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  3. Discovery of novel quinolin-2-one derivatives as potential GSK-3β inhibitors for treatment of Alzheimer's disease: Pharmacophore-based design, preliminary SAR, in vitro and in vivo biological evaluation

Discovery of novel quinolin-2-one derivatives as potential GSK-3β inhibitors for treatment of Alzheimer's disease: Pharmacophore-based design, preliminary SAR, in vitro and in vivo biological evaluation

  • Bioorg Chem. 2024 May:146:107324. doi: 10.1016/j.bioorg.2024.107324.
Esraa Abdo Moustafa 1,  Heba Abdelrasheed Allam 2,  Marwa A Fouad 3,  Ahmed M El Kerdawy 4,  Nahed Nasser Eid El-Sayed 1,  Christoph Wagner 5,  Hatem A Abdel-Aziz 6,  Manal Abdel Fattah Ezzat 7
Affiliations

Affiliations

  • 1 Egyptian Drug Authority (EDA), 51 Wezaret El-Zeraa St., Giza 35521, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt; Pharmaceutical Chemistry Department, School of Pharmacy, Newgiza University, Newgiza, km 22 Cairo- Alexandria Desert Road, Cairo, Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt; School of Pharmacy, College of Health and Science, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, United Kingdom.
  • 5 Institut für Chemie, Naturwissenschaftliche FakultätII, Universität Halle, Kurt-Mothes-Str. 206120, Halle, Germany.
  • 6 Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, 11562 Cairo, Egypt. Electronic address: Manal.salem@pharma.cu.edu.eg.
PMID: 38569322 DOI: 10.1016/j.bioorg.2024.107324
Abstract

Recently, glycogen synthase kinase-3β (GSK-3β) has been considered as a critical factor implicated in Alzheimer's disease (AD). In a previous work, a 3D pharmacophore model for GSK-3β inhibitors was created and the results suggested that derivative ZINC67773573, VIII, may provide a promising lead for developing novel GSK-3β inhibitors for the AD's treatment. Consequently, in this work, novel series of quinolin-2-one derivatives were synthesized and assessed for their GSK-3β inhibitory properties. In vitro screening identified three compounds: 7c, 7e and 7f as promising GSK-3β inhibitors. Compounds 7c, 7e and 7f were found to exhibit superior inhibitory effect on GSK-3β with IC50 value ranges between 4.68 ± 0.59 to 8.27 ± 0.60 nM compared to that of staurosporine (IC50 = 6.12 ± 0.74 nM). Considerably, compounds 7c, 7e and 7f effectively lowered tau hyperphosphorylated aggregates and proving their safety towards the SH-SY5Y and THLE2 normal cell lines. The most promising compound 7c alleviated cognitive impairments in the scopolamine-induced model in mice. Compound 7c's activity profile, while not highly selective, may provide a starting point and valuable insights into the design of multi-target inhibitors. According to the ADME prediction results, compounds 7c, 7e and 7f followed Lipinski's rule of five and could almost permeate through the BBB. Molecular docking simulations showed that these compounds are well accommodated in the ATP binding site interacting by its quinoline-2-one ring through hydrogen bonding with the key Amino acids Asp133 and Val135 at the hinge region. The findings of this study suggested that these new compounds may have potential as anti-AD drugs targeting GSK-3β.

Keywords

Alzheimer’s disease; Glycogen synthase kinase inhibitor; Quinolin-2-one; Tau hyperphosphorylation, ADME.

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