Synthesis And Structure-activity Relationship Of N-4′-(tertiary Amines)Alkoxychalcone Derivatives As Cholinesterase Inhibitors

Alzheimer’s disease(AD) is a progressive, chronic, neurodegenerative disord er, characterized by declining in memory and cognitive abilities. It is estimated that about 6% of the population worldwide aged over 65 currently suffer from AD. Current treatment of AD mainly focuses on the inhibition of ACh E activity aimed at rectifying the deficiency of cerebral acetylcholine. Based on the cholinergic hypothesis, the deterioration of memory and cognition in AD patients is mainly caused by the extensive decline of ACh, which released into presynaptic neuron to transport nervous signal and then rapidly hydrolyzed by ACh E. Up to now, the drugs developed by “the cholinergic deficiency hypothesis” remained the main clinical treatment of Alzheimer disease.Chalcones, one of the classes major of natural products with widespread in fruits and vegetables, belong to the flavonoid family and chemically consist of two aromatic rings connected by an α, β-unsaturated carbonyl group. Due to the flexible structure, chalcones can bind effectively to many kinds of enzymes or receptors and exhibit diverse biological activities. Based on the research of the flavokawain B derivatives as the ACh EI, we synthesized a series of chalcones with different tertiary amines through different basic side chains(n=2-6) and evaluated their biological activity of inhibiting ACh E for the purpose of developing potential drugs for the treatment of AD.The main contents were summarized as following:(1) We synthesized a series of chalcones with straight chain amines through different basic side chains(n=2-6) and evaluated their biological activity of cholinesterase. Moreover, the study on structure-activity relationship was performed to study the relationship of chains, straight chain amines and biological activities. Enzyme kinetic study suggested that the inhibition mechanism of compounds was a mixed-type inhibition. Meanwhile, the result of molecular docking rationalized its potent inhibition of ACh E and high selectivity for ACh E over Bu Ch E. The log P values of the compounds were shown to range from1.49 to 2.19, which indicated that they were sufficiently lipophilic to pass blood brain barriers in vivo.(2) We synthesized a series of chalcones with cyclic tertiary amines through different basic side chains(n=2-6) and evaluated their biological activity of cholinesterase. Moreover, the study on structure-activity relationship was performed to study the relationship of chains, cyclic tertiary amines and biological activities. Enzyme kinetic study suggested that the inhibition mechanism of compounds was a mixed-type inhibition. Meanwhile, the result of molecular docking rationalized its potent inhibition of ACh E and high selectivity for ACh E over Bu Ch E. The log P values of the compounds were shown to range from1.39 to 1.94, which indicated that they were sufficiently lipophilic to pass blood brain barriers in vivo.(3) The compounds exhibited potent biological activities of inhibiting ACh E were choose to synthesize the chalcone-2H-pyrazole derivatives by the structural transformation. Through the compare of their activities and the chalcone derivatives, we get the conclusion that the structure of acrylketone is important for the biological activities of inhibiting ACh E.