Design,Synthesis And Biological Activity Evaluation Of Xanthone-Alkylbenzylamine Derivatives Against Alzheimer’s Disease

Alzheimer’s disease（AD）,one of the most severe and prevalent neurodegenerati-ve diseases,is characterized by progressive memory loss and general cognitive decline,which usually arises in people over 65 years old.According to the World Alzheimer’s disease Report,approximately 50 million people worldwide are suffering from AD and the population of AD will be increased up to 115 million by 2050,which will bring heavy burden on societies and families.Due to the complex and unidentified etiology,it is difficult to effectively control the occurrence and development of the disease simply by regulating only one of the targets or pathways,and it may also bring the side effects of compensatory enhancem-ent of other pathways to maintain the stability of the disease.Therefore,the current development of AD drugs mostly focuses on the strategy of"Multi-Target-Directed Ligands"（MTDLs）.In the clinical treatment of AD,although cholinesterase inhibitors cannot completely reverse the occurrence and development of the disease,these drugs are currently the most effective and main AD treatment drugs.Therefore,new multi-target drugs are usually designed by combining one or more targets with other pharmacological effects on the basis of the cholinesterase target.As we all know,natural products play a very important role in the process of drug discovery and development because of their rich diversity of structure and extensive biological activities.Therefore,we used the MTDLs strategy to design and synthesize20 multifunctional xanthone-alkylbenzylamine derivatives with cholinesterase inhibitory ability,antioxidant ability and metal chelating ability,and carried out the related biological activity evaluation with the expectation of additional effects.This paper mainly concludes the following parts:1.The main pathogenesis of Alzheimer’s disease and the current research and development of anti-AD drugs were briefly introduced.2.According to the MTDLS strategy,20 multifunctional xanthone-alkyl-benzylamine derivatives were designed and synthesized by conjugated-pharmaco-phore strategy and the structure or purity of them were confirmed by ¹H NMR,¹³C NMR,HR-ESI-MS and HPLC.3.The 20 compounds were determined for the inhibitory activity of acetyl-cholinesterase（AChE）and butyrylcholinesterase（BuChE）,the antioxidant capacity and the blood-brain barrier（BBB）penetration capacity.The results showed that the compounds exhibited good dual cholinesterase inhibitory activity,and compound 4j had the best and most balanced inhibitory activity on AChE and BuChE(AChE:IC₅₀=0.85μM;BuChE:IC₅₀=0.59μM);In addition,most of the compounds exhibited good antioxidant activity;With exception of the compounds 4f and 5b,the other 18compounds could permeate the BBB and act on related targets of central nervous system.The structure-activity relationships of 20 compounds were discussed.4.The results of enzyme kinetics analysis showed that 4j was a mixed-type inhibitor for both AChE and BuChE.Molecular docking experiments have proved that the two pharmacophores of 4j could occupy the PAS and CAS of cholinesterase throughπ-πstacking interaction,hydrogen bond interaction and other interactions.Metal chelation experiments showed that 4j could selectively chelate with Cu²⁺or Al³⁺at a molar ratio of 1:1.4.5.The cytotoxicity results showed that 4j had a moderate therapeutic safety range;The acute toxicity of 4j was evaluated in vivo,and the results showed that mice were well tolerated at a dose of 2500 mg/kg,and pathological sections showed no obvious tissue damage;The therapeutic effect in vivo showed that compound 4j could improve the memory impairment induced by scopolamine.