Abstract
Alzheimer´s disease (AD) is the most common and severe age-dependent neurodegenerative disorder worldwide. Notwithstanding the large amount of research dedicated to both the elucidation of this pathology and the development of an effective drug, the multifaceted nature and complexity of the disease are certainly a rationale for the absence of cure so far. Currently available drugs are used, mainly to compensate the decline of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition, though they only provide temporary symptomatic benefits and cannot stop AD progression. Although the multiple factors that contribute to trigger AD onset and progression are not yet fully understood, several pathological features and underneath pathways have been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding, oxidative stress and neurotransmitter deficiencies, some of them being interconnected. Thus, there is widespread recent interest in the development of multitarget-directed ligands (MTDLs) for simultaneous interaction with several pathological targets of AD. In this review, a selection of the most recent reports (2016-up to present) on metal chelators of MTDLs with multifunctionalities is presented. These compounds enable the hitting of several AD targets or pathways, such as modulation of specific biometal ions (e.g., Cu, Fe, Zn) and of protein misfolding (β-amyloid and tau protein), anti-oxidant activity and AChE inhibition. The properties found for these hybrids are discussed in comparison with the original reference compounds, some MTDLs being outlined as leading compounds for pursuing future studies in view of efficient potential applications in AD therapy.
Keywords: Alzheimer's disease, multitarget drugs, biometals, metal chelators, Aβ aggregation, AChE inhibitors, antioxidant properties, drug repositioning.
Current Medicinal Chemistry
Title:Recent Multi-target Approaches on the Development of Anti- Alzheimer's Agents Integrating Metal Chelation Activity
Volume: 28 Issue: 35
Author(s): Sílvia Chaves, Katalin Várnagy and M. Amélia Santos*
Affiliation:
- Centro de Quimica Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa,Portugal
Keywords: Alzheimer's disease, multitarget drugs, biometals, metal chelators, Aβ aggregation, AChE inhibitors, antioxidant properties, drug repositioning.
Abstract: Alzheimer´s disease (AD) is the most common and severe age-dependent neurodegenerative disorder worldwide. Notwithstanding the large amount of research dedicated to both the elucidation of this pathology and the development of an effective drug, the multifaceted nature and complexity of the disease are certainly a rationale for the absence of cure so far. Currently available drugs are used, mainly to compensate the decline of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition, though they only provide temporary symptomatic benefits and cannot stop AD progression. Although the multiple factors that contribute to trigger AD onset and progression are not yet fully understood, several pathological features and underneath pathways have been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding, oxidative stress and neurotransmitter deficiencies, some of them being interconnected. Thus, there is widespread recent interest in the development of multitarget-directed ligands (MTDLs) for simultaneous interaction with several pathological targets of AD. In this review, a selection of the most recent reports (2016-up to present) on metal chelators of MTDLs with multifunctionalities is presented. These compounds enable the hitting of several AD targets or pathways, such as modulation of specific biometal ions (e.g., Cu, Fe, Zn) and of protein misfolding (β-amyloid and tau protein), anti-oxidant activity and AChE inhibition. The properties found for these hybrids are discussed in comparison with the original reference compounds, some MTDLs being outlined as leading compounds for pursuing future studies in view of efficient potential applications in AD therapy.
Export Options
About this article
Cite this article as:
Chaves Sílvia , Várnagy Katalin and Santos Amélia M. *, Recent Multi-target Approaches on the Development of Anti- Alzheimer's Agents Integrating Metal Chelation Activity, Current Medicinal Chemistry 2021; 28 (35) . https://dx.doi.org/10.2174/0929867328666210218183032
DOI https://dx.doi.org/10.2174/0929867328666210218183032 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Recent Advances in Enone and NO-Releasing Derivatives of Oleanolic Acid with Anti-cancer Activity
Mini-Reviews in Organic Chemistry Boron Nitride Nanotubes: A Novel Vector for Targeted Magnetic Drug Delivery
Current Nanoscience Oncoproteomics of Neuroblastoma: A Blueprint for Future Progress
Current Proteomics Papillary Thyroid Carcinoma in Pediatric Age: An Example of a Rare Tumour Managed Within a Cooperative Comprehensive Project
Current Pediatric Reviews Ligand-Targeted Liposomes for Cancer Treatment
Current Drug Delivery Biosafety of Herpesvirus Vectors
Current Gene Therapy Dual Inhibitors of β-Amyloid Aggregation and Acetylcholinesterase as Multi-Target Anti-Alzheimer Drug Candidates
Current Topics in Medicinal Chemistry Basolateral Aggregated Rat Amyloidβ(1-42) Potentiates Transmigration of Primary Rat Monocytes through a Rat Blood-Brain Barrier
Current Neurovascular Research Cytotoxic and Allergenic Potential of Bioactive Proteins and Peptides
Current Pharmaceutical Design Role of Endogenous Granulocyte-Macrophage Colony Stimulating Factor Following Stroke and Relationship to Neurological Outcome
Current Neurovascular Research Autism, Mitochondria and Polybrominated Diphenyl Ether Exposure
CNS & Neurological Disorders - Drug Targets An Overview of the α4β1 Integrin and the Potential Therapeutic Role of its Antagonists
Current Medicinal Chemistry Vascular Endothelial Growth Factor as an Anti-Angiogenic Target for Cancer Therapy
Current Drug Targets Exploring the Role of Nerve Growth Factor in Multiple Sclerosis: Implications in Myelin Repair
CNS & Neurological Disorders - Drug Targets Organosulphur Compounds Induce Apoptosis and Cell Cycle Arrest in Cervical Cancer Cells via Downregulation of HPV E6 and E7 Oncogenes
Anti-Cancer Agents in Medicinal Chemistry Anaplastic Lymphoma Kinase Inhibitors in Non-Small Cell Lung Cancer
Current Drug Targets Antioxidants and its Properties as Affected by Extrusion Process: A Review
Recent Patents on Food, Nutrition & Agriculture Novel Drug Delivery Systems for Releasing Growth Factors to the CNS: Focus on Alzheimer`s and Parkinson`s Diseases
Mini-Reviews in Medicinal Chemistry Amyloid-β Aggregation Inhibitory and Neuroprotective Effects of Xanthohumol and its Derivatives for Alzheimer’s Diseases
Current Alzheimer Research Investigation on the Molecular Interactions Stabilizing the Structure of α-synuclein Fibril: An In silico Study
Central Nervous System Agents in Medicinal Chemistry