Rivastigmine structure-based hybrids as potential multi-target anti-Alzheimer’s drug candidates

In recent years, an increasing amount of work has been carried out regarding the study of the etiopathology of Alzheimer's Disease (AD). This neurodegenerative disease is characterized by several organic and molecular correlates, which paint a complex picture that also reflects the historic challenge faced by the worldwide scientific community in finding an effective cure for it. In this paper, we describe the synthesis of novel rivastigmine derivatives and their characterization as wide-spectrum enzyme (AChE, BChE, FAAH, MAO-A and MAO-B) inhibitors with potential application in the therapy of AD following the paradigm of multi-target design. 5 (ROS151) and 23 show similar inhibitory profile compared to donepezil on cholinesterases, and ca. two hundred twenty-three and eighty-seven times more active than rivastigmine on AChE. Moreover, ROS151 was found to be a potential metal chelator. Compounds 6 and 8 are very interesting and original multi-functional promising hybrids, with comparable potency on distinct panels of enzymes. All these promising rivastigmine-like hybrids were assayed for their pharmacokinetic properties by using different bio-analytical techniques, showing interesting applicability profiles. Moreover, cytotoxicity assays displayed a safety profile on three different cell lines.