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.