Evaluation of the effects of halogens on the anti-cholinesterase activity of potent multi-targeted hybrids designed for the treatment of Alzheimer's disease

Alzheimer’s disease (AD) is a chronic-progressive neurodegenerative disorder and constitutes a significant socioeconomic burden on public healthcare systems and caregivers. This is the most common form of age-related dementia: according to predictive estimates the number of affected individuals may triple by 2050. AD has multiple causative factors, and several hypotheses support its classification as a multifactorial condition. Currently, all AD treatments, most of which exhibit anticholinesterase activity, merely alleviate AD symptoms, slowing disease progression without substantially altering its course. Recent studies have focused on the identification of hybrid compounds obtained fusing the chemical structure of different aryloxyacetic acids with donepezil and rivastigmine. Notably, some of these compounds exhibited potential multitarget activity, suggesting additional effects on other pathogenic mechanisms implicated in AD. The present work reports an analysis of the role of nitro and halogen substituents and their respective positions within the molecule, with the aim of optimising anticholinesterase activity.