# 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
Isovitexin (**44**), the regioisomer of vitexin having the \(\beta\)-d-glucopyranosyl group linked to C6, is inactive (IC\({}_{50}\) > 100 uM) [79]. The same happens when the \(\beta\)-d-glucopyranosyl group is linked to OH-5. Indeed, the 5-O-(\(\beta\)-d-glucopyranosyl)luteolin (**45**) is also inactive against BACE1 (IC\({}_{50}\) = 969.75 uM) [74]. Orientin, the 8-(\(\beta\)-d-glucopyranosyl)-3\({}^{\prime}\),5,7-tetrahydrooxyflavone (**46**), and isoorientin, the 6-(\(\beta\)-d-glucopyranosyl)-3\({}^{\prime}\),4\({}^{\prime}\),5,7-tetrahydroxyflavone (**47**), with the \(\beta\)-d-glucopyranosyl group, respectively on C8 and C6, are also weak inhibitors of BACE1 with IC\({}_{50}\) of 15.95 and 20.88 uM, respectively [76]. Seven alkyl-substituted flavones from methanol extract of _Morus lhou_, namely kuwanon C (**48**), morusin (**49**), kuwanon A (**50**), cyclomorusin (**51**), morusinol (**52**), neocyclomorusin (**53**) and mormin (**54**), present BACE1 IC\({}_{50}\) values of 3.40, 59.40, 5.30, 102.20, 135.90, 146.10 and 103.50 uM, respectively, suggesting that BACE1 inhibition is significantly influenced by the presence of two hydroxy groups at ring B and the isoprenyl group at C3 [52; 82]. Several biflavones exhibit BACE1 inhibitory activity. Amentaflavone-type flavonoids, where the flavonoid moieties are connected through a C3\({}^{\prime}\)-C8\({}^{\prime}\) bond, showed BACE1 inhibition. Robustaflavone (**55**), cupressuflavone (**56**), and hinokiflavone (**57**), biflavones where the two flavonoid moieties are connected through, respectively, C3\({}^{\prime}\)-C6\({}^{\prime}\), C8-C8\({}^{\prime}\) and C4\({}^{\prime}\)-C6\({}^{\prime\prime}\) bonds, are inactive [84]. Amentoflavone (**58**) and all the monomethoxy analogs of it, sequoiaflavone (**59**), bilobetin (**60**), setotsuflavone (**61**), and podocarpusflavone A (**62**), showed a strong BACE1 inhibition (IC\({}_{50}\) range of 0.99-2.02 uM). The dimethoxy amentoflavones ginkgetin (**63**), amentoflavone-7,7\({}^{\prime\prime}\)-dimethyl ether (**64**), podocarpusflavone B (**65**), and isoginkgetin (**66**) showed a decrease in the BACE1 inhibition (IC\({}_{50}\) range of 3.01-6.25 uM) when compared with their monomethoxy analogs. The other dimethoxy amentoflavones, 4\({}^{\prime}\),7\({}^{\prime\prime}\)-di-O-methylamentoflavone (**67**) and 7\({}^{\prime\prime}\),4\({}^{\prime\prime}\)-di-O-methylamentoflavone (**68**), were inactive, as well as the trimethoxy amentoflavones, 4\({}^{\prime}\),7,7\({}^{\prime\prime}\)-tri-O-methylamentoflavone (**69**), sciadipitysin (**70**), heveaflavone (**71**), and kayaflavone (**72**), and the tetramethyl amentoflavone, 7,7\({}^{\prime\prime}\),4\({}^{\prime}\),4\({}^{\prime\prime}\)-tetra-O-methylamentoflavone (**73**). The 2,3-dihydroamentoflavone (**74**) showed an increase in BACE1 inhibition (IC\({}_{50}\) = 0.75 uM) whereas 2,3-dihydro-6-methylginkgetin (**75**) showed the strongest inhibitory activity (IC\({}_{50}\) = 0.35 uM) [84]. Thus, it can be concluded that the amentaflavone-type biflavonoids, which have a scaffold consisting of two apigenin molecules linked by the C3\({}^{\prime}\) of one molecule with the C8\({}^{\prime\prime}\) of the other apigenin molecule, have significant inhibitory activity against BACE1. The results suggest that more than two hydroxy groups at C7, C4\({}^{\prime}\), C7\({}^{\prime\prime}\) and C4\({}^{\prime\prime}\) are needed for the inhibitory activity of the biflavonoid. From the data obtained for the biflavones **74** and **75** it can be concluded that the presence of a flavanone moiety in these amentaflavone-type biflavonoids increases the BACE1 inhibition, even more so if there is a methyl group at C6 to increase the hydrophobic interactions with the enzyme [84]. Figure 7 shows the chemical structure of flavones (compounds **29-75**) that inhibit BACE1 with an IC\({}_{50}\) range of 0.35 to 146.10 uM, except for compounds **44**, **45**, **55**-**57** and **67**-**73** that were inactive. Figure 7: _Cont._