Multi-Targeting Derivatives For Alzheimer’s Disease: Utilization of Quinazoline Ring Scaffolds
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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 at the C2-position as well as one regioisomer. The general observations from this collection revealed on par activities toward AChE inhibition with slight improvements toward BuChE inhibition for some derivatives. In addition, the overall Aβ40/42 inhibitory profiles were also improved, although the ROS scavenging derivative was not as potent compared to its dimethoxy counterpart. That said, the first nanomolar Aβ40 inhibitor was identified within this series so was the first low-mid micromolar Aβ42 aggregation inhibitor. Chapter five describes the design, development and evaluation of 2-substituted-N-(3,4-dimethoxyphenethyl)-quinazolin-4-amines. This was primarily a measure of the additional methylene group’s validity in dual-ChE targeting and anti-amyloid aggregation potential. This was a larger series with 12 derivatives carrying the same functional groups at the C2-position as those in Chapters 3 and 4, a regioisomer and an additional 12 derivatives. These additional derivatives explored the addition of a chlorine atom on the Qnz-scaffold at three positions (C6-, C7-, or C8-) with the top 4 C2-groups to expand the SAR data. With respect to Chapter 3 counterparts, the general observations from this collection revealed on par activities toward AChE inhibition with slight improvements toward BuChE inhibition for some derivatives. Mixed outcomes were observed with respect to Aβ40/42 targeting capacities, while the weakest ROS scavenger was identified within this series of derivatives. More so, the outcomes of the chloroquinazoline counterparts were not as promising as anticipated with respect to dual ChE and dual Aβ40/42 targeting, although some exceptions do apply. Interestingly, this series revealed some of the first potent and dual, non-selective Aβ aggregation inhibitors, along with the selectivity toward Aβ42 with 8-chloro-based quinazoline derivatives. Chapter six describes the design, development and evaluation of 2-substituted-N-phenethylquinazolin-4-amines. This elicited a dual measure of the validity of the 3,4-dimethoxy moiety as well as the additional methylene linker in dual-ChE targeting and anti-amyloid aggregation potential with respect to the counterparts in Chapters 4 and 5. This series included the original 12 functional groups at the C2-position, two regioisomers and the additional 12 chloroquinazoline-based derivatives. With respect to Chapter 4 and 5 counterparts, the general observations from this collection revealed on par activities toward AChE inhibition with significant improvements toward BuChE inhibition for some derivatives. Mixed outcomes were observed with respect to Aβ40/42 targeting capacities, while the ROS scavenger within this series was more potent compared to its counterparts in Chapters 4 and 5. More so, the outcomes of the chloroquinazoline counterparts were more promising with respect to dual ChE and dual Aβ40/42 targeting, when compared to those in Chapter 5. Besides revealing some potent and dual, non-selective Aβ aggregation inhibitors, the most potent BuChEI was identified within this series. Chapter seven describes the design, development and evaluation of 2,4-disubstituted pyridopyrimidines as rational counterparts to leading derivatives from Chapters 5 and 6. This series included 10 derivatives and was developed to assess iron chelation potential and assess Qnz vs. Ppd. SAR data. The derivatives here did not impart significant improvements toward AChE, but as expected, were inactive toward BuChE. Activity toward Aβ40 was of mixed outcomes, while improvements toward Aβ42 inhibition were observed. Lastly, chelation capacity was considered weak to moderate at best. Chapter eight describes the design, development and evaluation of monosubstituted quinazoline-2,4-diamines to further investigate the regioisomeric impact on Aβ40/42 targeting as an expansion on two isomeric pairs from Chapters 4 and 6. This series discussed 30 isomeric derivatives (15 C2-amino, and 15 C4-amino) in comparison to the previously disclosed isomers. The general observations from this collection revealed that C2-amino-based isomers were more effective at targeting Aβ40 (compared to their C4-amino isomers), while the opposite was true with respect to Aβ42. The most potent Aβ40 aggregation inhibitor across the collective library was identified within this Chapter. Chapter nine provides closing conclusions and a future works/outlook plan.