Synthesis, Structure identification and Bioactivity Studies of Potential AChE Compound
Project no. 21421 · Status: Kapanmış · 2020
Summary
Alzheimer’s Disease is the most common type of demantia and it is a neurodegenerative disease that affects approximately 50 million people worldwide. Alzheimer's disease has a poor prognosis and results in death. It is frequenlty seen in the population over 65 years old and its symptoms are decreased cognitive function, memory loss and behavioral impairments. Multiple factors play role in the pathology of Alzheimer’s Disease. These include decreased cholinergic transmission, accumulation of ß-amyloid peptide in senile plaques as a result of proteins misfolding, abnormal phosphorilated tau proteins, oxidative stress, metal dishomeostasis, neuroinflammation, mitocondrial dysfunction and presense of ApoE4 gene. The drugs currently used in the treatment of Alzheimer’s Disease are acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. AChE inhibitors aim to improve cognitive and behavioral functions by increasing cholinergic transmission by inhibiting AChE enzyme. However, today, treatment is symptomatic and the progression of disease can not be stoped. AChE is not the only target. There are many factors such as inhibition of both catalytic active site and pheripheral anionic site of AChE, inhibiton of butyrylcholinesterase enzyme which is known to play a role in Alzheimer’s Disease, inhibition the accumulation of Aß and tau proteins. Dual-binding compounds that can interact with both CAS and PAS sites of AChE have been synthesized and a new approach has been developed in the treatment of Alzheimer’s Disease. In recent years, Multi Target Directed Ligands (MTDLs) strategy has been a new approach for the treatment of multi factorial disease such as Alzheimer’s Disease. The MTDLs strategy can be summarized as the combination of two active pharmacophore groups with a linker group, directing a single molecule to two distinct targets. In our thesis, synthesis and bioactivity studies of two tacrine- hydrazone derivative compounds were carried out. In our study tacrine was determined as a pharmacophore VIII group and it was aimed to combine pyridine derivatives with hydrazone group and aimed to synthesize potential AChE enzyme inhibitors. Synthesis studies consisted of 3 stages. In the first step, 9-chloro-1,2,3,4-tetrahydoacridine compound was synthesized and through this compound 9-hydrazino-1,2,3,4-tetrahydroacridine compound was synthesized. Then, as a result of condensation reactions of between 9- hydrazino-1,2,3,4-tetrahydroacridine compound and pyridine carbaldehyde derivatives, final compounds in the form of HCl salt were obtained. According to the bioactivity results it has been observed that the compounds that synthesized, have inhibitory activity against the AChE enzyme and BuChE enzyme. The tacrinhydrazone derivative compounds synthesized within the scope of the thesis are reported by us for the first time.