Symbiotic approach applied to the synthesis of new agents for the treatment of Alzheimer’s disease

Alzheimer disease (AD) is a progressive age-dependent neurodegenerative pathology. The number of people with AD is steadily increasing and has a severe impact on individuals, families, and society. Although the etiology of AD is not yet completely explored, it is now commonly established that it is a multifactorial neurodegenerative pathology. Nowadays, many agents have been synthesized for the treatment of memory and cognition impairments able to interact with different targets. Unfortunately, AD therapy still lack in effectiveness therefore, the search for new potential drugs is heavily pursued. Consistently, the search for new multitarget agents has led us to design and synthesize a series of tacrine–hydroxycinnamic acid (caffeic or ferulic acid) hybrids that showed acetylcholinesterase (AChE) inhibitory activity and antioxidants properties1 . Recently, with the aim of increasing the affinity for the butyrylcholinesterase (BuChE) we reported the synthesis and in vitro activities of novel rivastigmine-hydroxycinnamic acid hybrids as inhibitors of AChE and BuChE, ROS scavengers and inhibitors of Aβ aggregation 2.. In order to expand the SAR study for this new class of compounds, herein we describe the design and synthesis of analogs 1-6 obtained by the symbiotic combination of rivastigmine skeleton with natural antioxidant agents such as gallic acid and 2-chromonecarboxylic acid. The new ligands were evaluated in different systems for neuroprotective, antioxidant, ChE inhibitory and inhibitory of Aβ aggregation properties.