Date of Award

5-31-2018

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry/Biological Chemistry

First Advisor

Marianna Török

Second Advisor

Bela Török

Third Advisor

Daniel Dowling

Abstract

Complex diseases such as Alzheimer’s disease (AD), diabetes and cancer are difficult to manage with single target treatment approaches and unfortunately, they are wide-spread. For example, over 16 million people are expected to have AD in the US by 2050, thus new therapeutic approaches have to be developed. Multi-functional drug candidates have gained increasing popularity in treating complex diseases. The impact of oxidative stress in almost every disease progression makes them essential components in therapies for complex diseases. Endogenous systems typically maintain redox homeostasis within the cell, but in the diseased state these systems fail to alleviate oxidative stress. Supplementation with exogenous antioxidants can boost the endogenous systems and maintain redox homeostasis. Therefore, the development of multi-functional drug candidates should also include investigations of the radical scavenging activity of the compounds screened.

The radical scavenging activity and multi-target profiles of 61 small molecules were assessed by three different radical scavenging activity assays. These compounds were selected or designed by taking into account the presence of structural motifs common to currently used therapeutic compounds. The drug candidates were screened for amyloid β (Aβ) oligomer and fibril formation as well as cholinesterase inhibition. In addition, this work aims to address the structure-activity relationship (SAR) between experimental radical scavenging effect and the structural characteristics of the compounds studied. In a continuation of this idea, phenol and aniline model compounds were investigated to identify important physicochemical properties such as the bond dissociation energy (BDE) and ionization potential (IP).

The work completed here highlights several compounds with multi-functional activity for further development. The SAR studies have identified important structural motifs responsible and necessary for therapeutic function. These results can be applied to future compound design and further support the multi-functional drug development process.

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