Structural optimization of donepezil-like hybrids toward an improved multi-target and ADME-related profile

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving mainly cholinergic dysfunction, protein misfolding, and metal dyshomeostasis. Considering the complexity of the pathology, multi-target approaches represent a valuable alternative to current approved mono-target treatments. In this study, starting from two previously identified lead compounds, fifteen new derivatives were designed. Various functional groups were introduced to evaluate their impact on cholinesterases (ChEs) and fatty-acid amide hydrolase (FAAH) and in some cases potent selective human acetylcholinesterase inhibition was observed (IC₅₀ up to 9 ± 1 nM for compound 1 and 3). Among the series, the amine-based derivatives (9 and 11) were further evaluated for Fe³⁺, Cu²⁺, and Zn²⁺ chelation ability, under a metal targeted strategy, showing high selectivity (pFe³⁺ = 16.1, pCu²⁺ = 11.0 and pZn²⁺ = 6.03 for compound 11) and a metal-binding pattern suitable for anti-AD activity. Additionally, these molecules exhibited noteworthy antioxidant properties (IC₅₀ = 17-45 μM for compounds 9-11), thus potentially beneficial in overcoming ROS overproduction typical of the disease. Finally, the whole series was subjected to an extensive in vitro ADME-related profiling, showing promising experimental ADME-related properties.