# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 2 Activities of Flavonoids from Natural Sources
### Inhibition of Acetylcholinesteraseerase (AChE)  
#### 2.4.1 Catechins, Flavanones and 3-Hydroxylavanones  
EGCG (**4**), extracted from the leaves of green tea (_Camelia sinensis_ L.), is a very potent inhibitor of AChE (IC\({}_{50}\) = 9.6 nM) [58] whereas catechchin (**107**) is inactive [97], suggesting that the hydroxy group at C5\({}^{\prime}\) increases the hydrogen bonding to the enzyme. Naringenin (**6**) presents AChE inhibition, with an IC\({}_{50}\) of 3.81 uM [60], pinostrobin (**8**) is inactive, having an IC\({}_{50}\) > 236.79 uM [62], and naringin (**85**) has an IC\({}_{50}\) of 26.40 uM [60], indicating that activity is increased by the hydroxy group at C4\({}^{\prime}\) and decreased by alkylation at C7. From the seeds of _Milletia pachyarpa_ Benth, two compounds were isolated, namely: dorspoinsetofiloin, the 4\({}^{\prime}\)-methoxy-6\({}^{\prime\prime}\),6\({}^{\prime\prime}\)-dimethyldihydropyproprano [2\({}^{\prime\prime}\),3\({}^{\prime\prime}\),7,8]flavanone) (**108**), that presents an AChE IC\({}_{50}\) of 91.07 uM and 4\({}^{\prime}\)-hydroxysiolsonchoocarpin (4\({}^{\prime}\)-hydroxy-6\({}^{\prime\prime}\),6\({}^{\prime\prime}\)-dimethyldihydropyproprano [2\({}^{\prime\prime}\),3\({}^{\prime\prime}\),7,8]flavanone) (**109**), which was inactive, suggesting how important is for flavanones the methoxy group at C4\({}^{\prime}\) for the AChE inhibition [98]. The glycosylatedflavanones didymin (**17**), prunin (**19**) and poncirin (**18**), also present AChE inhibition with IC\({}_{50}\) values of 2.13, 6.31 and 12.96 uM, respectively [59], or hesperidin (**20**) with an IC\({}_{50}\) of 22.80 uM [66]. Five geranylatedflavanones, isolated from Okinawa propolis, exhibit AChE IC\({}_{50}\) values ranging from 7.23 to 15.70 uM, as follows: 6-geranyl-3\({}^{\prime}\),4\({}^{\prime}\),5,7-tetrahydrooxyflavan-4-one (nymphaeol A, **110**, 7.77 uM); 2\({}^{\prime}\)-geranyl-3\({}^{\prime}\),4\({}^{\prime}\),5,7-tetrahydrooxyflavan-4-one (nymphaeol B, **111**, 15.09 uM); 2\({}^{\prime}\)-geranyl-3\({}^{\prime}\),4\({}^{\prime}\),5,7-tetrahydrooxy-6-(3-methylbut-2-enyl)flavan-4-one (nymphaeol C, **112**, 15.70 uM); 5\({}^{\prime}\)-geranyl-3\({}^{\prime}\),4\({}^{\prime}\),5,7-tetrahydrooxyflavan-4-one (isonymphaeol B, **113**, 7.23 uM); and (25)-3\({}^{\prime}\)-geranyl-4\({}^{\prime}\),5,7-trihydroxyflavan-4-one (3\({}^{\prime}\)-geranylnaringenin, **114**, 12.34 uM) [99]. These results might suggest a steric hindrance by the geranyl group (3,7-dimethylocta-2,6-dienyl) when it is linked to C2\({}^{\prime}\). It should also be highlighted that pharmacokinetics and toxicological properties determination suggest that these propolis components might be beneficial in inflammation and AD treatment [99]. From _Paulovonia tometosa_ Steud. another series of five geranylated flavanones were extracted, exhibiting AChE inhibition with IC\({}_{50}\) range of 22.90 to 316.30 uM as follows: (2\(R\),3\(R\))-6-geranyl-3\({}^{\prime}\),5,7-trihydroxy-4\({}^{\prime}\)-methoxyflavan-4-one (4\({}^{\prime}\)-\(O\)-methyldiplacone, **115**, 92.40 uM); (2\(R\),3\(R\))-6-geranyl-4\({}^{\prime}\),5,7-trihydroxy-3\({}^{\prime}\)-methoxyflavan-4-one (3\({}^{\prime}\)-\(O\)-methyldiplacone, **116**, 109.20 uM); 6-geranyl-3\({}^{\prime}\),5,7-tetrahydroxy-4\({}^{\prime}\)-methoxyflavan-4-one (**117**, 22.90 uM); (2\(R\),3\(R\))-6-geranyl-4\({}^{\prime}\),5,7-trihydroxyflavan-4-one (mimulone, **118**, 91.50 uM); and 6-geranyl-4\({}^{\prime}\),5,7-trihydroxy-3\({}^{\prime}\),5\({}^{\prime}\)-dimethoxy3 flavan-4-one (**119**, 316.30 uM) [100]. These results suggest how important is the presence of two hydroxy groups on ring B for the hydrogen bonding of the flavanone to the enzyme.