title: Design, synthesis and biological evaluation of tasiamide B derivatives as BACE1 inhibitors.
abstract: 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.
authors.affiliation: School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, China.
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.affiliation: The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, China.
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Sumei
authors.initials: S
authors.lastname: Ren
authors.affiliation: School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: zhangw416@fudan.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Li
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; C480062:tasiamide B; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; BACE1 inhibitor; Docking; Synthesis; β-Secretase