# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 1 Introduction
Ubiquitously presented in plants, flavonoids, a class of polyphenic compounds, are present in plant-based foods, and so are consumed by humans through the diet. Dietary flavonoids are considered able to cross the blood-brain barrier (BBB) and are known for their CNS-related activity [44]. Flavonoids are biosynthesized through the phenylpropanoid-acetate pathway (Figure 1) [44] as a response to protect themselves against foreign agents such as UV radiation, parasites, or virus, as well as to regulate enzymes involved in cell metabolism [44; 45; 46; 47]. Flavonoids themselves are subdivided in different classes [48]. Those flavonoids with a C6-C3-C6 carbon skeleton may have the structure of a chromane or that of a chromene, with the aromatic ring being designated as ring A and the pyran or the 3,4-dihydro-2\(H\)-pyran as ring C. Ring B is the substituent linked to ring C. The class of flavonoids in restricted sense has ring B linked to chromane/chromene position 2, whereas that of isoflavoids has ring B connected to position 3. Chalcones and dihydrochalcones are flavonoids with a C6-C3-C6 skeleton but ring C is absent (Figure 2). Depending on the oxidation of ring C, flavonoids can be named as flavans, such as the catechins, or flavanones, 3-hydroxyflavanones, flavones and flavonols, when ring C is a pyrone. The several flavonoids differ greatly due to diverse substitutions on the different scaffolds including glycosylation, hydrogenation, hydroxylation, malonylation and alkylation. Usually the scaffolds comprising conjugation, glycosylation or methylation are responsible for several biological properties and for the hydrophilicity of the compounds [47]. Figure 1: Biosynthetic pathway of flavonoids illustrated for naringenin and derivatives. ANS, anthocyanin synthase; CHI, chalcone isomerase; CHR, chalcone reductase; CHS, chalcone synthase; DFR, dihydroflavonol 4-reductase; F3H, flavanone 3-hydroxylase; FLS, flavonol synthase; FNS, flavone synthase; HID, 2-hydroxyisoflavanone dehydrogenase; IFS, isoflavone synthase; LAR, leucoanthocyanin reductase; LDOX, leucoanthocyanidin dioxygenase; UF3 GT, UDP-glucose flavonoid 3-O-glucosyltransferase. Some flavonoids are in clinical trials for the treatment of several signs and symptoms of AD [49]. Examples are quercetin (3,3',4',5,7-pentahydroxyllavone, (**1**), genistein (4',5,7-trihydroxyisoflavone, (**2**), daidzein (4',7-dihydroxyisoflavone, (**3**) and epigallocatechin-3-gallate, the (2R,3R)-3',4',5,7-pentahydroxyllavan-3-yl 3,4,5-trihydroxybenzoate (EGCG, (**4**) (Figure 3 and Table 1). On this review, the several flavonoids from natural sources are presented, which have shown activity on the mechanisms highlighted below (Figure 4 and Table 2). Although several reviews have been presented on the last years, the main objective of this review is to recognize and discuss, for each CI, the scaffolds leading to the highest activity (lower IC\({}_{50}\)) and so to attempt to achieve molecules targeting more than one CI, the multitarget-directed ligands (MTDLs), which have the potential to become a lead in AD treatment. In addition, the log10 value of the partition coefficient (LogP) of flavonoids discussed in this review is also presented in Table 2. This constant is a measure of lipophilicity of a compound that can be used as a quick and simple prediction of its BBB permeability.