# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 3 Conclusions
It is interesting to note that this molecule, although not having the scaffold of flavones, allows also that the \(\pi\) system is extended as there is an increase in two more conjugated double bonds, and the molecule will be stabilized in a planar configuration. On the other hand, it bears hydroxy groups on C3 (the corresponding C3\({}^{\prime}\) of flavones), C4 (the corresponding C4\({}^{\prime}\) of flavones), C2\({}^{\prime}\) (the corresponding C5 of flavones) and C4\({}^{\prime}\) (the corresponding C7 of flavones). The inhibition of production of NO increases from isovitexin (**44**) to isoorientin (**47**), suggesting the importance of having on the ring B hydroxy groups at C4\({}^{\prime}\), and another one in the position _ortho_ to it. Finally, the flavonoid fiesetin (**105**) with hydroxy groups on C3, C3\({}^{\prime}\), C4\({}^{\prime}\) and C7 presents an IC\({}_{50}\) against NO production of 13.5 uM, suggesting that the closure of ring C with an oxygen on it is important for the inhibition of NO production. The flavonoid quercetin (**1**) with hydroxy groups on C3, C3\({}^{\prime}\), C4\({}^{\prime}\), C5, and C7 has the ring C closed and has one more hydroxy group at C5 when compared with fiesetin (**105**). In conclusion, quercetin (**1**) should be the flavonoid with the highest activity against NO production when compared to fiesetin (**105**) by presenting a hydroxy group at C5. When compared with butein (**89**), quercetin presents the ring C closed by an atom of oxygen, thus favoring an increase in the hydrogen bonding. When considering the natural flavonoids which inhibit AChE, EGCG, the (2\(R\),3_R_)-3\({}^{\prime}\)_A_\({}^{\prime}\)_,5_\({}^{\prime}\)_,7_-pentahydroyflavan-3-yl 3,4,5-trihydroxybenzoate (**4**), extracted from the leaves of green tea (_Camellia sinensis_ L.), is the most active flavonoid against AChE (IC\({}_{50}\) = 9.6 nM). Although for the other enzymes the scaffold of a flavonoid is the most active one, for inhibiting AChE the more active scaffold is the one presented by catechins. It is interesting that, even for this different scaffold, the presence of hydroxy groups at C5 and C7 and at C3\({}^{\prime}\), C4\({}^{\prime}\) and C5\({}^{\prime}\) increases the inhibition of AChE. The results herein reported only concern the interaction of one flavonoid with the active site of one enzyme. However, as described above, AD has multiple pathogenic factors which may work together through interaction between genetic, molecular and cellular events. Thus, one possible successful strategy might be the use of MTDLs, that is to say, using a multitarget therapy. MTDLs is a therapy where only one active ingredient is administered [113], and so there is no risk of interaction between drugs, as in the case of mixing several compounds. Additionally, the prevision of pharmacokinetic and pharmacodynamics properties is simplified as there is only one single compound. Analyzing the scaffold of the several isolated flavonoids, which inhibit one of the mechanisms of AD, it is concluded that all the described mechanisms--A\(\beta\) plaques, NFTs, pro-inflammatory factors and AChE--are inhibited mostly by flavonoids with a planar core. Even, for the AChE inhibition, nevertheless not being as planar as the scaffolds for flavone or flavonoids, the catechin one presents two rings (A and B) which are completely planar. Ring C is a ring with three carbon atoms in a sp\({}_{3}\) hybridization, and an oxygen atom. So, it is not as planar as rings A and B. The data obtained suggest that the AChE site adjusts better to a molecule with this scaffold. All these data suggest that a biflavonoid where two moieties, one from 3,3',4',5,7-pentadroxyflavone linked by C3 to the C3 of the other moiety, (2\(R\),3_R_)-3',4',5,5',7-pentahydroxflavan-3-yl, i.e., linking quercetin (**1**) to EGCG (**4**). The linkage between the two C3 should be made directly or through a hydrophilic group (X), such as \(\alpha\)-L-rhamnopyranosyl-(1\(\rightarrow\)6)-\(\beta\)-D-glucopyranoside (**163**) (Figure 19).