Waly_2025_Arch.Pharm.(Weinheim)_358_e70025

Multitargeted directed ligands (MTDLs) represent an appealing tactic to treat Alzheimer's disease (AD) as a multifactorial neurodegenerative disorder. In this study, the pyrazolopyridine scaffold was used to design three different series of integrated MTDLs that could inhibit the main causes of AD. They possess common structure features essential for such a goal. The planar pyrazolopyridine core allows binding with the catalytically active site of cholinesterase enzymes and intercalating between the residues of Abeta and tau protein. In addition, the planar ring is attached to different linkers and hydrophobic side chains to prop interaction with the peripheral anionic site of AChE, preventing Abeta(1-42) aggregation. They also provide tools for binding with hGSK3beta hydrophobic tails responsible for tau hyperphosphorylation and NFTs formation. Moreover, basic nitrogen atoms are also present, which chelate biometals, hindering their oxidative damage to the brain. Compounds 15 and 23 fulfilled all the mentioned anticipated activities. Furthermore, compound 31, which is the possible metabolite of the ethyl ester 23, appeared as MTDL, proving that compound 23 would have a long duration of action. Finally, compounds 15 and 23 exhibited a wide safety range upon WI-38 cell line, obeyed Lipinski's rule of five, and could virtually penetrate the blood-brain barrier.