The Study Of Double Target Anti-AD Agents Based On Click Chemistry And The Synthesis Of A New Hexadentate ⁶⁸Ga³⁺ Chelator

Coumarin derivatives had been extensively studied in recent years because of their strong monoamine oxidase-B（MAO-B）inhibitory activity,and MAO-B was an important target for the treatment of Alzheimer’s disease（AD）.Based on the pathogenesis of AD disease and the structure-activity relationship of coumarin monoamine oxidase inhibitors,and with the help of click chemistry,novel coumarin-HPOs hybrids linked by 1,2,3-triazole moiety were designed and synthesized rapidly as multi-target agents for the treatment of Alzheimer’s disease.The MAO-B inhibitory activity and pKa were determined by fluorescence probe and spectrophotometry respectively.In addition,a new class of ⁶⁸Ga³⁺ chelator was also designed and synthesized.This thesis was divided into three chapters.The first chapter gave a brief introduction of the Alzheimer’s disease and its pathogenesis,outlined the study of anti-Alzheimer’s drugs,the progress of the research on coumarin monoamine oxidase B inhibitors and the application of click chemistry in the construction of bioactivity coumarin molecules.In the second chapter,novel coumarin-HPOs hybrids Linked by 1,2,3-triazole moiety were designed and synthesized rapidly as multi-target agents for the treatment of Alzheimer’s disease.The MAO-B inhibitory activity was predicted by the molecular docking method,and determined by the fluorescence probe method.However the inhibitory activity of these six compounds were not good.The pKa and LogP values of these compounds were determined by spectrophotometry,and the pFe3+ was predicted,the results showed that all of these compounds had a strong iron chelating ability.The last chapter presented a brief overview of ⁶⁸Ga³⁺ chelators and their applications in PET-CT,the introduction of siderophores and their applications in medicine.The siderophore-based hydroxamate-peptide conjugate was gained as a ⁶⁸Ga³⁺ ligand by solid-phase peptide synthesis.