Synthesis and evaluation of novel multi-target compounds for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, and a major cause of death worldwide. The prevalence of this debilitating disorder is rising exponentially, and there is an urgent unmet need for a cure. AD is a complex, multifactorial disease and therefore the multi-target strategy is considered to be a promising approach to drug development for this disease. The aim of this work was to design and synthesise novel hybrid compounds with the potential to be applied as multi-target therapeutics for AD. To achieve this aim, derivatives combining an antioxidant group with an aromatic system, which could act as a cholinesterase inhibitor or prevent the aggregation of toxic proteins, were developed and fully characterised. The multi-target activity of these novel compounds was evaluated in vitro, and select compounds demonstrated potent antioxidant and anti-cholinesterase activities and low levels of iron chelation. The compounds also exhibited low toxicity in a neuroblastoma cell line. Using molecular modelling simulations, the binding affinity of the novel compounds for several major targets of AD was determined and the potential of these compounds to cross the blood brain barrier was predicted. The in si/ico calculations were used to elucidate the in vitro inhibitory activity of the compounds, and the majority of the compounds were predicted to pass into the brain. Based on the in vitro results, principal component analysis was performed to aid in the selection of lead compounds which were then tested for their cell protective effects. The compounds demonstrated moderate protective effects against three cytotoxic stressors (A~2s-3s, juglone, and rotenone). Select compounds which had the strongest protective effects in cells were then tested for their in vitro activities against other targets of AD. Furthermore, the mechanism of their cell protective effects was investigated along with the multi-target activity in cell-based assays. The lead compounds demonstrated potent anti-aggregation activity against amyloid and tau in vitro, as well as strong inhibition of BACE-1 and moderate inhibition of MAO-B. In cell-based models, the compounds reduced oxidative stress and lipid peroxidation and could act as anti-apoptotic and anti-inflammatory agents. The novel compounds could reduce the activity of acetylcholinesterase in a cellular model, and prevent the extracellular aggregation of amyloid. Subsequently, the protective effects of the novel compounds in an in vivo model were studied. C. elegans was employed as an animal model due to the low costs, simplicity, and capacity to be used as a model of AD. The compounds protected against the toxic effects of amyloid and tau accumulation in C. e/egans models of AD and tauopathy. Furthermore, the compounds increased resistance to oxidative stress and select compounds were found to reduce lipid peroxidation in vivo. Overall, the novel compounds synthesised in this work demonstrate potential as multi-target therapeutics for AD and the findings of this project provide a strong basis for the continuation of preclinical studies.

Author dc:creator

• Blaikie, Laura Margaret

Advisor dc:contributor.advisor

• P. Kong Thoo Lin, G. Kay and P. Maciel

• Alzheimer's disease
• Multi-target
• Vanillin
• Phthalimide
• Molecular modelling
• Oxidative stress
• Lipid inflammation
• Apoptosis

Language dc:language

en

Identifier

oai:rgu-repository.worktribe.com:3027109
https://doi.org/10.48526/rgu-wt-3027109

Author Identifier

0000-0002-7980-8023

OAI identifier oai:identifier

oai:rgu-repository.worktribe.com:3027109