|dc.description.abstract||Our brain is remarkably special and unique. It has billions of neurons that govern actions and reactions, and enables us to have thoughts, memories, and personality traits – outmost precious assets – that define who we are as individuals. What if we lose a certain part of the brain function? This is the case for the very first Alzheimer’s patient – August Deter, who suffered from memory loss and psychological changes, and eventually succumbed to the devastating disease, known as Alzheimer’s disease (AD). Indeed, it steals more than memory – it steals independence and breaks hearts. The two main culprits behind AD are the sticky amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) nestled in the brain, which have been the main target for many researchers to chase them with hope to remove them directly so that they could conquer this disease. And finally, the first-of-its-kind therapy aducanumab directed at the underlying disease process of Alzheimer’s just received its FDA approval, first new drug for AD in 17 years via the accelerated approval pathway, emphasizing the complexities in AD therapeutic design and concurrently suggesting that it requires more research and innovation.
As such, this thesis research presented here is to design and develop novel small molecules that can reduce and prevent the formation of two known Aβ peptides - Aβ40 and Aβ42 aggregation. A chemical library of ~47 derivatives, based on diphenylthiazolamine ring systems possessing a central thiazole-4-amine or thiazole-2-amines was designed, synthesized, and evaluated as inhibitors of both Aβ40 and Aβ42 aggregation. Specifically:
Chapter 1 guides the readers to the understanding of Alzheimer’s background information and literature with an overview of key hypotheses such as cholinergic dysfunction, amyloid-β cascade and tauopathy and their disease pathology and therapies.
Chapter 2 provides a summary on the utility of the thiazole based derivatives in pharmaceutical industry and links them to the rationale, design, and development of the thiazole library that is capable of preventing Aβ40 and Aβ42 aggregation and their SAR studies based on in vitro fluorescence spectroscopy experiments, computational modeling studies, transmission electron microscopy (TEM) studies and cell viability assay.
Chapter 3 describes the design, development and evaluation of N,4-diphenylthiazol-4-amines. This section reports a series with 12 derivatives (1a-j, 2a, 2b) incorporating various EDG and EWG substituents demonstrating their significant inhibition toward Aβ40 and Aβ42 aggregation in vitro and their activity was translated from the solution based in vitro experiments to cell culture studies in HT22 hippocampal neuronal cells, where they were able to reduce the Aβ40 or Aβ42 induced cytotoxicity.
Chapter 4 describes the design, development and evaluation of N-methyl-N,4-dimethylthiazol-4-amines. This section reports a series with 11 derivatives (3a-i, 4a, 4b) incorporating similar substituents as those in Chapter 3. The outcomes show that some compounds in the series were able to show their inhibition activity profile toward both Aβ40 and Aβ42 in vitro although N-methylation reduced their activity profile compared to the corresponding N,4-diphenylthiazol-4-amine. However, compounds in this series were able to translate their anti-Aβ aggregation properties from the solution based in vitro experiments to cell culture studies in HT22 cells to reduce both Aβ40 and Aβ42 cytotoxicity.
Chapter 5 describes the design, development and evaluation of alkylsulfonamide and sulfamide substituted N,4-diphenylthiazol-2-amines. This section reports a series of ten alkysulfonamide or sulfamide containing derivatives (5a-j), which was developed to assess their anti-Aβ40 and Aβ42 aggregation potential. The results demonstrated that they exhibited superior inhibition of Aβ40 aggregation compared to the N,4-diphenylthiazol-2-amine and N-methyl derivatives in Chapter 3 and 4. Several compounds in this series demonstrated neuroprotective effects against both Aβ40 and Aβ42-induced cytotoxicity in HT22 hippocampal cells.
Chapter 6 describes the design, development and evaluation of alkylsulfonamide and sulfamide substituted N-methyl-N-4,diphenylthiazol-2-amine derivatives. This was a series of ten derivatives (6a-j). The N-methylation was not a major factor in modulating their Aβ aggregation inhibition properties. Compounds in this series were able to exhibit excellent inhibition of Aβ40 and Aβ42-induced cytotoxicity in HT22 hippocampal neuronal cells.
Chapter 7 describes the design, development and evaluation of a mini library of four from N,2-diphenylthiazol-4-amine derivatives (7a-d), which are the regioisomers of N,4-diphenylthiazol-2-amine derivatives described in Chapter 3. The biochemical assay outcomes demonstrated their anti-aggregation properties toward Aβ40 and Aβ42, in addition to their ability to rescue HT22 cells from Aβ40 and Aβ42-induced cytotoxicity, which further supports their development as novel class of agents to target the amyloid cascade in AD therapy.
Chapter 8 provides closing conclusions on the research findings related to the development of diphenylthiazolamines as a novel class of small molecules, which have the potential to reduce and or prevent the amyloid cascade of AD by, direct binding and outlines the next research directions.||en