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The action of β-secretase is strongly tied to the onset of Alzheimer’s disease. The development of inhibitors of β-secretase is thus critical to combating this disease, which threatens an ever increasing number of the population and grows in importance as the population ages. Herein we show that flavones from Morus lhou potently inhibit β-secretase. Our aim in this manuscript is to explore the inhibitory kinetics of natural compounds and develop a phamacophore model which details the critical features responsible for inhibitory activity. The IC50 values of compounds for β-secretase inhibition were determined to range between 3.4 and 146.1 μM. Prenylated flavone 2 (IC50 = 3.4 μM) was 20 times more effective than its parent compound, noratocarpetin 1 (IC50 = 60.6 μM). The stronger activity was related with resorcinol moiety on B-ring and isoprenyl functionality at C-3. Kinetic analysis shows that the four effective compounds (1–4) have a noncompetitive mode of action. The binding affinity of flavones for β-secretase calculated using in silico docking experiments correlated well with their IC50 values and noncompetitive inhibition modes.

Although it has not been extensively studied, a significant volume of literature suggests that TREK2 will probably turn out to be an important channel in charge of tuning neuronal transmitter and hormone levels. Thus, pharmacological tools which can manipulate this channel, such as selective agonists are essential both in drug design and to further our understanding of this system. Our investigations have shown that sulfonate ('O') chalcone and sulfonamide ('N') chalcones regulate the TREK2 channel in remarkably different ways: sulfonamide chalcone 5 behaved as an inhibitor with an IC(50) of 62 microM, whereas the sulfonate analogue 11 activated TREK2 with EC(50) value of 167 microM.