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

• Published in: Bioorganic chemistry Vol. 146; p. 107324
• Main Authors: Abdo Moustafa, Esraa, Abdelrasheed Allam, Heba, Fouad, Marwa A., El Kerdawy, Ahmed M., Nasser Eid El-Sayed, Nahed, Wagner, Christoph, Abdel-Aziz, Hatem A., Abdel Fattah Ezzat, Manal
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2024
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Animals; Glycogen Synthase Kinase 3 beta - metabolism; Glycogen synthase kinase inhibitor; Humans; Mice; Molecular Docking Simulation; Neuroblastoma; Pharmacophore; Phosphorylation; Quinolin-2-one; Tau hyperphosphorylation, ADME; tau Proteins - metabolism; Glycogen synthase kinase inhibitor; Quinolin-2-one; Alzheimer’s disease; Tau hyperphosphorylation, ADME
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107324

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•New quinolin-2-one derivatives were synthesized as potential anti-Alzheimer's agents.•Compounds 7c, 7e and 7f had the highest GSK-3β inhibitory activity.•Compounds 7c, 7e and 7f effectively reduced tau hyperphosphorylated aggregates in the HTRF tau aggregation assay.•Compounds 7c, 7e and 7f showed low cytotoxicity against human neuroblastoma (SH-SY5Y) and normal human hepatic (THLE2) cell lines.•In silico studies of the most active compounds at GSK-3β active were done.
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.