Design, Synthesis and Biological Evaluation of Novel Adamantane Derivatives as Potential Treatments for Alzheimer’s Disease

Alzheimer"s disease;Amyloid beta;Small molecules;Aggregation inhibitors

Shakeri, Arash

University of Waterloo

关键词: Alzheimer";    s disease;    Amyloid beta;    Small molecules;    Aggregation inhibitors;   

Others  :  https://uwspace.uwaterloo.ca/bitstream/10012/11312/1/Shakeri_Arash.pdf

瑞士|英语

来源: UWSPACE Waterloo Institutional Repository

【 摘 要 】

Alzheimer’s disease (AD) is a complex, multifactorial, and rapidly neurodegenerative disorder characterized by cognitive impairment and progressive dementia. Its pathology was first characterized by Alois Alzheimer as ;;a peculiar disease of cerebral cortex” in 1907. Amyloid beta, tau and cholinergic hypotheses are at the forefront of AD research. The currently available treatments that follow the traditional approach of ;;one target, one drug” are insufficient to treat AD and with the growing number of patients and an aging population developing novel derivatives as potential treatment for AD is critical. We believe that aminoadamantane derivatives can be used as suitable scaffold for developing treatments that can inhibit the aggregation of Aβ due to their favorable lipophilicity, safety profile and ease of chemical modifications. The goal of this project was to develop a library of novel aminoadamantane derivatives with suitable pharmacophores that exhibit Aβ aggregation inhibition properties. A total of 48 derivatives were synthesized and biologically evaluated in vitro for their potential Aβ anti-aggregation activity and structure-activity relationship (SAR) data was analyzed. The molecular docking studies of the lead candidates were investigated to gain insight into their mode of action. The most potent Aβ40 inhibitor was 2n(4-amino-N-(3,5-dimethyladamantan-1-yl)benzamide; (Aβ40 IC50 = 0.4 μM)), closely followed by 2l (N-(4-bromobenzyl)-3,5-dimethyladamantan-1-amine; (Aβ40 IC50 = 1.8 μM)) and 3m (N-(1-(adamantan-1-yl)ethyl)-3-aminobenzamide; (Aβ40 IC50 = 1.8 μM)). In conclusion, this project provides a new class of novel aminoadamantane derivatives as potential treatments for AD.