Synthesis And Cholinesterase Inhibition Activity Of Chalcone Analogues Which Contains Heterocycles

Chalcone, which belongs to the flavonoid compounds in natural products, is widely found in many kinds of medicinal plants. Because of its basic flexible structure, chalcones can bind effectively to many kinds of enzymes or receptors and exhibit diverse biological activities, such as antitumor, antiparasitic, anti histamine, antioxidant, antiviral and so on. In addition, its structure is relatively simple, easy preparation, so it can be used as a lead compound.Since the research focus is still on the acetylcholinesterase inhibitor drugs for Alzheimer's disease, based on the studies about acetylcholinesterase inhibitors made by research group members, such as Huang Xueqin simplified the structure of flavokawain B and designed a series of 3'-(tertiary amines)alkoxychalcone derivatives. Liu Xianjun synthesized a series of 4'-(tertiary amines)alkoxychalcone derivatives. Zhou Chao discussed the structure-activity relationship of halogenated chalcone derivatives. According to the introduction of the heterocyclic ring, is one of the important methods for the transformation of the lead compound, and by using the principle of bioisosterism, the benzene ring, furan ring, pyridine ring are similar in physical and chemical properties, swaps between the three is widely used in the design and synthesis of drugs, this paper is designed to synthesize a series of chalcone analogues which contains furan ring and pyridine ring, and carried out the preliminary structure-activity relationship study against cholinesterase, in order to have new discoveries and breakthroughs on previous research.The main contents were summarized as following:(1) A series of chalcone analogues A3,-A4d which contains furan heterocycles were synthesized, the activity test results showed that the compounds had a certain inhibition activities against cholinesterase, the compound A4d showed the highest inhibition activities and selectivity, the IC50 against AChE reached 2.05 ?mol/L, selectivity was 6.38, structure-activity relationship exhibited that the amine alkoxy side chain and tertiary amine groups had a great influence on biological activities, compared with chalcone derivatives, the inhibition activities against AChE showed different degrees of reduction, molecular docking experiments answered the reduction of this compounds in a certain extent.(2) A series of chalcone analogues B3a-B6d, C2a-C5d which contains pyridine ring were designed and synthesized, the activity test results showed that the compounds had a certain inhibition activities against cholinesterase, the compound B6d showed the highest inhibition activities and selectivity, the IC50 against AChE reached 0.051 ?mol/L, selectivity was 367.45, structure-activity relationship study revealed the great influence to biological activities by tertiary amine group, different positions of the tertiary amine alkoxy side chain, different length of the tertiary amine alkoxy side chain, compared with chalcone derivatives, the inhibition activities against AChE showed different degrees of increasement in a certain extent, enzyme kinetic experiments showed that the type of inhibition between compounds and AChE was a mixed type, molecular docking experiments exhibited that compounds combined with both PAS and CAS binding sites of AChE, and in a preliminary explanted of the reasons for the high AChE activity and selectivity of the compounds.(3) To explore the selectivity of the inhibition activities against cholinesterase. The inhibitory activity against the carboxylesterase and the aminopeptidase of the compounds A3a-A4d, B3a-B6d, C2a-Csd was tested and the selectivity and specificity of the compounds were verified by experiments.