2. Academic Validation
  3. Design, synthesis, and biological evaluation of tetrahydropyrimidine analogue as GSK-3β/Aβ aggregation inhibitor and anti-Alzheimer's agent

Design, synthesis, and biological evaluation of tetrahydropyrimidine analogue as GSK-3β/Aβ aggregation inhibitor and anti-Alzheimer's agent

  • Bioorg Chem. 2024 Sep 7:153:107811. doi: 10.1016/j.bioorg.2024.107811.
Sukanya Sukanya 1,  Aina Bellver-Sanchis 2,  Bhanwar Singh Choudhary 1,  Sunil Kumar 1,  Belén Pérez 3,  Antón Leandro Martínez Rodríguez 4,  Jose Brea 5,  Christian Griñán-Ferré 6,  Ruchi Malik 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, Central University of Rajasthan, Bandarsindari, Ajmer, Rajasthan 305817, India.
  • 2 Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry. Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
  • 3 Department of Pharmacology, Therapeutics and Toxicology, Institute of Neuroscience, Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain.
  • 4 Innopharma screening platform, Biofarma research group. Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • 5 Innopharma screening platform, Biofarma research group. Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela (SERGAS), Trav. Choupana s/n, 15706 Santiago de Compostela, Spain.
  • 6 Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry. Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Institute of Health Carlos III, Madrid, Spain.
  • 7 Department of Pharmacy, Central University of Rajasthan, Bandarsindari, Ajmer, Rajasthan 305817, India. Electronic address: ruchimalik1976@curaj.ac.in.
PMID: 39270527 DOI: 10.1016/j.bioorg.2024.107811
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.

Keywords

ATP-competition; Alzheimer’s Disease; Aβ aggregation; BBB permeation; GSK-3β; Tau phosphorylation.

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