Design,Synthesis And Evaluation Of Tacrine-coumarin Hybrids As Multifunctional Cholinesterase Inhibitors

Alzheimer’s disease (AD) is a nervous system degenerative disease characterized by cognitive function and memory dysfunction, which is a serious threat to the health of people, especially in the elderly. From the current drugs has been used to clinical, cholinesterase inhibitors is still the most important anti Alzheimer’s disease drug, which is approved by the FDA to treat Alzheimer’s disease drug five have four kinds of cholinesterase inhibitors. But because Alzheimer’s disease (AD) have multi mechanism, multi factor characteristics, at present the efficacy of clinical drug exist some defects.The treatment of AD with multi targets has become the research focus, and the design and synthesis of acetylcholinesterase inhibitor based on multi-target anti AD drug candidate is one of the important research directions.In this paper, cholinesterase inhibitor tacrine look as the basis, we designed and synthesized a class of multi-target cholinesterase inhibitors based on tacrine, this is tacrine coumarin hybrid body connected by triazole. The specific contents include the target product design, chemical synthesis, spectral analysis to determine the structure and biological activity in vitro screening testActivity tests showed that the synthetic hybrid is better than tacrine cholinesterase (AChE and BuChE) inhibitory activity, at the same time, the synthetic hybrid treat with self induced aggregation of beta amyloid (Aβ) also has good inhibitory activity, in product with good inhibitory activity of cholinesterase and the self induced aggregation of beta amyloid, we also found some compounds have good monoamine oxidase (MAO-B) inhibitory activity.IC50 values of AChE and BuChE inhibitory activity of optimal compound were reached 0.027μM and 0.024μM, IC50 values of MAO-B inhibitory activity is 0.18μM, in 20μM, inhibitory acticity for beta amyloid aggregation is 66.4%, Optimal compounds showed balanced inhibitory activity to cholinesterase, beta amyloid aggregation and MAO-B balance, and can be used as a multi target candidate drug for AD treatment.