# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 3 Conclusions  
Nowadays, 139 flavonoids, from natural sources, demonstrated as potential anti-AD agents: 4 (2.8%) flavonoids, 30 (21.6%) flavonones, 4 (2.8%) 3-hydroxyflavanones, 10 (7.2%) chalcones and dihydrochalcones, 52 (37.4%) flavones, 13 (9.5%) isoflav, and 26 (18.7%) flavonols. Considering flavones and flavonoids, a total of 78 (56.1%) flavonoids active against AD was achieved. They are characterized by a \(\pi\) system with various conjugated double bonds, and the molecule is stabilized in a planar configuration. The flavonoids discussed in this review exhibit LogP values ranging from \(-\)2.16 to 7.26, suggesting their potential to cross the BBB [112]. The most active flavonoid extracted from natural sources against BACE1 is rutin, the 3\({}^{\prime}\),4\({}^{\prime}\),5,7-tetrahydrooxy-3-[\(\alpha\)-L-rhamnopyranosyl-(1\(\to\)6)-\(\beta\)-d-glucopyranosylflavone (83), a glycosylated flavonol. On its scaffold it bears hydroxy groups on C5, C7 (on ring A) and on C3\({}^{\prime}\) and C4\({}^{\prime}\) (on ring B), as well as, linked to the oxygen of C3 \(\alpha\)-L-rhamnopyranosyl-(1\(\to\)6)-\(\beta\)-d-glucopyranoside group, which allows formation of several hydrogen bonding. The difference of activity against BACE1 between myricetin (78) (IC\({}_{50}\) = 2.40 uM) and rutin (83) (IC\({}_{50}\) = 0.004 uM) shows, for the increase in BACE1 inhibition, how significant is the bond between the oxygen at C3 with a group that allows several hydrogen bonds as \(\alpha\)-rhamnopyranosyl-(1\(\to\)6)-\(\beta\)-d-glucopyranoside. It should also be highlighted that the two hydroxy groups on ring B are in the _ortho_ position, showing the importance of these two hydroxy groups for hydrophilic interactions. Interestingly, the most active compounds against BACE1 of each group of flavonoids contain always on their scaffold three hydroxy substituents, one at C5 (or C2\({}^{\prime}\) for chalcones), another at C7 (or C4\({}^{\prime}\) for chalcones) and the last one at C4\({}^{\prime}\) (or C4 for chalcones) as: (\(-\))-epigallocatechin (5) belonging to the catechins' group; sophoroflavanone G (9), kurarinone (10), and selagintriflavonoid A (22) in the flavonones' group; phlorizin (28), representative of the dihydrochalcones' group; and kuwanon C (48), amentoflavone (58), sequoiaflavone (59), podocarppusflavone A (62),  
Figure 17: Structure of glycosylated flavonols 152–161 that inhibit AChE. Legend: Glu–glucopyranosyl, Rha–Rhamnopyranosyl and Rut–rutinosyl. Figure 18: Structure of lavandulylflavonol 162 that inhibits AChE. 2,3-dihydroamentoflavone (**74**), myricetin (**78**), or desmethylanhydroicaritin (**81**), which are members of the flavone and flavonoid groups. Luteolin (**34**), a flavone, presents the highest activity against the enzyme GSK-3\(\beta\) (IC\({}_{50}\) = 1.51 uM). This flavonoid also bears on its scaffold hydroxy groups on C5 and C7 (on ring A) and on C3\({}^{\prime}\) and C4\({}^{\prime}\) (on ring B). Glycoslation ring A, as on isovitexin (**44**), orientin (**46**), or isoorientin (**47**) decreases the inhibition of GSK-3\(\beta\), suggesting that side bulky group substitutions on the ring A of the flavonoid scaffold affect the GSK-3\(\beta\) activity in a significant manner, decreasing the interactions between the enzyme and inhibitors. It should also be noticed that flavonoids bearing on its scaffold hydroxy groups on C5 and C7 (on ring A) and on C4\({}^{\prime}\) (on ring B), such as kaempfer (**76**) (IC\({}_{50}\) = 3.47 uM), present a decrease in the inhibition of GSK-3\(\beta\). However, quercetin (**1**) (IC\({}_{50}\) = 2.00 uM), with hydroxy groups at C3 and at C3\({}^{\prime}\), C4\({}^{\prime}\) C5 and C7 presents an inhibition of the same magnitude of luteolin (**34**). The chalcone butein (**89**) exhibits one of the greatest inhibitory effects against NO production, one of the pro-inflammatory factors, with an IC\({}_{50}\) value of 10.90 uM.