Discovery of 6-amino pyridine clubbed heterocycles as potent dual GSK-3β/CK-1δ inhibitors for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive and chronic neurodegenerative disorder progression through various kinases. Glycogen synthase kinase 3β (GSK-3β) and Casein Kinase-1δ (CK-1δ) have gained a lot of attention for its role in tau pathology. Utilizing a multitarget strategy, a series of 6-amino pyridine derivatives were developed as promising dual GSK-3β/CK-1δ inhibitors for the treatment of AD. This study involved the design, synthesis, and evaluation of novel 6-amino pyridine derivatives as dual GSK-3β/CK-1δ inhibitors exhibiting excellent biological activities. The in-vitro results indicated that most of compounds displayed promising activity against GSK-3β/CK-1δ. Among the tested compounds, 8d exhibited strong inhibitory activity against GSK-3β and CK-1δ, with IC₅₀ values of 0.77 ± 0.01 μM and 0.57 ± 0.12 μM, respectively. Notably, compound 8d significantly reduced tau hyperphosphorylated aggregates while demonstrating safety in SH-SY5Y neuroblastoma cell lines. ADME prediction results indicated that compound 8d adhered to Lipinski's rule of five and exhibited potential to permeate the blood-brain barrier (BBB). Molecular docking analysis revealed that this compound fits well within the ATP binding site, forming hydrogen bonds between its 6-amino pyridine ring with key Amino acids, including Asp133 and Val135 in the hinge region of GSK-3β, as well as Leu85 of CK-1δ. These findings indicate that 6-amino pyridine derivatives have the potential to be effective dual-target candidates for AD.

Alzheimer's disease; CK-1δ; Dual inhibitors; GSK-3β; Heterocycles; Kinase inhibitors.