Natural Product-Based Synthetic Drug Molecules in Alzheimer's Disease: Therapeutic and Theranostic Agents

This book illustrates the importance of natural products as the source for the development of novel drugs for the treatment of neurodegenerative disorders, including Alzheimer's disease. It also highlights the role of reactive oxygen species and altered metal homeostasis in the progression of Alzheimer’s disease and examines the potential of antioxidants and anti-chelating agents in the clinical intervention of neurodegenerative diseases. The book also discusses the role of neuroinflammation in the pathogenesis of Alzheimer’s disease. The chapters provide information about the drug targets, progress in the development of natural product-based therapeutics, biomarkers, fluorescent diagnostic tools, and theranostic for Alzheimer's disease. The book also provides information about the design and synthesis of natural product-based derivatives against the various targets of Alzheimer's disease including epigenetic targets and the metal dyshomeostasis hypothesis. Cutting across different disciplines, this book is a valuable source for neuroscientists, chemical biologists, pharmaceutical researchers, and synthetic biologists. Preface Contents Editors and Contributors Part I: Introduction of Alzheimer ́s Disease 1: Alzheimer ́s Disease and Drug Targets 1.1 Introduction 1.2 Pathological and Therapeutic Target in AD 1.2.1 Amyloid Beta (Aβ) 1.2.2 Tau Phosphorylation 1.3 Mitochondrial Dysfunction and Oxidative Stress in Alzheimer ́s Disease 1.3.1 Alzheimer ́s Disease Drug Targets 1.3.1.1 Prevention of Aβ Accumulation and Amyloid Inhibitors 1.3.1.2 Prevention of Tau Protein Phosphorylation 1.3.1.3 MicroRNAs in the Management of AD 1.3.1.4 Pyroglutamate Aβ Cascade as a Potential Target 1.3.1.5 Immunotherapy in Alzheimer ́s Disease References 2: Oxidative Stress and Metals in Alzheimer ́s Disease 2.1 Introduction 2.2 Oxidative Stress 2.2.1 Oxidative Stress and Neurodegeneration 2.2.2 Relation Between Oxygen and Oxidative Stress 2.2.3 Mechanism of Generation of Reactive Oxygen Species (ROS) 2.2.4 Role of Amyloid Beta (Aβ)-Induced Oxidative Stress in Alzheimer ́s Disease (AD) 2.2.5 Oxidative Damage-Induced Tau Neurofibrillary Tangles 2.3 ROS-Induced Disruption of Calcium Signalling in Alzheimer ́s Disease 2.4 ROS-Induced Mitochondrial Dysfunction (Mitochondrial Cascade Hypothesis) 2.5 Oxidative Stress and Damage to Biomolecules (Lipids, Proteins, DNA/RNA) 2.6 Role of Metals in AD 2.7 Zinc 2.8 Iron Toxicity 2.9 Copper Toxicity 2.10 Aluminium 2.11 Manganese 2.12 Cadmium 2.13 Lead 2.14 Conclusion References 3: Neuroinflammation in Alzheimer ́s Disease 3.1 Introduction 3.2 Epidemiology 3.3 Neuroinflammation 3.3.1 Etiology 3.4 Mechanism of Neuroinflammation in AD 3.4.1 Microglial Activation 3.4.1.1 MyD88-Dependent Pathways 3.4.1.2 Activation of MyD88-Independent Pathways 3.4.2 Activation of Astrocytes 3.4.3 Damage to Cell Membrane 3.4.4 Oxidative Stress and Neuroinflammation 3.4.5 Activation of Caspases 3.4.6 Activation of Complement System 3.5 Conclusion References Part II: Biomarkers and Diagnosis in Alzheimer ́s Disease 4: Biomarkers for Alzheimer ́s Disease 4.1 Introduction 4.2 Biomarkers of AD 4.2.1 Biomarkers Based on AD Stages 4.3 Invasive Biomarkers 4.3.1 CSF 4.3.1.1 Diagnostic Markers 4.3.1.2 State Markers 4.3.1.3 Stage Markers 4.3.1.4 Biomarkers in CSF for AD 4.3.1.4.1 Aβ1-42 4.3.1.4.2 Tau Protein 4.3.1.4.3 Phosphorylated Tau Protein 4.3.2 Association of Biological Biomarkers in CSF: The Diagnosis of AD in Different Cases 4.3.2.1 Role of Plasma Amyloid Proteins in Patients whose Diagnosis is Hereditary 4.3.2.2 Role of Plasma Amyloid Proteins in Down Syndrome Patients who are Diagnosed with AD 4.3.2.3 Role of Sex Differentiation Linked to AD Biomarkers ́ Prominence and Intellectual Depreciation 4.3.2.3.1 Influence of Sex on Aβ42 4.3.2.3.2 Influence of Sex on Tau 4.3.2.4 Role of CSF Abundance and Clearance Associated with the Prominence of AD Biomarkers and Other Factors 4.4 Noninvasive Biomarkers 4.4.1 Oral 4.4.1.1 Beta Amyloid 4.4.1.2 Tau 4.4.1.3 Acetylcholinesterase (AChE) 4.4.1.4 Lactoferrin 4.4.1.5 Others 4.4.2 Eye 4.4.2.1 Retinal Biomarkers 4.4.2.1.1 Retinal Nerve Fiber Layer (RNFL) and Optic Nerve 4.4.2.1.2 Retinal Blood Flow and Vasculature 4.4.2.1.3 Intraretinal Tau and Amyloid Deposition 4.4.2.1.4 Choroidal Thickness 4.4.2.2 Nonretinal Biomarker 4.4.2.2.1 Pupillary Reactions 4.4.2.2.2 Crystalline Lens 4.4.2.2.3 Eye Movements 4.4.2.3 Potential Future Biomarkers 4.4.2.3.1 Ocular Fluid Biomarkers 4.4.2.3.2 Corneal Nerve Imaging 4.4.3 Urine 4.4.4 Olfactory 4.4.5 Blood 4.4.5.1 Aβ 4.4.5.2 Tau 4.4.5.3 Isoprostanes 4.4.5.4 Post translational Modification (PTM)-Plasma 4.4.5.5 Autoantibodies 4.4.5.6 MicroRNA 4.4.5.7 Blood-Derived Genetic Markers 4.4.5.8 Transcriptome 4.4.5.9 Markers of Inflammation 4.4.6 Biomarkers Through Noninvasive Diagnostic Methods 4.4.6.1 Cognitive Biomarkers 4.4.6.2 Imaging Biomarkers 4.5 Conclusion References 5: Fluorescent Organic Molecules as Diagnostic and Theranostic Tools for Alzheimer ́s Disease 5.1 Introduction 5.2 Hypothesis of AD 5.2.1 Amyloid Hypothesis 5.2.2 Tau Hypothesis 5.3 Diagnosis of AD 5.3.1 A Summary of Various Diagnostic Imaging Methods and Their Clinical Relevance 5.4 Fluorescent Molecules as Diagnostic Tools in AD 5.4.1 Fluorescent Probes for AD Biomarker Detection 5.4.1.1 Fluorogenic and Standard Optical Probes 5.4.2 Classification of Fluorescent Probes for Amyloid (Aβ) Species and Tau Species Based on Fluorophore Structure 5.4.2.1 Thioflavin Derivatives for Aβ Peptides 5.4.2.2 Thioflavin Derivatives for Tau Proteins 5.4.2.3 Curcumin Derivatives for Aβ Peptides 5.4.2.4 Curcumin Derivatives for Tau Proteins 5.4.2.5 BODIPY Derivatives for Amyloid Aggregates 5.4.2.6 BODIPY Derivatives for Tau Proteins 5.4.2.7 Donor-Π-Acceptor-Based Probes (DANIR) for Amyloid Species 5.4.2.8 Naphthalene Derivatives for Aβ Aggregates and Tau Fibrils 5.4.2.9 Quinoxaline-Naphthalene Derivatives for Aβ Protein and Tau Fibrils 5.4.2.10 Novel Benzoselenazole Derivatives for Aβ Plaques 5.4.2.11 Cyanine-Based Derivatives for Amyloid Peptide and Tau Proteins 5.4.2.12 Thiophene Derivatives for Aβ Aggregates 5.4.2.13 Oligothiophene-Containing Probes for Aβ and Tau Fibrils 5.5 Natural Products as Theranostics in AD 5.5.1 Nanotechnology-Based Approach 5.5.1.1 Nanotechnology in Alzheimer ́s Disease Diagnosis 5.5.1.1.1 In Vitro Diagnostics Nanoparticle Conjugates Localized Surface Plasmon Resonance-Based Nanosensor (LSPR) Scanning Tunnelling Microscopy (STM) and Two-Photon Rayleigh Spectroscopy 5.5.1.1.2 In Vivo Nanodiagnostics for Alzheimer ́s Disease Magnetic Resonance Imaging (MRI) Optical Imaging 5.5.1.2 Nanotechnology in Alzheimer ́s Disease Therapy 5.5.1.2.1 Nanogels, Fullerene, and Nanoceria 5.5.1.2.2 Dendrimers 5.5.1.2.3 Gold Nanoparticles 5.5.1.2.4 Diamondoid and Its Derivatives 5.5.1.2.5 Quantum Dots 5.6 Natural compounds in Clinical Trials for AD 5.7 Conclusion References 6: Nanostructure-Based Molecules as Diagnostic and Theranostic Tools in Alzheimer ́s Disease 6.1 Introduction 6.2 Biosensors in Alzheimer ́s Disease 6.2.1 Based on Transduction Mechanism 6.2.1.1 Electrochemical Biosensors 6.2.1.2 Optical Biosensors 6.2.2 Based on Biorecognition Element 6.2.2.1 Antibodies 6.2.2.2 Enzymes 6.2.2.3 Genetic Material 6.3 Biomarkers for Detection of Alzheimer ́s Disease 6.3.1 CSF Biomarkers 6.3.2 Plasma Biomarkers 6.3.3 Genetic Mutations 6.4 The Application of Nanostructure-Based Molecules in the Diagnosis of Alzheimer ́s Disease 6.5 The Application of Nanostructure-Based Molecules in Alzheimer ́s Disease Theranostics 6.6 Toxicity Concerns with Use of Nanotechnology in Alzheimer ́s Disease 6.7 Conclusion References Part III: Drug Derivatives: A Strategy for New Multifunctional Drug Development for Alzheimer ́s Disease 7: Approved Cholinesterase Inhibitor-Based Derivatives: Synthesis and Their Biological Evaluation 7.1 Introduction 7.2 Current Treatment Available for AD Patients 7.3 Structure of Acetylcholinesterase and Butyrylcholinesterase 7.4 Interactions of Acetylcholine with Acetylcholinesterase 7.5 Interaction of Rivastigmine with Cholinesterase 7.5.1 Designing of Rivastigmine-Based New Molecules 7.6 Interaction of Donepezil with Cholinesterase Enzymes 7.6.1 Design and Development of Donepezil-Based Compounds 7.7 Interaction of Tacrine with Cholinesterases 7.8 Conclusion References 8: Memantine-Based Derivatives: Synthesis and Their Biological Evaluation 8.1 Introduction 8.2 Synthesis of Memantine 8.3 Structure and Domains of NMDA Receptor 8.4 Physiology and Pathogenesis 8.5 N-Methyl-D-Aspartate Receptor (NMDAR) and Memantine 8.6 Other Inhibitors 8.7 Developments on Memantine 8.8 Conclusion and Future Perspectives References Part IV: Natural Molecules Inspired Novel Derivatives for Alzheimer ́s Disease 9: Huperzine-Based Derivatives: Design, Synthesis, and Anti-Alzheimer Activity 9.1 Introduction 9.2 Huperzine Alkaloids 9.2.1 Source 9.2.2 Chemistry 9.3 Huperzine and Alzheimer ́s Disease 9.4 Huperzine: Derivatives and Analogues 9.4.1 Analogs of Huperzine A 9.4.2 Huperine X, Hup X (HupA-Tacrine Hybrid) 9.4.3 AVCRI104PO3 Hup Y (HupA-Donepezil Hybrid) 9.4.4 Design of HupA Derivatives 9.4.5 Structure-Activity Relationship 9.5 Synthesis of Huperzine-Based Derivatives 9.6 Analysis of Huperzine-Based Derivatives 9.6.1 HPLC Method 9.6.2 Capillary Electrophoretic Method 9.6.3 NMR Assignments of Huperzine A 9.7 Pharmacokinetic and Associated Toxicities 9.7.1 Pharmacokinetic Studies 9.7.2 Clinical Trials 9.7.3 Toxicology 9.7.4 Drug Interactions 9.8 Patents Published 9.9 Conclusion References 10: Polyphenol: Development of Polyphenol-Inspired Derivatives Targeting Pathological Factors of AD 10.1 Introduction 10.2 Natural Polyphenols Reported for the Treatment of AD 10.3 Polyphenols in Clinical Trials for AD 10.4 Polyphenol-Inspired Derivatives Targeting Pathological Features of AD 10.4.1 Caffeic Acid Inspired Molecules 10.4.2 Ferulic Acid Inspired Molecules 10.4.3 Sinapic Acid Naturally Inspired Molecules 10.4.4 Resveratrol-Based Natural Inspired Molecules 10.4.5 Curcumin-Based Natural Inspired Molecules 10.4.6 Other Natural Product-Inspired Molecules 10.5 Future Prospects 10.6 Conclusion References 11: Flavonoid-Based Derivatives for Modulating Various Targets of Alzheimer ́s Disease 11.1 Introduction 11.2 Alzheimer ́s Disease (AD): Molecular Targets 11.2.1 Amyloid Beta (Aβ) Protein 11.2.2 Cholinesterase 11.2.3 Tau Protein 11.2.4 Oxidative Stress 11.2.5 Monoamine Oxidases (MAO) 11.2.6 NMDA Receptor 11.2.7 Histone Deacetylases (HDACs) 11.2.8 Cyclase 11.2.9 Exopeptidase 11.2.10 Lipid Dys-Homeostasis 11.2.11 Neurovascular Dysfunction 11.2.12 Cysteine Protease 11.2.13 Glycogen Synthase Kinase-3 11.2.14 Pathogen Porphyromonas gingivalis 11.3 Flavonoids, Their Cellular and Molecular Aspects Towards Cognitive Effects 11.3.1 By Reducing Accumulation of Neuropathological Protein 11.3.2 By Stimulating Neuronal Signalling Pathways and Synaptic Plasticity 11.3.3 Neuroinflammation 11.3.4 Vascular Function and Angiogenesis 11.3.5 By Interactions with the Microbiome 11.4 Flavonoids Derivatives in AD Management 11.4.1 Flavone Analogues 11.4.2 Isoflavone Analogues 11.4.3 Homoisoflavonoids Analogues 11.5 Flavonoid Therapy, Challenges, and Future Studies 11.6 Conclusion References 12: Vitamin-Based Derivatives for the Management of Alzheimer ́s Disease 12.1 Introduction 12.2 Vitamins and Their Derivatives 12.2.1 Vitamin A 12.2.2 Vitamin B 12.2.3 Vitamin C 12.2.4 Vitamin D 12.2.5 Vitamin E 12.2.6 Vitamin K 12.3 Conclusion References Part V: Metal Dyshomeostasis: A Hypothesis for Developing Drugs for the Treatment of Alzheimer ́s Disease 13: Metal Chelators as a Potential Therapeutic Agent for Alzheimer ́s Disease 13.1 Introduction to Alzheimer ́s Disease 13.1.1 Discovered Therapies and Highlighted AD Targets 13.1.2 Molecular Targets for AD Treatment 13.2 Metals and Their Role in Central Nervous System 13.2.1 Therapeutic Agents Containing Metals 13.2.2 Role of Metals in Central Nervous System 13.3 Metal Dyshomeostasis and Alzheimer ́s Disease 13.3.1 Copper 13.3.2 Iron 13.3.3 Zinc 13.4 Metal Chelators for AD 13.4.1 Targeting Iron 13.4.2 Targeting Copper and Zinc 13.4.3 Miscellaneous Compounds 13.5 Prospective and Conclusion References 14: Ferroptosis Modulators: A Potential Therapeutic Target in Alzheimer ́s Disease 14.1 Introduction 14.1.1 Statistics of AD 14.1.2 Current Treatment for AD 14.1.3 Ferroptosis 14.2 Mechanism Concerned to the Fundamental Ferroptotic Pathway 14.2.1 Iron Homeostasis 14.2.2 Glutathione Metabolism 14.2.3 Lipid Peroxidation and Oxidative Stress 14.3 Role of Ferroptosis During AD Progression 14.4 Ferroptosis Inhibitors 14.4.1 Radical Trapping Antioxidants (RTAs) 14.4.2 Vitamin E Analogs 14.4.3 Lipoxygenase Inhibitor 14.4.4 Ferrostatin 14.4.5 Liproxstatin 14.4.5.1 Role of Ubiquinol (UQH2) or Coenzyme Q10 (Antioxidant Synthesized by Body) in the Activity of Liproxtatin-1 14.4.6 ACSL4 Inhibitors 14.4.7 Deuterated Phospholipids 14.5 Conclusion References Part VI: Natural Products/Synthetic Molecules as Epigenetic Modulators in Alzheimer ́s Disease 15: Sirtuin Modulator: Design, Synthesis, and Biological Evaluation 15.1 Introduction 15.2 Types of Sirtuin 15.3 Pharmacological Sirtuin Modulation 15.3.1 Sirtuin Activators 15.3.1.1 Resveratrol 15.3.1.2 Sirtuin Activators Structurally Unrelated to Resveratrol 15.3.2 Sirtuin Blockers 15.3.2.1 Splitomicin and Its Derivatives 15.3.2.2 Sirtinol 15.3.2.3 AGK2 15.3.2.4 Cambinol 15.3.2.5 Suramin 15.3.2.6 Tenovin 15.3.2.7 Salermide 15.3.2.8 Other Inhibitors of Human Sirtuins 15.4 Natural Sirtuin Inhibitors and Modulators Beneficial Effects on Health 15.5 Conclusions References 16: Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation 16.1 Introduction 16.2 Histone Deacetylation and Its Implication in Alzheimer ́s Disease 16.3 HDAC Inhibitors in Alzheimer ́s Disease 16.4 Summary References