Design, Synthesis, and Evaluation of Tacrine-Based Derivatives: Potential Agents to Treat Alzheimer’s Disease
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With the incidence of Alzheimer’s disease (AD) growing worldwide and in Canada along with the growing economic and social burdens, the need for more effective therapies becomes of great importance. Since the discovery of AD, a number of proposed theories have arisen to explain the pathophysiology including the i) cholinergic theory, ii) oxidative stress pathways, and iii) metal ion imbalance. The major class of drug therapies to treat AD are cholinesterase inhibitors; however, the “one drug, one target” approach has not proven fruitful and generally becomes ineffective in later stages of disease progression. In this project, we synthesized a library of 1,2,3,4-tetrahydroacridine derivatives (10a-d, 11a-e, 12a-e, and 13a-f) as potential agents to target the cholinergic and oxidative stress pathways of AD. Chapter I provides background information on the role of AChE and BuChE enzymes in AD. Furthermore, this chapter describes the neurotoxicity of reactive oxygen species (ROS) and metals in AD. Chapter II provides a summary of project hypothesis and rationale. Chapter III describes the synthetic details regarding the synthesis of target small molecules. It further describes the principles involved in carrying out biological evaluation such as AChE and BuChE inhibition, antioxidant properties via DPPH stable radical scavenging, iron chelation capacity using ferrozine and in vitro cell viability data in neuroblastoma cells. Chapter IV describes the SAR details on ChE inhibition, antioxidant activities, iron chelation and cell viability profiles and molecular modeling details. A brief conclusion and future directions are included in Chapter V and the final section, Chapter VI provides experimental details for synthetic chemistry including analytical data of synthesized compounds and protocols for biological evaluations. This study identified novel tetrahydroacridine derivatives with nanomolar inhibition of both human AChE and human BuChE enzymes that were more potent relative to the reference agent tacrine. Compound 10d[N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified as a potent inhibitor of BuChE (IC50 = 24.0 nM) and compound 13c [6-chloro-N-(pyridine- 2-ylmethyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified as a potent inhibitor of AChE (IC50 = 95.0 nM) with good inhibition of BuChE (IC50 = 1.61 μM) whereas compound 11e [6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified with an optimum combination of dual AChE and BuChE inhibition (AChE IC50 = 0.9 μM; BuChE IC50= 1.4 μM). In conclusion, our studies provide new insight into the design and development of novel tetrahydroacridine derivatives to target multiple pathological routes of AD.