Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer’s Disease

Alzheimer’s disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle key pathogenetic mechanisms disease. In this study, two novel series melatonin- and donepezil-based hybrid molecules with hydrazone (3a–r) or sulfonyl (5a–l) fragments were designed, synthesized, evaluated as multifunctional ligands against AD-related mechanisms. Two lead compounds (3c 3d) exhibited well-balanced profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, FRAP methods, well inhibition lipid peroxidation in linoleic acid system. Compound 3n, possessing indole scaffolds, showed highest butyrylcholinesterase (BChE) high selectivity index (SI = 47.34), pronounced protective effect H2O2-induced oxidative stress SH-SY5Y cells. Moreover, 3c, 3d, 3n low neurotoxicity malignant neuroblastoma cell lines human (SH-SY5Y) murine (Neuro-2a) origin, normal fibroblast cells (CCL-1) that indicate vitro biocompatibility experimental compounds. Furthermore, capable penetrating blood–brain barrier (BBB) PAMPA-BBB study. The molecular docking compound 3c could act ligand both MT1 MT2 receptors, AchE BchE enzymes. Taken together, those results outline prototypes search innovative for treatment AD-associated neurodegeneration stress. This study demonstrates derivatives melatonin donepezil are appropriate further new AChE/BChE inhibitory agents.