Piperine Derivatives as Modulators of Amyloid-Beta (Aβ) Aggregation

Alzheimer’s Disease (AD) is a life-changing neurodegenerative disease that progresses in stages and currently has no effective cure. More than 597,000 Canadians suffer from AD. Symptoms of late-stage AD are severe and include memory loss, apathy, depression, and psychosis, resulting in large burdens for caregivers and the economy. A major factor leading to AD is the aggregation of a protein known as amyloid-β (Aβ). However, most pharmacotherapies for AD provide only symptomatic relief and target other pathways. The recently approved monoclonal antibodies (mAbs) are the only disease-modifying therapies targeting Aβ peptide aggregation in AD that are available in the US. Limitations of mAb therapies include high-cost for patients, high manufacturing costs and resource-intensive parenteral administration. In this regard, the current study focused on the development of novel anti-amyloid small molecules based on piperine, derived from the black pepper plant, that was reported to enhance cognition. Advantages of small molecule AD therapeutics include being highly scalable and applicable to non-invasive routes of drug administration. A library of 13 piperine derivatives were designed, synthesized, and evaluated as potential inhibitors of Aβ42 aggregation. The experiments carried out include i) developing chemistry reaction conditions to synthesize the target compounds, ii) compound characterization by analytical chemistry, iii) determining their inhibition activity toward Aβ42 aggregation by fluorescence aggregation kinetics studies and transmission electron microscopy, iv) computational modeling studies in the Aβ42 model to understand the binding interactions of lead compounds and v) cell viability studies in mouse hippocampal HT22 cells. The structure activity relationship (SAR) studies led to the identification of three piperine derivatives 4a (R = pyrrolidine), 4b (R = thiomorpholine) and 4c (R = morpholine) as the lead compounds with inhibition ranging from 35-48 % (at 10 µM). The results were also confirmed by electron microscopy studies which demonstrated the ability of these compounds to reduce Aβ42 aggregation. Molecular docking studies in the Aβ42 pentamer model show that the terminal acyl substituents play a major role in stabilizing the Aβ42 pentamer assembly by interacting at the amyloidogenic interface consisting of the C- and N-terminal residues. This prevents further self-assembly and aggregation. Cell culture assays in HT22 mouse hippocampal cells showed that the lead compounds 4a, 4b and 4c were not toxic (cell viability >90 %, at 25 µM). This is the first study that reports the discovery of novel piperine based compounds as direct inhibitors of Aβ42 aggregation. Overall, the results obtained from this thesis provide valuable insights in the design, development, and application of novel small molecules to study and treat AD.

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