Multi-Targeting Derivatives For Alzheimer’s Disease: Utilization of Quinazoline Ring Scaffolds

by Tarek Mohamed

Institution: University of Waterloo
Year: 2016
Keywords: Alzheimer's disease; Medicinal chemistry; Amyloid; Cholinesterase; Dementia; Drug Design; Quinazoline; Computational Chemistry; Biochemistry; Structure-Activity Relationship
Posted: 02/05/2017
Record ID: 2104529
Full text PDF: http://hdl.handle.net/10012/10721


The complex and multifaceted nature of Alzheimer’s pathology has significantly hindered the discovery and development of viable therapeutics, let alone the cause and initiation of the disease. Over the past century, what was known as the ‘one drug, one target’ approach has only recently shifted to the multifunctional ideology. By investing, discovering and developing therapeutic options with multi-targeting capabilities, not only would patient outcomes improve, but the road to multi-targeting therapeutics can help shed new light on Alzheimer’s disease (AD) pathogenesis. In order to undertake the multifunctional ideology, viable and interconnecting targets need to be identified. As such, the work presented herein employed computer-aided drug design (CADD) to develop bicyclic small-molecules against three key targets of AD pathology – the cholinesterases (AChE and BuChE), amyloid-β (Aβ) aggregation and reactive oxygen species (ROS) generation. A chemical library of ~ 140 derivatives, based on a quinazoline (Qnz) or a pyridopyrimidine (Ppd) ring scaffold, was generated to gather structure-activity relationship (SAR) data in the target-specific assays with the goal of identifying lead multi-targeting candidates for future optimization and pre-clinical assessment. Specifically: Chapter one provides the background information and literature survey with respect to the statistics of AD, the current hypotheses with a keen focus on cholinergic dysfunction and amyloid toxicity, and an overview of the interconnectivity observed with each of the hypotheses put forth in relation to disease pathology and progression. Chapter two surveys the utility of the quinazoline and pyridopyrimidine scaffolds in medicinal chemistry and ties that with previously utilized templates and those found in marketed therapies to develop a AD-specific hypothesis bearing a multi-targeting focus. From that survey and hypothesis, a chemical design and development plan was generated to yield the sought-after chemical derivatives. Chapter three is dedicated to the design, development and evaluation of the first series of compounds, which were based on a Qnz-scaffold and featured a dimethoxybenzylamine group at the C4-position (2-substituted-N-(3,4-dimethoxybenzyl)-quinazolin-4-amines). This series contained 13 derivatives with varying functional groups at the C2-position. The general observations from this collection revealed the lack of inhibitory activity toward BuChE and Aβ42, while AChE and Aβ40 targeting were considered moderate. The most active AChEI and ROS scavenger across the research program was discovered within this series. This chapter also included the bulk of synthetic and biochemical assessment protocols/methodologies. Chapter four describes the design, development and evaluation of 2-substituted-N-benzylquinazolin-4-amines. This was primarily a measure of the 3,4-dimethoxy moiety’s validity in dual-ChE targeting and anti-amyloid aggregation potential. This series also contained 12 derivatives with varying functional groups…