论文部分内容阅读
目的发现新结构的β-分泌酶抑制剂。方法基于β-分泌酶抑制剂的构效关系,设计合成了含羟乙胺结构片段的间位1,1-二氧代-N-甲基-2,3-(2H)-异噻唑酮取代的间苯二甲酸衍生物;采用时间分辨荧光法检测化合物对β-分泌酶的抑制活性。结果合成了8个目标化合物,利用MS和1H-NMR对化合物的结构进行了确证,利用HPLC对化合物的纯度进行了测定,利用旋光仪测定了化合物的比旋光度;活性数据显示有2个化合物对β-分泌酶有较强的抑制作用,其中化合物2c的IC50值为3.7 nmol.L-1。结论发现了新的β-分泌酶抑制剂,分析了其初步的构效关系,为进一步进行结构优化进而发现活性更好的化合物奠定了基础。
Aim To find a novel β-secretase inhibitor. Methods Based on the structure-activity relationship of β-secretase inhibitors, a series of 1,1-dioxo-N-methyl-2,3- (2H) -isothiazolone substitutions Of the isophthalic acid derivatives; the use of time-resolved fluorescence assay compounds inhibit the activity of β-secretase. Results Eight target compounds were synthesized. The structures of the compounds were confirmed by MS and 1H-NMR. The purity of the compounds was determined by HPLC. The specific rotation was measured by polarimetry. The activity data showed that there were 2 compounds Β-secretase has a strong inhibitory effect, which compound 2c IC50 value of 3.7 nmol.L-1. Conclusions A new β-secretase inhibitor was discovered. The preliminary structure-activity relationship was found, which laid the foundation for further structural optimization and the discovery of more active compounds.