Design, synthesis and biological evaluation of tasiamide B derivatives as BACE1 inhibitors.

Nineteen new derivatives based on the structure of marine natural product tasiamide B were designed, synthesized, and evaluated for their inhibitory activity against BACE1, a potential therapeutic target for Alzheimer’s disease. The hydrophobic substituents Val at P3 position, Leu at P1′ position, Ala at P2′ position, and Phe at P3′ position were found to significantly affect the inhibition. Free carboxylic acid at C-terminus was also found to be important to the activity. In addition, the structure–activity relationships (SARs) were supported by molecular docking simulation.