Date of Award

8-1-2012

Document Type

Campus Access Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Béla Török

Second Advisor

Marianna Török

Third Advisor

Michelle Foster

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive deterioration of memory and cognition. Several factors, such as the formation of amyloid-β (Aβ) deposits, oxidative stress and low level of the neurotransmitter acetylcholine (ACh) play major roles in the pathophysiology of the disease. The cholinergic hypothesis of AD suggests that dysfunction in learning and memory is due to the low levels of ACh in specific regions of the AD affected brain. The concentration of ACh can be increased by inhibiting the metabolic enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The goal of my work was to explore the fundamentals of multifunctional anti-Alzheimer’s compounds. We designed and synthesized novel molecules that can effectively inhibit the activity of the cholinesterases and at the same time interfere with other key processes that contribute to the development of Alzheimer’s disease, such as amyloid self-assembly and oxidative stress. We designed and tested about 120 compounds with several core structures, including β-carbolines, sulfonamides, chalcones, coumarines and hydrazones. These molecules were evaluated by standard in vitrobiochemical assays for their ability to inhibit cholinesterase enzymes and Aβ selfassembly, to disassemble preformed Aβ aggregates and to scavenge free radicals. The validation of the binding mechanism in AChE inhibition was carried out in silicousing molecular docking. Some of the tested compounds exhibited promising effects in the enzyme activity measurements and self-assembly studies and were also excellent free radicals scavengers. Therefore these molecules could be promising scaffolds for the further development of multifunctional therapeutics for Alzheimer's disease.

Comments

Free and open access to this Campus Access Thesis is made available to the UMass Boston community by ScholarWorks at UMass Boston. Those not on campus and those without a Healey Library (UMass Boston) barcode may gain access to this thesis through resources like Proquest Dissertations & Theses Global. If you have a Healey Library barcode and would like to download this work from off-campus, click on the "Off-Campus UMass Boston Users" link above.

Share

COinS