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 P-3 position, Leu at P-1' position, Ala at P-2' position, and Phe at P-3' 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. (C) 2015 Published by Elsevier Ltd.