Triazolyl tryptoline derivatives as β-secretase inhibitors

Tryptoline, a core structure of ochrolifuanine E, which is a hit compound from virtual screening of the Thai herbal database against BACE1 was used as a scaffold for the design of BACE1 inhibitors. The tryptoline was linked with different side chains by 1,2,3-triazole ring readily synthesized by catalytic azide-alkyne cycloaddition reactions. Twenty two triazolyl tryptoline derivatives were synthesized and screened for the inhibitory action against BACE1. JJCA-140 was the most potent inhibitor (IC50 = 1.49 μM) and was 100 times more selective for BACE1 than for Cat-D.

A focused library from 22 different alkynes and an azide-containing tryptoline pharmacophore from virtual screening were synthesized by Cu(I)-catalyzed [3+2] azide-alkyne cycloaddition reaction. The lead compound (JJCA-140) showed IC50 of 1.49 μM against BACE1 and 100 times more selective to BACE1 than Cathepsin-D.Figure optionsDownload as PowerPoint slide