Gao_2021_Int.J.Mol.Sci_22_

The aggregation of amyloid beta (Abeta) peptides and deposition of amyloid plaques are implicated in the pathogenesis of Alzheimer's disease (AD). Therefore, blocking Abeta aggregation with small molecules has been proposed as one therapeutic approach for AD. In the present study, a series of ranitidine analogs containing cyclic imide isosteres were synthesized and their inhibitory activities toward Abeta aggregation were evaluated using in vitro thioflavin T assays. The structure-activity relationship revealed that the 1,8-naphthalimide moiety provided profound inhibition of Abeta aggregation and structural modifications on the other parts of the parent molecule (compound 6) maintained similar efficacy. Some of these ranitidine analogs also possessed potent inhibitory activities of acetylcholinesterase (AChE), which is another therapeutic target in AD. These ranitidine analogs, by addressing both Abeta aggregation and AChE, offer insight into the key chemical features of a new type of multi-target directed ligands for the pharmaceutical treatment of AD.