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Advances in Alzheimer’s Disease Drug Research and Development

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (16 June 2023) | Viewed by 12416

Special Issue Editor

Prof. Dr. José Luis Marco-Contelles

E-Mail Website
Guest Editor
Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain
Interests: Alzheimer’s disease; biological evaluation; drug discovery; medicinal chemistry; molecular design; neurodegenerative diseases; stroke; synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Increased quality of life provided by modern healthcare has resulted in improved longevity associated with dementia. Alzheimer’s disease (AD) is the most common cause of dementia among elderly people, affecting more than 30 million people worldwide. The mechanism of neuronal degeneration in AD remains unknown. However, hallmarks of AD are the deficit of neurotransmitters, the formation and aggregation of amyloid plaques, intracellular hyperphosphorylated tau tangles, and oxidative stress. No cure for AD currently exists. The complex nature of AD has prompted the therapeutic shift towards multitarget, single-molecule entities able to inhibit/modulate a number of relevant AD biological targets, involved in the progress and development of the disease. This Special Issue will provide updated information regarding the progress of multifaceted research surrounding AD. Original papers, communications, and review articles covering various topics—such as rational design, discovery of antioxidants, discovery of neuroprotectants, development of multitarget compounds, and repositioning approaches (excluding pure clinical studies)—are welcome.

Prof. Dr. José Luis Marco-Contelles
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • biological activity
  • chemical synthesis
  • drug discovery
  • hybrid molecules
  • molecular modeling
  • multitarget small molecules
  • neuroprotectants
  • polypharmacology
  • rational design
  • repositioning

Published Papers (7 papers)

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Research

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14 pages, 7661 KiB  
Communication
The Proof-of-Concept of MBA121, a Tacrine–Ferulic Acid Hybrid, for Alzheimer’s Disease Therapy
by Emelina R. Rodríguez-Ruiz, Raquel Herrero-Labrador, Ana P. Fernández-Fernández, Julia Serrano-Masa, José A. Martínez-Montero, Daniel González-Nieto, Mayuri Hana-Vaish, Mohamed Benchekroun, Lhassane Ismaili, José Marco-Contelles and Ricardo Martínez-Murillo
Int. J. Mol. Sci. 2023, 24(15), 12254; https://doi.org/10.3390/ijms241512254 - 31 Jul 2023
Viewed by 1252
Abstract
Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer’s disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine–ferulic acid hybrid, and its [...] Read more.
Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer’s disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine–ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good β-amyloid (Aβ) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as Aβ1–40, Aβ1–42, and H2O2, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the Aβ plaque burden in the cerebral cortex and hippocampus in APPswe/PS1ΔE9 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD. Full article
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
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17 pages, 6171 KiB  
Article
Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer’s Disease Treatment
by Imen Dakhlaoui, Paul J. Bernard, Diana Pietrzak, Alexey Simakov, Maciej Maj, Bernard Refouvelet, Arnaud Béduneau, Raphaël Cornu, Krzysztof Jozwiak, Fakher Chabchoub, Isabel Iriepa, Helene Martin, José Marco-Contelles and Lhassane Ismaili
Int. J. Mol. Sci. 2023, 24(11), 9742; https://doi.org/10.3390/ijms24119742 - 04 Jun 2023
Cited by 3 | Viewed by 1478
Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for [...] Read more.
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy. Full article
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
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22 pages, 8079 KiB  
Article
Structural-Activity Relationship of Rare Ginsenosides from Red Ginseng in the Treatment of Alzheimer’s Disease
by Xianwen Ye, Haixia Zhang, Qian Li, Hongmin Ren, Xinfang Xu and Xiangri Li
Int. J. Mol. Sci. 2023, 24(10), 8625; https://doi.org/10.3390/ijms24108625 - 11 May 2023
Cited by 5 | Viewed by 1647
Abstract
Rare ginsenosides are the major components of red ginseng. However, there has been little research into the relationship between the structure of ginsenosides and their anti-inflammatory activity. In this work, BV-2 cells induced by lipopolysaccharide (LPS) or nigericin, the anti-inflammatory activity of eight [...] Read more.
Rare ginsenosides are the major components of red ginseng. However, there has been little research into the relationship between the structure of ginsenosides and their anti-inflammatory activity. In this work, BV-2 cells induced by lipopolysaccharide (LPS) or nigericin, the anti-inflammatory activity of eight rare ginsenosides, and the target proteins expression of AD were compared. In addition, the Morris water maze test, HE staining, thioflavins staining, and urine metabonomics were used to evaluate the effect of Rh4 on AD mice. Our results showed that their configuration influences the anti-inflammatory activity of ginsenosides. Ginsenosides Rk1, Rg5, Rk3, and Rh4 have significant anti-inflammatory activity compared to ginsenosides S-Rh1, R-Rh1, S-Rg3, and R-Rg3. Ginsenosides S-Rh1 and S-Rg3 have more pronounced anti-inflammatory activity than ginsenosides R-Rh1 and R-Rg3, respectively. Furthermore, the two pairs of stereoisomeric ginsenosides can significantly reduce the level of NLRP3, caspase-1, and ASC in BV-2 cells. Interestingly, Rh4 can improve the learning ability of AD mice, improve cognitive impairment, reduce hippocampal neuronal apoptosis and Aβ deposition, and regulate AD-related pathways such as the tricarboxylic acid cycle and the sphingolipid metabolism. Our findings conclude that rare ginsenosides with a double bond have more anti-inflammatory activity than those without, and 20(S)-ginsenosides have more excellent anti-inflammatory activity than 20(R)-ginsenosides. Full article
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
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21 pages, 4745 KiB  
Article
Rivastigmine–Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases
by David Vicente-Zurdo, Leonardo Brunetti, Luca Piemontese, Beatriz Guedes, Sandra M. Cardoso, Daniel Chavarria, Fernanda Borges, Yolanda Madrid, Sílvia Chaves and M. Amélia Santos
Int. J. Mol. Sci. 2023, 24(9), 8312; https://doi.org/10.3390/ijms24098312 - 05 May 2023
Cited by 1 | Viewed by 1563
Abstract
With the goal of combating the multi-faceted Alzheimer’s disease (AD), a series of Rivastigmine-Benzimidazole (RIV–BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase [...] Read more.
With the goal of combating the multi-faceted Alzheimer’s disease (AD), a series of Rivastigmine-Benzimidazole (RIV–BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase inhibitors, and inhibited amyloid-β (Aβ) aggregation. Herein, we moved forward in this project, studying their ability to chelate redox-active biometal ions, Cu(II) and Fe(III), with widely recognized roles in the generation of oxidative reactive species and in protein misfolding and aggregation in both AD and Parkinson’s disease (PD). Although Cu(II) chelation showed higher efficiency for the positional isomers of series 5 than those of series 4 of the hybrids, the Aβ-aggregation inhibition appears more dependent on their capacity for fibril intercalation than on copper chelation. Since monoamine oxidases (MAOs) are also important targets for the treatment of AD and PD, the capacity of these hybrids to inhibit MAO-A and MAO-B was evaluated, and they showed higher activity and selectivity for MAO-A. The rationalization of the experimental evaluations (metal chelation and MAO inhibition) was supported by computational molecular modeling studies. Finally, some compounds showed also neuroprotective effects in human neuroblastoma (SH-SY5Y cells) upon treatment with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxic metabolite of a Parkinsonian-inducing agent. Full article
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
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34 pages, 2902 KiB  
Article
Discovery of Compounds That Selectively Repress the Amyloidogenic Processing of the Amyloid Precursor Protein: Design, Synthesis and Pharmacological Evaluation of Diphenylpyrazoles
by Christophe Mesangeau, Pascal Carato, Nicolas Renault, Mathilde Coevoet, Paul-Emmanuel Larchanché, Amélie Barczyk, Luc Buée, Nicolas Sergeant and Patricia Melnyk
Int. J. Mol. Sci. 2022, 23(21), 13111; https://doi.org/10.3390/ijms232113111 - 28 Oct 2022
Viewed by 1527
Abstract
The rationale to define the biological and molecular parameters derived from structure–activity relationships (SAR) is mandatory for the lead selection of small drug compounds. Several series of small molecules have been synthesized based on a computer-assisted pharmacophore design derived from two series of [...] Read more.
The rationale to define the biological and molecular parameters derived from structure–activity relationships (SAR) is mandatory for the lead selection of small drug compounds. Several series of small molecules have been synthesized based on a computer-assisted pharmacophore design derived from two series of compounds whose scaffold originates from chloroquine or amodiaquine. All compounds share similar biological activities. In vivo, Alzheimer’s disease-related pathological lesions are reduced, consisting of amyloid deposition and neurofibrillary degeneration, which restore and reduce cognitive-associated impairments and neuroinflammation, respectively. Screening election was performed using a cell-based assay to measure the repression of Aβ1–x peptide production, the increased stability of APP metabolites, and modulation of the ratio of autophagy markers. These screening parameters enabled us to select compounds as potent non-competitive β-secretase modulators, associated with various levels of lysosomotropic or autophagy modulatory activities. Structure–activity relationship analyses enabled us to define that (1) selectively reducing the production of Aβ1–x, and (2) little Aβx–40/42 modification together with (3) a decreased ratio of p62/(LC3-I/LC3-II) enabled the selection of non-competitive β-secretase modulators. Increased stability of CTFα and AICD precluded the selection of compounds with lysosomotropic activity whereas cell toxicity was associated with the sole p62 enhanced expression shown to be driven by the loss of nitrogen moieties. These SAR parameters are herein proposed with thresholds that enable the selection of potent anti-Alzheimer drugs for which further investigation is necessary to determine the basic mechanism underlying their mode of action. Full article
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
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22 pages, 16355 KiB  
Article
Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer’s Disease
by Karolina Maciejewska, Kamila Czarnecka, Paweł Kręcisz, Dorota Niedziałek, Grzegorz Wieczorek, Robert Skibiński and Paweł Szymański
Int. J. Mol. Sci. 2022, 23(11), 5876; https://doi.org/10.3390/ijms23115876 - 24 May 2022
Cited by 4 | Viewed by 1948
Abstract
A series of new cyclopentaquinoline derivatives with 9-acridinecarboxylic acid and a different alkyl chain length were synthesized, and their ability to inhibit cholinesterases was evaluated. All designed compounds, except derivative 3f, exhibited a selectivity for butyrylcholinesterase (BuChE) with IC50 values ranging [...] Read more.
A series of new cyclopentaquinoline derivatives with 9-acridinecarboxylic acid and a different alkyl chain length were synthesized, and their ability to inhibit cholinesterases was evaluated. All designed compounds, except derivative 3f, exhibited a selectivity for butyrylcholinesterase (BuChE) with IC50 values ranging from 103 to 539 nM. The 3b derivative revealed the highest inhibitory activity towards BuChE (IC50 = 103.73 nM) and a suitable activity against AChE (IC50 = 272.33 nM). The 3f derivative was the most active compound to AChE (IC50 = 113.34 nM) with satisfactory activity towards BuChE (IC50 = 203.52 nM). The potential hepatotoxic effect was evaluated for both 3b and 3f compounds. The 3b and 3f potential antioxidant activity was measured using the ORAC-FL method. The 3b and 3f derivatives revealed a significantly higher antioxidant potency, respectively 35 and 25 higher than tacrine. Theoretical, physicochemical, and pharmacokinetic properties were calculated using ACD Labs Percepta software. Molecular modeling and kinetic study were used to reveal the mechanism of cholinesterase inhibition in the most potent compounds: 3b and 3f. Full article
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
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Review

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26 pages, 1473 KiB  
Review
The Sigma Receptors in Alzheimer’s Disease: New Potential Targets for Diagnosis and Therapy
by Tao Wang and Hongmei Jia
Int. J. Mol. Sci. 2023, 24(15), 12025; https://doi.org/10.3390/ijms241512025 - 27 Jul 2023
Cited by 4 | Viewed by 2313
Abstract
Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence [...] Read more.
Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer’s disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy. Full article
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
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