in the IND moiety (5a2-3, 5b2-3, 5c2-3) have good antioxidant activity (EC50 7.8–20.7 µM). The most effective inhibitors of Aβ42 self-aggregation are 5a3, 5b3 and 5c3 (47.8–55.5%), and compounds 5b2 and 5c2 can prevent the toxicity induced by Aβ1-42 to cells. The in silico evaluation of the drug-likeness of the hybrids also showed that all the compounds seem to have potential oral availability. Overall, within this class of RIV-IND hybrids, 5a3 and 5c3 appear as lead compounds for anti-AD drug candidates, deserving further investigation. Full article
(This article belongs to the Special Issue The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs)
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14 pages, 1286 KiB  
Article
Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca2+ Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties
by Irene Pachón-Angona, Paul J. Bernard, Alexey Simakov, Maciej Maj, Krzysztof Jozwiak, Anna Novotna, Carina Lemke, Michael Gütschow, Helene Martin, María-Jesús Oset-Gasque, José-Marco Contelles and Lhassane Ismaili
Pharmaceutics 2024, 16(1), 121; https://doi.org/10.3390/pharmaceutics16010121 - 17 Jan 2024
Viewed by 1445
Abstract
This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference [...] Read more.
This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities. Full article
(This article belongs to the Special Issue The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs)
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Review

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32 pages, 5508 KiB  
Review
Drug Development for Alzheimer’s and Parkinson’s Disease: Where Do We Go Now?
by Lisa Sequeira, Sofia Benfeito, Carlos Fernandes, Inês Lima, Joana Peixoto, Catarina Alves, Cláudia Sofia Machado, Alexandra Gaspar, Fernanda Borges and Daniel Chavarria
Pharmaceutics 2024, 16(6), 708; https://doi.org/10.3390/pharmaceutics16060708 - 24 May 2024
Cited by 4 | Viewed by 1632
Abstract
Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an [...] Read more.
Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases’ progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop new, disease-modifying drugs to treat AD and PD, describing as representative examples some advances in the development of drug candidates targeting oxidative stress and adenosine A2A receptors. Full article
(This article belongs to the Special Issue The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs)
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13 pages, 3299 KiB  
Review
Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease
by Thomas Guiselin, Cédric Lecoutey, Christophe Rochais and Patrick Dallemagne
Pharmaceutics 2023, 15(10), 2382; https://doi.org/10.3390/pharmaceutics15102382 - 26 Sep 2023
Cited by 6 | Viewed by 2067
Abstract
The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug–drug interactions or low adherence to treatment. The use of [...] Read more.
The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug–drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design. Full article
(This article belongs to the Special Issue The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs)
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