Raghuvanshi_2025_Bioorg.Chem_167_109232

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder that demands therapeutic approaches targeting multiple pathological pathways. Among these, the cholinergic deficit, amyloid-beta (Abeta) aggregation, and tau hyperphosphorylation are recognized as key contributors to disease progression. This study aimed to develop multitarget-directed ligands (MTDLs) by rationally modifying the potent but poorly soluble glycogen synthase kinase 3beta (GSK-3beta) inhibitor, kenpaullone 17b, to simultaneously inhibit cholinesterases (ChEs) and GSK-3beta while improving physicochemical properties. Initial substitution of the C9-bromo group in 17b with a sulfonamide moiety produced compound 17m, which retained strong GSK-3beta inhibition (IC50 = 0.35 microM) and acquired modest acetylcholinesterase (AChE) inhibitory activity (IC50 = 20 microM). Further elongation of the C9 substituent with a cyclohexylaminopropyl chain yielded compound 18o, exhibiting balanced dual inhibition of AChE (IC50 = 1.7 microM), butyrylcholinesterase (BChE) (IC50 = 5.3 microM), and GSK-3beta (IC50 = 5.7 microM). Compound 18o also inhibited Abeta(1-42) self-aggregation by 21 % at 10 microM and demonstrated blood-brain barrier (BBB) permeability with a 100-fold improvement in aqueous solubility compared with 17b. Molecular docking and molecular dynamics simulations revealed stable dual binding conformations within the AChE and GSK-3beta active sites, supported by key hydrogen bonds and hydrophobic interactions. Overall, the structurally flexible analog 18o represents a promising dual ChE/GSK-3beta inhibitor with improved drug-like characteristics, warranting further preclinical evaluation as a potential therapeutic lead for AD.