Bioactive Prenylated Phenyl Derivatives Derived From Marine Natural Products: Novel Scaffolds For The Design Of Bace Inhibitors

Abnormal accumulation of neurotoxic beta-amyloid peptides (Ab) is a key factor in the development of Alzheimer's disease (AD) and strategies to reduce Ab production constitute an active field of research for the development of novel therapeutic agents for the treatment of AD. In particular, beta-secretase-1 (BACE-1) has been a prime target for modulating Ab production although obtaining drug-like BACE-1 inhibitors has proven to be highly challenging. Here we report the isolation and biochemical characterization of a marine natural product, the prenylated hydroxybenzoic acid 1, with BACE-1 inhibitory activity and ability to decrease Ab production in cell-based assays. Synthesis and biological activity of a number of new synthetic analogues are also reported, as well as initial structure-activity relationship (SAR) analysis on this chemical family. Hence, these compounds constitute novel scaffolds from which more potent and selective BACE-1 inhibitors could be designed as potential therapeutic agents for the treatment of Alzheimer's disease.