# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 2 Activities of Flavonoids from Natural Sources
### Inhibition of A\(\beta\) Production
#### 2.1.1 Catechins and Flavanones  
Green tea catechchins present inhibitory activity of BACE1, with (\(-\))-epigallocatechin (**5**) as the most potent one with an IC\({}_{50}\) of 2.40 uM. That activity is attributed to the pyrogallol moiety linked to C2 of the catechin [50]. From _Tamarix gallica_ L. [109], _Dryanarie rhizomethe_[58] and several citrus fruits [49; 109], naringenin, the (25)-4',5,7-trihydroxyflavanone (**6**), can be extracted, presenting a BACE1 IC\({}_{50}\) of 38.06 uM) [59]. Pinocembrin, the 5,7-dihydroxyflavanone (7), existing in a variety of plants, mainly from _Pinus_ heartwood, _Eucalyptus_, _Populus_, _Euphoria_, _Sparattsoperma leucanthum_ and _Turrena diffusa_, presents a BACE1 IC\({}_{50}\) of 27.01 uM [61]. _Dryanria roosii_ ([PERSON]), also called _D. fortunei_ ([PERSON]) [PERSON], a large epiphyichr fern of the family Polypodiaceae, known as \"Gusuibu\", contains pinostrobin, the (25)-5-hydroxy-7-methoxyflavanone (**8**), which presents a BACE1 IC\({}_{50}\) of 4.35 uM [61]. These results suggest that the BACE1 inhibition is influenced by the presence of the pyrogallol moiety linked to C2 of the catechchin.  
Eight flavanones were isolated from _Sophora flavscens_ Ait. (Leguminosae), a plant widely distributed in Asia, Oceania, and the Pacific islands, namely: five lavandulyl flavanones, sophoraflavanone G (9), kurarinone (**10**), leachianone A (**11**), kushenol A (**12**), and (25)-2'-methoxykurarinone (**13**), which present BACE1 IC\({}_{50}\) values of 5.20, 3.30, 8.40, 2.60, and 6.70 uM, respectively; two hydrated lavandulyl flavanones, kushenol T (**14**) and kurarinol (**15**), with BACE1 IC\({}_{50}\) values of 36.80 and 39.20 uM, respectively, and one isoprenyl flavanone, isoxanthohumol (**16**), with a BACE1 IC\({}_{50}\) of 27.70 uM [63]. Thus, the lavandulyl substituent at C8 increases by ten times the BACE1 inhibition when compared with the hydrated lavandulyl flavanones or the isoprenyl flavanone, suggesting that the hydrophobic interactions are decreased on these two latter scaffolds.  
The glycosylated flavanones didymin, the (25)-5-hydroxy-4'-methoxy-7 -[\(\alpha\)-L-rhamnopyranosyl-(l\(\rightarrow\)6)-\(\beta\)-D-glucopyrananoylyl]flavan-4-one (**17**), and poncirin, the (25)-5-hydroxy-4'-methoxy-7-[\(\alpha\)-L-rhamnopyranosyl-(l\(\rightarrow\)2)-\(\beta\)-D-glucopyrananoylyl]flavan-4-one (**18**), existing in several citrus fruits, present BACE1 IC\({}_{50}\) values of 2.34 and 3.96 uM, respectively [59]. Another glycosylated flavanone existing in citrus fruits is prunin, the (25)-7-(\(\beta\)-D-glucopyrananoyl)-4',5-dihydroxyflavan-4-one (**19**), which exhibits a BACE1 IC\({}_{50}\) of 13.41 uM [59]. Hesperidin, the (25)-3',5-dihydroxy-4'-methoxy-7-[\(\alpha\)-L-rhamnopyranosyl-(l\(\rightarrow\)6)-\(\beta\)-D-glucopyrananoylyl]flavan-4-one (**20**), and neoeriocitrin, the 3',4',5-trihydroxy-7-(\(\alpha\)-L-rhamnopyranosyl-(l\(\rightarrow\)2)-\(\beta\)-D-glucopyrananoylyl)flavan-4-one (**21**), existing also in several citrus fruits, present BACE1 IC\({}_{50}\) values of 10.02 [65] and 22.49 uM [60], respectively, suggesting again that, when the number of hydroxy groups on the ring B of the flavanone increases, the BACE1 inhibition decreases. Selagintriflavonoid A (22), an uncommon tri-flavonoid consisting of three naringenin units, isolated from the plant _Selaginella doederleinii_ that is widely distributed in southern China, exhibits a strong BACE1 inhibition (IC\({}_{50}\) of 0.75 uM), and is thus a promising compound for AD treatment [67].  
Figure 5 shows the chemical structure of catechins and flavanones (compounds **5**-**22**) that inhibit BACE1 with IC\({}_{50}\) range of 0.75 to 39.20 uM.