# Terpenes as Potential Anti-Alzheimer's Disease Agents
## 2 Activities of Terpenes on the Mechanisms Associated with AD
### Inhibition of Acetylcholinesterase (AChE)
#### 2.4.2. Sesquiterpenes  
Farnesene (**106**), also found in essential oils of several plants, revealed high AChE inhibitory activity in a Marston assay [121]. Cornigeraline A (**107**), a chlorinated sesquiterpene lactone, extracted from wild articohoke (_Cynara cornigena_ L.) native to the Mediterranean region, northwestern Africa, and the Canary Islands, presents an IC\({}_{50}\) value of 20.5 uM as an inhibitor of AChE [114; 122]. From the same plant, sibthorpein (**108**), 3-hydroxy-grosheimin (**109**), grosheimin (**110**), solstitalin A (**111**), 13-chlorosolstitialine (**112**), and cynaropicrin (**113**) also presented AChE inhibition with IC\({}_{50}\) values of 35.8, 30.5, 61.8, 25.7, 62.1, and 31.3 uM, respectively [114]. Cornigeraline A (**107**) is the most active, suggesting that the chlorine atom is important for the inhibition of AChE; however, when it is compared with its epimer, 13-chlorosolstitialine (**112**), the activity of the latter decreases 3-fold. As cornigeraline A (**107**) possess two hydrophobic moieties located in the sesquiterpene nucleus, which is close to C10 and between C1 and C3, it might pass through the BBB. Sesquiterpenenes with a dihydro-\(\beta\)-agaofuran skeleton were isolated from aerial parts and seeds of _Mayetens disticha_ (Hook F.) at Chile. They were identified as 1\(\alpha\),6\(\beta\),8\(\alpha\)-triacetoxy-9\(\beta\)-furoyloxy-\(\beta\)-agaofuran (**114**), 1\(\alpha\)-hydroxy-6\(\beta\),8\(\alpha\)-diacetoxy-9\(\beta\)-furoyloxy-\(\beta\)-agaofuran (**116**), 1\(\alpha\)-acetoxy-6\(\beta\),8\(\alpha\)-dihydroxy-9\(\beta\)-furoyloxy-\(\beta\)-agaofuran (**117**), 1\(\alpha\),2\(\alpha\),6\(\beta\),8\(\alpha\)-pentaacetoxy-9\(\beta\)-benzoyly-\(\beta\)-agaofuran (**118**), 1\(\alpha\),2\(\alpha\),3\(\beta\),15-tetraacetoxy-6\(\beta\),9\(\beta\)-dibenzoyl-8-oxo-\(\beta\)-agaofuran (**119**), 1\(\alpha\),6\(\beta\),15-triacetoxy-9-benzoyly-\(\beta\)-agaofuran (**120**), 2\(\alpha\),3\(\beta\),6\(\beta\),8\(\alpha\),15-pentaacetoxy-1\(\alpha\),9\(\beta\)-benzoyly-\(\beta\)-agaofuran (**121**), and 1\(\alpha\)-acetoxy,6\(\beta\),9\(\beta\)-difluoroxy-4\(\beta\)-hydroxy-\(\beta\)-agaofuran (**122**). The IC\({}_{50}\) values for the inhibition of AChE were 248, 738, 161, 312, 122, 463, 695, 482, and 738 \(\mu\)M, respectively. These results show that these compounds are weak but selective inhibitors of AChE [114; 123]. Five caryophilene-type sesquiterpenes (compounds **123-127**) were isolated from the aerial parts of _Pulicaria vulgaris_ Gaerntn. collected at Monastir (Tunisia). While compounds (15,5Z,9R,11S)-12,14-dihydroxycaryophylla-2(15),5-dien-7-one (**127**) and (15,6\(R\),9S,11R)-13,14-dihydroxycaryophyll-2(15)-en-7-one (**124**) presented AChE inhibition with IC\({}_{50}\) values of 25.8 and 40.0 \(\mu\)M, respectively, the other compounds, pulicaryenne A (**123**), (5Z)-14-hydroxycaryophyll-7-one (**125**), and (15,5Z,9R)-12-acetoxy-14-hydroxycaryophylla-2(15),5-dien-7-one (**126**) were much weaker as inhibitors of AChE, presenting IC\({}_{50}\) values of 214.9, 108.3, and 101.2 \(\mu\)M, respectively. This difference in behavior can be explained by the different substitution pattern on carbons C-5, C-6, and C-11 and the difference in the configuration of the stereogenic centers on the caryophyllene basic scaffold. For instance, when comparing the scaffold of compounds **127** and **124**, the first does not present a C6 asymmetric center being replaced by an endocyclic double bond (C5-C6) [114; 124]. The molecule **127** becomes much more planar as the endocyclic bond has the configuration Z and is conjugated with the carbonyl group located at C7. When comparing **126** and **127**, the acetylation of the alcohol at C12 on compound **127** explains the attenuation of the AChE inhibition of compound **126**[124]. Artemisinin (**53**), from _A. annuau_ in Cameroon, exhibits moderate AChE inhibition with an IC\({}_{50}\) value of 103.9 uM [125].