Synthesis And Cholinesterase Activity Evaluation Of Halogenated Chalcone Derivatives

Alzheimer's disease, AD, so called senile dementia, is a progressive neurodegenerative disorders that associate with cognitive function and spatial awareness. The main symptoms of it are memory impairment, aphasia, behavior disorders and being unable doing activities of daily living in the end. Though the pathology of AD is complex and diversified, the theory of cholinergic deficit is universally recognized, based on which the acetylcholinesterase inhibitors (AChEI) is developed and now is the primary medicine to treat AD clinically.Chalcones is a kind of flavonoids exiting in wide range in nature has various biological activities. This paper is a deeper expansion of the research made by Research Group members. Based on it and the characteristic of halogen atoms often improving the biological activity of compound, this paper is designed to synthesize a series of chlorochalcones substituted amino alkoxyl derivatives and fluorochalcones substituted amino alkoxyl derivatives, and obtain halogenated dihydrogen pyridine substituted amino alkoxyl derivatives by cyclization with preliminary exploration on its biological activities to have new findings and breakthroughs compared with previous research results.This paper consists of the following aspects,(1)A series of chlorochalcones and fluorochalcones substituted amino alkyl derivatives as well as halogenated dihydrogen pyridine substituted amino alkoxyl derivatives are synthesized. The whole synthesis experiment operates easily with high output and less accessory substance. Methods like H1NMR, IR and etc, are utilized for the structure characterization of target compounds.(2)The evaluation of cholinesterase is conducted for target compounds and as for screened high AChE inhibition activity, kinetic studies is made on AChE. The experiment result shows that chlorochalcone derivatives and fluorochalcone derivatives have different degrees of inhibitory activity toward AChE and BuChE, and compares to the original chalcone derivatives without halogen substituent have different degrees of increase of AChE activity.among which chlorochalcone derivatives B3L and fluorochalcone derivatives B3I have the highest inhibitory activity toward AChE in compounds of homologous series, the IC50 values of which reach 0.17?M and 0.20?M. The most promising compound B3L and B3I were 653-fold and 65-fold more selective for AChE than BuChE. We chose compound B3L and B3I for further kinetic measurement, which indecates that compounds B3L and B3I revealed mixed inhibiting effect against AChE.(3)MOE2008 software is utilized to further study the combination way of target compounds and AChE protein molecules at the molecular level. The molecular simulation result shows that all the halogenated chalcone derivatives and halogenated dihydrogen pyridine can be combined with both catalytic active site (CAS) and Perioheral binding site (PAS) and it is a dual sites of AChEI, same as the results of kinetic studies experiment.(4)To explore the ability of halogenated chalcone derivatives penetrate blood brain barrier (BBB), HPLC method is used to measure the oil-water partition coefficient (log P) of target product. The results shows that the log P values of all target products are within the range of 2.0±0.7, meeting the requirement on log P of compounds penetrating BBB.Additionally, the evaluation of cholinesterase is conducted for halogenated dihydrogen pyridine derivatives indicated that all the compounds showed good inhibitory activity of AChE, but compared to the original chorochalcone derivatives (B31-B3L) and fluorochalcone derivatives (B3i-B3I), all the halogenated dihydrogen pyridine derivatives have decreased in different degrees about inhibitory activity toward AChE. Therefore, we speculated that the flexible acrylic ketone structure of chalcone are the necessary structure to enhance the inhibition activity of AChE.