bace1抑制剂的设计 合成与构效关系分析word格式论文.docxVIP

优秀毕业论文 精品参考文献资料 crystal structure ?-secretase and the SAR of being reported BACE1 inhibitors and the pharmacological activity data of the lead compounds. Four types of target compounds were designed，Then the compounds, which would be synthesized in this study, were selected by molecular docking (Surflex Model of Sybyl 8.1 program) against active site of BACE-1. Finally, twenty target compounds of isothiazolone substituted isophthalic acid derivatives were synthesized. These compounds have not been reported and the structures ha ve been confirmed by 1H-NMR and MS. The purity of these compounds had been determined by HPLC. Six different synthetic routes including thirty five reactions have been selected to synthesize target compounds. And all reaction conditions were investigated and optimized. Especially, by controlling temperature and feeding mode, the yield of isothiazolone substituted isophthalic acid could be improved by 40%. The conditions of Suzuki coupling reaction were optimized and improved by changing catalyst, solvent, temperature and reaction mode. The result reveals that possibility of homocoupling of borate intermediates can be reduced by using sodium carbonate solution and microwave. Due to the influence of neighboring groups, the activity of fluoride group is enhanced. Converting the reaction sequence and using aprotic solvent can obviously reduce its activity in order to synthesize the key intermediate 1, 4-butane sulfonlactam successfully. Intermediate F was synthesized by using trimethylsulfoxonium iodide to make the synthesis of cycloxane smoothly at room temperature, avoiding using low temperature and expensive reagent. All compounds’ separatory conditions have been preliminarily analyzed with CHIRALPAK AD-H column. Time-resolved fluorescence was used to evaluate in vitro inhibitory activities of these compounds against BACE-1 in the molecular level. The result reveals that thirteen compounds show high inhi