{"title":"Design, synthesis, and biological evaluation of tetrahydropyrimidine analogue as GSK-3β/Aβ aggregation inhibitor and anti-Alzheimer’s agent","authors":"","doi":"10.1016/j.bioorg.2024.107811","DOIUrl":null,"url":null,"abstract":"<div><p>The complex nature of Alzheimer’s disease (AD) etiopathology is among the principal hurdles to developing effective anti-Alzheimer agents. Tau pathology and Amyloid-β (Aβ) accumulation are hallmarks and validated therapeutic strategies of AD. GSK-3β is a serine/threonine kinase involved in tau phosphorylation. Its excessive activity also contributes to the production of Aβ plaques, making GSK-3β an attractive AD target. Taking this into account, In this article, we outline the design, synthesis, and biological validation of a focused library of 1,2,3,4-tetrahydropyrimidine based derivatives as inhibitors of GSK-3β, tau phosphorylation, and Aβ accumulation. The inhibitory activity of forty nine synthetic compounds was tested against GSK-3β and other AD-relevant kinases. The kinetic experiments revealed the mode of GSK-3β inhibition by the most potent compound 44. The <em>in- vitro</em> drug metabolism and pharmacokinetic studies were thereafter performed. The anti-aggregation activity of the most potent GSK-3β inhibitor was tested using AD transgenic <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) strain CL2006 for quantification of Aβ plaques and BR5706 <em>C. elegans</em> strain for tau pathology evaluation. We then evaluated the blood–brain barrier permeability and got promising results. Therefore, we present compound 44 as a potential ATP-competitive GSK-3β inhibitor with good metabolism and pharmacokinetic profile, anti-aggregation properties for amyloid beta protein, and reduction in tau-phosphorylation levels. We recommend more investigation into compound 44-based small molecules as possible targets for AD disease-modifying treatments.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824007168","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The complex nature of Alzheimer’s disease (AD) etiopathology is among the principal hurdles to developing effective anti-Alzheimer agents. Tau pathology and Amyloid-β (Aβ) accumulation are hallmarks and validated therapeutic strategies of AD. GSK-3β is a serine/threonine kinase involved in tau phosphorylation. Its excessive activity also contributes to the production of Aβ plaques, making GSK-3β an attractive AD target. Taking this into account, In this article, we outline the design, synthesis, and biological validation of a focused library of 1,2,3,4-tetrahydropyrimidine based derivatives as inhibitors of GSK-3β, tau phosphorylation, and Aβ accumulation. The inhibitory activity of forty nine synthetic compounds was tested against GSK-3β and other AD-relevant kinases. The kinetic experiments revealed the mode of GSK-3β inhibition by the most potent compound 44. The in- vitro drug metabolism and pharmacokinetic studies were thereafter performed. The anti-aggregation activity of the most potent GSK-3β inhibitor was tested using AD transgenic Caenorhabditis elegans (C. elegans) strain CL2006 for quantification of Aβ plaques and BR5706 C. elegans strain for tau pathology evaluation. We then evaluated the blood–brain barrier permeability and got promising results. Therefore, we present compound 44 as a potential ATP-competitive GSK-3β inhibitor with good metabolism and pharmacokinetic profile, anti-aggregation properties for amyloid beta protein, and reduction in tau-phosphorylation levels. We recommend more investigation into compound 44-based small molecules as possible targets for AD disease-modifying treatments.
期刊介绍:
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.