Phenylimino-2H-chromen-3-carboxamide derivatives as novel small molecule inhibitors of β-secretase (BACE1)

The inhibition of β secretase (BACE1) is potentially important approach to treatment of Alzheimer disease (AD). A novel series of 4-bromophenyl piperazine derivatives coupled to the phenylimino-2H-chromen-3-carboxamide scaffold were investigated as BACE1 inhibitors in this study. Docking study suggested that the phenyl-imino group of the scaffold establishes favorable π–π stacking interaction with side chain of Phe108 of flap pocket. Some of the docking proposed derivatives were synthesized and evaluated for BACE1 inhibitory activity using a FRET-based assay. High BACE1 inhibitory activities were observed from derivatives containing fused heteroaromtic groups attached through the aliphatic linkage to the N4-piperazine moiety, which may be attributed to the engagement of effective interactions with S1–S′1 sub-pocket residues. Of the most potent compounds, 9e displayed an IC50 value for BACE1 of 98 nM. Some of these derivatives demonstrated good inhibitory activity on Aβ production in N2a-APPswe cells at 5 and 10 μM. These compounds might be considered as promising BACE1 inhibitory agents that could lower Aβ production in AD.

Design, synthesis and biological evaluation of a novel series of 4-bromophenyl piperazine derivatives coupled to the phenylimino-2H-chromen-3-carboxamide scaffold as β-secretase (BACE1) inhibitors are investigated in this study. High enzymatic BACE1 inhibitory activities were observed from derivatives containing fused heteroaromtic moieties attached through the aliphatic linkage into the N4-piperazine group, which may be attributed to the engagement of effective hydrophobic and hydrogen bonding interaction with S1–S′1 sub-pocket residues. Some of these derivatives demonstrated good inhibitory activity on Aβ production in N2a-APPswe cells at 5 and 10 μM.Figure optionsDownload as PowerPoint slide