{"title":"Design strategies, structural insights, and biological potential of amyloid-beta inhibitors in Alzheimer's disease.","authors":"Mridul Guleria, Arprita Malhan, Ghanshyam Teli, Nidhi Bisht, Subheet Kumar Jain","doi":"10.1007/s11030-025-11278-4","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an insidious neurodegenerative condition characterized by dementia, cognitive decline, and eventual mortality. The pathogenesis of AD is complex, influenced by multiple factors including neurotransmitter deficiencies, particularly acetylcholine (ACh) and the dysregulation of mental homeostasis, reactive oxygen species (ROS), and amyloid-beta (Aβ) peptide accumulation. The latter is firmly linked to the formation of neurofibrillary tangles (NFTs) and amyloid plaques in the cortical and hippocampal regions, which are hallmarks of the disease pathology. Recent advancements in therapeutic strategies have focused on inhibiting the amyloid-beta peptide, a key contributor to AD progression. This study explores the development of novel amyloid-beta inhibitors and their biological activities, focusing on the synthesis of radiolabeled compounds used in the diagnosis and treatment of Alzheimer's disease. Additionally, we explore the roles of crucial enzymes such as Electrophorus electricus acetylcholinesterase (eeAChE), human acetylcholinesterase (hAChE), and human butyrylcholinesterase (hBuChE) in the disease's neurochemical landscape. The goal of this review is to furnish the scientific community with insight into the design of innovative amyloid imaging agents. These agents are based on diverse scaffolds including flavone, pyrimidine, benzimidazole, imidazole, pyridine, pyrrole, quinoline, indanone, acridine, and peptide-based derivatives, serving as core structures for further research and development. This comprehensive evaluation not only elucidates the molecular underpinnings of AD but also propels forward the quest for efficacious diagnostic and therapeutic tools.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-025-11278-4","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
Alzheimer's disease (AD) is an insidious neurodegenerative condition characterized by dementia, cognitive decline, and eventual mortality. The pathogenesis of AD is complex, influenced by multiple factors including neurotransmitter deficiencies, particularly acetylcholine (ACh) and the dysregulation of mental homeostasis, reactive oxygen species (ROS), and amyloid-beta (Aβ) peptide accumulation. The latter is firmly linked to the formation of neurofibrillary tangles (NFTs) and amyloid plaques in the cortical and hippocampal regions, which are hallmarks of the disease pathology. Recent advancements in therapeutic strategies have focused on inhibiting the amyloid-beta peptide, a key contributor to AD progression. This study explores the development of novel amyloid-beta inhibitors and their biological activities, focusing on the synthesis of radiolabeled compounds used in the diagnosis and treatment of Alzheimer's disease. Additionally, we explore the roles of crucial enzymes such as Electrophorus electricus acetylcholinesterase (eeAChE), human acetylcholinesterase (hAChE), and human butyrylcholinesterase (hBuChE) in the disease's neurochemical landscape. The goal of this review is to furnish the scientific community with insight into the design of innovative amyloid imaging agents. These agents are based on diverse scaffolds including flavone, pyrimidine, benzimidazole, imidazole, pyridine, pyrrole, quinoline, indanone, acridine, and peptide-based derivatives, serving as core structures for further research and development. This comprehensive evaluation not only elucidates the molecular underpinnings of AD but also propels forward the quest for efficacious diagnostic and therapeutic tools.
期刊介绍：
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;
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