Identification of aplysinopsin as a blood-brain barrier permeable scaffold for anti-cholinesterase and anti-BACE-1 activity.

Aplysinopsins are a group of marine-derived indole alkaloids that display diverse array of pharmacological effects. However, their effect on anti-Alzheimer targets has not been reported. Herein, we report the synthesis of aplysinopsin (1) and its effect on cholinesterases and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1). It inhibits electric eel acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and human BACE-1 with IC50 values of 33.9, 30.3, and 33.7 µM, respectively, and excellent BBB permeability (Pe 8.92 × 10-6 cm/s). To optimize its sub-micromolar activity, the first-generation analogs were prepared and screened. Two most active analogs 5b and (Z)-8g were found to effectively permeate the BBB (Pe > 5 × 10-6 cm/s). The N-sulphonamide derivative 5b display better cholinesterase inhibition, whereas the other analog (Z)-8g strongly inhibits BACE-1 (IC50 0.78 µM) activity. The analog 5b interacts primarily with PAS of AChE, and thus exhibit a mixed-type of inhibition. In addition, aplysinopsin along with new analogs inhibited the self-induced Aβ1-42 aggregation. The data presented herein indicate that the aplysinopsin-scaffold holds a potential for further investigation as a multi-targeted anti-Alzheimer agent.