Design and Synthesis of Ranitidine Analogs as Multi-Target Directed Ligands for the Treatment of Alzheimer’s Disease

Abstract

The aggregation of amyloid β (Aβ) peptides and deposition of amyloid plaques are implicated in the pathogenesis of Alzheimer’s disease (AD). Therefore, blocking Aβ 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 Aβ aggregation were evaluated using in vitro thioflavin T assays. The structure–activity relationship revealed that the 1,8-naphthalimide moiety provided profound inhibition of Aβ 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 Aβ 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.

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

“…Recent studies have shown that BACE1 has a copper-binding site in its cytoplasmic domain and that BACE1 interacts with copper clad steel (CCS), which is an important protein that transports copper to SOD1 for activation. Because BACE1 competes with SOD1 for interaction with CCS, the up-regulation of BACE1 results in decreased SOD1 activity in cells [63,64]. Our results showed that copper up-regulated BACE1 in N2a-sw cells, and the addition of PCu significantly inhibited Cu 2+ -induced BACE1 expression and Aβ secretion.…”