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Multifunctional Ligands Against Alzheimer's Disease

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 21824

Special Issue Editor

Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
Interests: medicinal chemistry; drug design; Alzheimer’s disease; multifunctional ligands; cholinesterase inhibitors; beta-secretase inhibitors; amyloid-beta aggregation; tau inhibitors; physicochemical properties

Special Issue Information

Dear Colleagues,

Over 100 years ago, Dr. Alois Alzheimer described an unknown brain disorder that today bears his name. Alzheimer’s disease is a progressive, incurable, and complex neurodegenerative disease that affected over 30 million people worldwide in 2018. The main hallmarks of the disease, found in the brains of Alzheimer’s patients, are deposits of beta-amyloid aggregates (senile plaques) that are located outside neurons, and twisted strands of protein tau (neurofibrillary tangles) that are located inside neurons. These pathological changes develop in the brain regions that are related to the memory and cognitive functions. As the cholinergic system is associated with memory and cognition, impaired cholinergic neurotransmission induces symptoms of cognitive decline and memory impairment in AD patients. Moreover, the pathogenesis of the disease includes excitotoxicity, neuroinflammation, mitochondria damage, oxidative stress, and metal ion dysregulation, which lead to a massive damage of neurons, synaptic dysfunction, neuronal death, and finally, to advanced dementia. At present, there is no available treatment that may slow down or stop the neurons’ damage and death.

As a result of the multiple factors that cause Alzheimer’s disease as well as the identification of many potential biological targets, a multi-target approach has been applied in search for potential drugs. Its goal is to create a single molecule, called a multifunctional ligand, that can interact selectively with several of the desired biological targets relevant for the disease. This strategy has been successfully developed since 2000, based on the observation that many marketed drugs are substantially promiscuous agents. The development of multifunctional ligands as potential anti-Alzheimer’s drugs has also accelerated over the recent years. This Special Issue aims to provide a forum for the presentation and dissemination of the results of the design, synthesis, and biological evaluation of novel multifunctional compounds against Alzheimer's disease. It is a very attractive topic; thus, we expect that this Special Issue will be a good platform for sharing our research results.

Prof. Dr. Barbara Malawska
Guest Editor

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Keywords

  • Alzheimer’s disease
  • Neurodegeneration
  • Multi-target drug discovery
  • Multifunctional ligands
  • Polypharmacology
  • Enzymes inhibitors: cholinesterase, β-secretase, and monoaminooxidase
  • Neurotoxic peptide (beta amyloid, tau protein) aggregation inhibitors
  • Glycogen-synthase kinase-3β inhibitors
  • G-protein coupled receptors (serotoninergic, histaminergic, cannabinoid, and adenosine) ligands
  • Antioxidants
  • Metal chelators
  • Neuroinflammation

Published Papers (6 papers)

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Research

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22 pages, 4148 KiB  
Article
Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection
by Jutamas Jiaranaikulwanitch, Hataichanok Pandith, Sarin Tadtong, Phanit Thammarat, Supat Jiranusornkul, Nattapong Chauthong, Supitcha Nilkosol and Opa Vajragupta
Molecules 2021, 26(6), 1562; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26061562 - 12 Mar 2021
Cited by 9 | Viewed by 2955
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds 2c and 5c exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds 2c and 5c were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2. Full article
(This article belongs to the Special Issue Multifunctional Ligands Against Alzheimer's Disease)
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13 pages, 6447 KiB  
Article
Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity
by Jakub Jończyk, Justyna Godyń, Ewelina Stawarska, Beata Morak-Młodawska, Małgorzata Jeleń, Krystian Pluta and Barbara Malawska
Molecules 2020, 25(11), 2604; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25112604 - 03 Jun 2020
Cited by 12 | Viewed by 2149
Abstract
The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity [...] Read more.
The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with IC50 values from 0.78 to 19.32 μM, while their IC50 values against eqBuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an IC50 value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives. Full article
(This article belongs to the Special Issue Multifunctional Ligands Against Alzheimer's Disease)
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25 pages, 3790 KiB  
Article
Multitarget Approach to Drug Candidates against Alzheimer’s Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets
by Larisa Ivanova, Mati Karelson and Dimitar A. Dobchev
Molecules 2020, 25(8), 1846; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25081846 - 17 Apr 2020
Cited by 13 | Viewed by 4425
Abstract
Alzheimer’s disease is a neurodegenerative condition for which currently there are no drugs that can cure its devastating impact on human brain function. Although there are therapeutics that are being used in contemporary medicine for treatment against Alzheimer’s disease, new and more effective [...] Read more.
Alzheimer’s disease is a neurodegenerative condition for which currently there are no drugs that can cure its devastating impact on human brain function. Although there are therapeutics that are being used in contemporary medicine for treatment against Alzheimer’s disease, new and more effective drugs are in great demand. In this work, we proposed three potential drug candidates which may act as multifunctional compounds simultaneously toward AChE, SERT, BACE1 and GSK3β protein targets. These candidates were discovered by using state-of-the-art methods as molecular calculations (molecular docking and molecular dynamics), artificial neural networks and multilinear regression models. These methods were used for virtual screening of the publicly available library containing more than twenty thousand compounds. The experimental testing enabled us to confirm a multitarget drug candidate active at low micromolar concentrations against two targets, e.g., AChE and BACE1. Full article
(This article belongs to the Special Issue Multifunctional Ligands Against Alzheimer's Disease)
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25 pages, 4932 KiB  
Article
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease
by Sílvia Chaves, Simonetta Resta, Federica Rinaldo, Marina Costa, Romane Josselin, Karolina Gwizdala, Luca Piemontese, Vito Capriati, A. Raquel Pereira-Santos, Sandra M. Cardoso and M. Amélia Santos
Molecules 2020, 25(4), 985; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25040985 - 22 Feb 2020
Cited by 27 | Viewed by 4237
Abstract
A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid [...] Read more.
A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD. Full article
(This article belongs to the Special Issue Multifunctional Ligands Against Alzheimer's Disease)
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32 pages, 3262 KiB  
Article
Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly
by Nishad Thamban Chandrika, Marina Y. Fosso, Oleg V. Tsodikov, Harry LeVine III and Sylvie Garneau-Tsodikova
Molecules 2020, 25(1), 77; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25010077 - 24 Dec 2019
Cited by 8 | Viewed by 2855
Abstract
The fact that the number of people with Alzheimer’s disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 [...] Read more.
The fact that the number of people with Alzheimer’s disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-β (Aβ) peptides as well as cholinesterases (i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). We present the design, synthesis, and biochemical evaluation of these two series of novel 1,3-chalcone-donepezil (15a15f) or 1,4-chalcone-donepezil (16a16f) hybrids. We evaluate the relationship between their structures and their ability to inhibit AChE/BChE activity as well as their ability to bind Aβ peptides. We show that several of these novel chalcone-donepezil hybrids can successfully inhibit AChE/BChE as well as the assembly of N-biotinylated Aβ(1–42) oligomers. We also demonstrate that the Aβ binding site of these hybrids differs from that of Pittsburgh Compound B (PIB). Full article
(This article belongs to the Special Issue Multifunctional Ligands Against Alzheimer's Disease)
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Review

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30 pages, 4685 KiB  
Review
Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy
by Agnieszka Zagórska and Anna Jaromin
Molecules 2020, 25(15), 3337; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153337 - 23 Jul 2020
Cited by 30 | Viewed by 4639
Abstract
Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple [...] Read more.
Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered. Full article
(This article belongs to the Special Issue Multifunctional Ligands Against Alzheimer's Disease)
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