Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor

The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of β-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8-methoxypsoralen (31), which has an IC50 value of 9.9 μM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5-methoxypsoralen (35), 8-geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC50 values <25.0 μM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non-competitive inhibitors.