Design And Synthesis Of Novel Metal Chelator As Multifunctional Agents For The Treatment Of Alzheimer’s Disease

Alzheimer’s disease (AD) is the fourth leading cause of death in people over 65 years old. In the world, more than 24 million people were affected every year. Although one hundred years have passed since its discovery, AD remains a big challenge because of lacking of effective treating drugs. Over the past few decades, studies are more concentrated on the pathogenesis and treatment of AD. Especially, the concept of "one-compound-multiple-targets" has promoted a growing number of targeted drugs.Although AD etiology is not understood completely, it has been recognized as a multifaceted disorder which in the patients brains show several features, such as misfolding of proteins and associated aggregation, low levels of acetylcholine, free radical formation and oxidative stress, metal dyshomeostasis and mitochondrial and neuroinflammatory dysfunctions. Among the complexity of this pathology, the neurofibrillary tangles and senile plaques are the main hallmarks of AD and as a result of deposition of a τ-protein and beta-amyloid (Aβ). In the past few years, several studies have proved that the abnormal concentration of Cu2+, Zn2+and Fe3+ cause protein deposition and cause oxidative damage. Therefore, metal imbalance plays an important role in chelation therapy, which is an attractive and challenging strategy. Great efforts have been devoted to designing multifunctional metal-chelators.Firstly,a review of the structure, properties and applications of anti-Alzheimer’s disease agents in rencent years have been made, and based on the literature review, in consideration of the new paradigm for medicinal chemistry that is termed’one-compound-multiple-targets’, three series of compouds were designed following the leading compound deferasirox, tacrine and 8-hydroxyclioquinoline and synthetized 7 new target compounds. All compounds were confirmed through 1H-NMR,13C-NMR, IR and mass pectrometry.The hybrids were evaluated as possible multifunctional anti-alzheimer’s disease drugs. Their capacity to inhibit AChE, iron chelation and anti-oxidant capacity were assayed. The target compouds TD were tested for their AChE inhibitory acticity in vitro.All of them exhibited high AChE inhibitory activity and TDa and TDC are higher than positive control drug tacrine. Targeted compound TDe displayed better neuroprotective properties against DPPH free radicals and low cell toxicity. They selectively complex Cu2+ and (or) Fe3+ except compound DEF.The work of this thesis provides guidance for further study high activity compounds.