# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 2 Activities of Flavonoids from Natural Sources
### Inhibition of A\(\beta\) Production
#### 2.1.3 Flavones  
Apigenin, the 4',5,7-trihydroxyflavone (**29**), which exists in oregano, mint, rosemary sage, celery, bell pepper, garlic, French peas, thyme, _Tabernaapontana pandaacaqui_ and _Phaganolan saxatile_ (L.) [PERSON], exhibits a BACE1 IC\({}_{50}\) of 38.50 uM [49; 50; 52; 53]. For baicalein, the 5,6,7-trihydroxyflavone (**30**), existing in _Scutellaria bicalensis_, also with three hydroxy groups, but all of them on ring A, the BACE1 inhibition decreases (IC\({}_{50}\) = 69.18 uM) [70]. For acacetin, the 5,7-dihydroxy-4'-methoxyflavone (**31**), extracted from _Agastache rugosa_ (Fisch. and C.A. Mey.) [PERSON] (Lamiacae), where the hydroxy group of C4' of ring B of apigenin is replaced by a methoxy group, there is also a decrease in BACE1 inhibition (IC\({}_{50}\) = 88.50 uM) [72]. Mosolfavone, the 5-hydroxy-6,7-dimethoxyflavone (**32**), where the OH-6 and OH-7 present in baicalein (**30**) are replaced by methoxy groups, exhibits a small increase in BACE1 inhibition (IC\({}_{50}\) = 43.65 uM) [70] when compared to baicalein. This flavone exists in _Desmos dumosus_ and _Phonus arborescens_. When acaetin (**31**) bears a hydroxy group on C-3' on ring B, this 3',5,7-trihydroxy-4'-methoxyflavone (**33**) has the trivial name diosmetin. It exists on the Caucasian vetch which occurs in the region of North Caucas [110]. There is an increase in BACE1 inhibition of **33** (IC\({}_{50}\) = 43.65 uM) when comparing with acaetin (**31**) [70]. Luteolin, the 3',4',5,7-tetrahydroxyflavone (**34**), exhibits a BACE1 IC\({}_{50}\) of 13.75 uM [74], showing the importance of the two hydroxy groups on C-3' and C-4' of ring B for hydrophilic interactions. It is interesting to notice that norntocarptein (**35**), the 2',4',5,7-tetrahydrooxyflavone, existing on _Morus lhou_ and regioisomer of luteolin, exhibits a decrease in BACE1 inhibition (IC\({}_{50}\) = 60.60 uM) [52], as the two hydroxy groups on ring B are at _meta_ position and not _ortho_ position as happens on luteolin. If the hydroxy group at C3' of diosmetin (**33**) is replaced by a methoxy group, as well as the one at C7, the resulting 5-hydroxy-3',4',7-trimethoxyflavone (**36**) is a natural product isolated from the medicinal plant _Lippia nodiffora_[111]. This flavone is a very potent inhibitor of BACE1 (IC\({}_{50}\) = 2.14 uM) [70], showing the importance of the methoxy groups on the ring A of the flavone. 3',4',5,7-Tetramethoxyflavone (**37**), existing in _Orthosiphon anristatus_ and _Bauhinia championii_, where all the hydroxy groups are replaced by methoxy groups, exhibit a BACE1 IC\({}_{50}\) of 1.66 uM even higher than **36** [70], suggesting an increase in hydrophobic interactions when the methoxy groups are linked to C5 and C7. There is a huge decrease in the inhibitory activity against BACE1 when citrus peels flavones such as tangeretin, the 4',5,6,7,8-pentamethoxyflavone (**38**), or nobiletin, the 3',4',5,6,7,8-hexamethoxyflavone (**39**), or sinenstein, the 3',4',5,6,7-pentamethoxyflavone (**40**) (IC\({}_{50}\) values of 49.00, 59.00 and 63.00 uM, respectively) [77], are compared with 3',4',5,7-tetramethyloxyflavone (**37**) owing to steric hindrance. The same happens when crissilined, the 4',5-dihydroxy-3',6,7-trimethoxyflavone (**41**), is considered. However, there are now increases in the hydrophilic interactions owing to the  
Figure 6: Structure of chalcones and dihydrochalcones that inhibit \(\beta\)-secretase. hydroxy group on the C-4\({}^{\prime}\) (IC\({}_{50}\) = 20.35 uM). Another flavone, extracted from _Ocinum sanctum_ (leaves), is isothymusin, the 5,8,4\({}^{\prime}\)-trihydroxy-6,7-dimethoxyylavone (**42**), also bearing a hydroxy group at C8, which exhibits an increase in BACE1 inhibition (IC\({}_{50}\) = 4.45 uM) [78]. Considering glycosylated flavones, vitexin, the 8-(\(\beta\)-d-glucopyranosyl)-4\({}^{\prime}\),5,7 -trihydroxyflavone (**43**), is a C-glycoside isolated from _Vigna radiata_ L. that presents a BACE1 IC\({}_{50}\) of 51.07 uM [79].