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.