N端为含氮杂环的新型羟乙基胺类BACE1抑制剂的设计、合成与活性评价

目的开发一类N端含氮杂环结构的新型羟乙基胺（hydroxyethylamine,HEA）类BACE1抑制剂,筛选对抑制活性有贡献的新型N端结构。方法设计并合成了8个N端为含氮杂环的HEA类化合物并鉴定其结构,同时,以儿茶酚类化合物（-）-表没食子儿茶素没食子酸酯（EGCG）作为阳性对照,分别测定它们对BACE1的抑制活性。结果所有化合物均通过核磁共振氢谱和质谱确证其结构。BACE1抑制活性评价结果表明,其中N端为吲哚结构的化合物Ⅰ6表现出明显的抑制活性。结论含取代基的吲哚结构与BACE1的S2口袋具有一定的相互作用,有利于提高这类化合物对BACE1的抑制活性,可作为进一步研究的先导结构。

Design, synthesis and evaluation of novel hydroxyethylamine derivatives with nitrogen heterocyclic moiety at N-terminal as BACE1 inhibitors

Objective To develop a new series of hydroxyethylamine （HEA） BACE1 inhibitors with nitrogen heterocyclic moiety at N-terminal and find new N-terminal moiety for enhancing BACE1 inhibition activity. Methods New HEA compounds with nitrogen heterocyclic moiety at N-terminal were synthesized and evaluated as BACE1 inhibitors,with （-）-epigallocatechin-3gallate EGCG as a positive control. Results All new compounds were characterized by 1H NMR and ESI-MS. Evaluation of BACE1 inhibition activity showed that the compound Ⅰ6 with indole moiety at N-terminal had BACE1 inhibition activity. Conclusion The results suggested that the indole moiety at N-terminal interact with S2 pocket of BACE1 and be favorable for enhancing BACE1 inhibition activity, Thus, the indole moiety at N-terminal can be used as lead structure for further finding more effient BACE1 inhibitors.