# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 2 Activities of Flavonoids from Natural Sources
### Inhibition of Acetylcholinesteraseerase (AChE)
#### 2.4.3 Flavones  
Apigenin (**29**) and acacetin (**31**) exhibit AChE inhibition with IC\({}_{50}\) values of 34.43 \(\upmu\)M [49] and 50.33 \(\upmu\)M [73], respectively, suggesting that for flavones the presence of a methoxy group at C4\({}^{\prime}\) decreases the AChE inhibition. From the roots of _Scutellaria hicalensis_ (Chinese Skullcap) was extracted baicalein (**30**) with an IC\({}_{50}\) of 0.61 \(\upmu\)M [55]. Wogonin (5,7-dihydroxy-8-methoxyflavone) (**92**), also isolated from _S. bialensis_, exhibits IC\({}_{50}\) value < 10 \(\upmu\)M [95], and luteolin (**34**) exhibits an IC\({}_{50}\) of 9.27 \(\upmu\)M [76]. Regarding glycosylated flavones, 7-O-(-(-b-d-glucopyranosyl)apigenin (**132**), isolated from _Phagnalon saxatile_ ([PERSON] [PERSON], is a much weaker inhibitor of AChE (IC\({}_{50}\) = 237.74 \(\upmu\)M) [101] when comparing with apigenin (**29**). Baicalin (**133**), the glycosylated form of baicalein at C7, exhibits an IC\({}_{50}\) value much higher (204.10 \(\upmu\)M) [102] than the aglycone (**30**). Cynaroside, the 7-O-(-\(\beta\)-d-glucopyranosyl)luteolin (**134**), isolated from _Drynaniae rhizome_[60], 4\({}^{\prime}\)-O-(-\(\beta\)-d-glucopyranosyl)luteolin (**135**), isolated from _Phagnalon saxatile_ ([PERSON]) [PERSON]. [101], or veronicastroside (7-O-rutinosyl luteolin) (**136**) from _Veronicastrum sibiricum_ var. _japonicum_[103], present IC\({}_{50}\) of 17.13, 147.41 and 6.783.80 \(\upmu\)M, respectively. Thus, these glycosylated luteolins are also weaker inhibitors of AChE than luteolin (**34**). Even C-glycosylation of luteolin at C6 and C8 decreases the AChE inhibition, as shown by orientin (**46**) and isoorientin (**47**), with IC\({}_{50}\) values of 20.06 and 29.48 \(\upmu\)M, respectively [76]. These results suggest that flavone glycosylation decreases the AChE inhibition. However,  
Figure 13: Structure of chalcones **125-131**, some of which inhibit AChE (**125**, **126** and **131**). 7-O-glucosyl-6-hydroxyluteolin (**137**), isolated from _Achillea millefolium_, is a remarkable AChE inhibitor exhibiting an IC\({}_{50}\) of 1.65 uM [55], being a more potent inhibitor than luteolin (**34**). The substitution of the proton by a hydroxy group at C6 makes the difference. Thus, 7-O-glucosyl-6-hydroxyluteolin (**137**) should be compared with baialein (**30**) (IC\({}_{50}\) = 0.61 uM) [55], showing the usual decrease in AChE inhibition due to the glycosylation. Violanthin, the \({}^{4}\)\({}^{\prime}\)5,7-trihydroxy-6-Dglucosyl-8-l-rhammosylflavone (**138**), isolated from _Piper bavinum_, exhibiting an IC\({}_{50}\) value of 79.80 uM [93], is another example. On the other hand, baialein (**133**), the glycosylated form of baialein at C7, exhibits an IC\({}_{50}\) value much higher (204.10 uM) [102], suggesting that the AChE inhibition of 7-O-glucosyl-6-hydroxyluteolin (**137**) is also due to the hydrogen bonding with the hydroxy groups of C3\({}^{\prime}\) and C4\({}^{\prime}\), as well as of C6 or, in the case of violanthin, with the hydroxy groups of C4\({}^{\prime}\). The decrease in activity when acacetin is glycosylated as in 7-O-(\(\beta\)-rhammosyl)acacetin (**139**) and 7-O-(\(\beta\)-glucosyl)acacetin (**140**), which are inactive [104], and 3-O-[\(\alpha\)-L-rhammopyranosyl-(1-\(\delta\))-\(\beta\)-D-glucopyranosyl]acacetin (**141**), which exhibits an IC\({}_{50}\) value of 165.0 uM [105], reinforces that glycosylation of flavones decreases AChE inhibition. Now, comparing vitexin (**43**), which is C-glycosylated apigenin at C8, with isovitexin (**44**) which is C-glycosylated apigenin at C6, and swertisin (7-O-methylisovitexin) (**142**), inhibiting AChE with IC\({}_{50}\) values of 12.16, 6.24 [79] and 71.89 uM [106], respectively, it can be assumed that the steric hinderance of the glycoside is higher when it is linked to C8 of the flavone. Even when a methoxy group is linked to C8 the hydrogen bonding is weaker.