# Terpenes as Potential Anti-Alzheimer's Disease Agents
## 3 Discussion  
At present, 221 terpen, isolated mainly from plants, have been studied as possible anti-AD agents: 2 (0.9%) trutterpenes, 114 (51.6%) triterpenes, 17 (7.7%) diterpenes, 35 (15.8%) sesquiterpenes, 24 (10.9%) monoterpenes, and 29 (13.1%) meroterpenes. The most active terpen against BACE1 are the meroterpenes asperterpene B (**12**) (IC\({}_{50}\) = 0.06 \(\upmu\)M) and asperterpene A (**11**) (IC\({}_{50}\) = 0.08 \(\upmu\)M), followed by the triterpene 218-hydroxyserrat-14-en-3,16-dione (**36**) (IC\({}_{50}\) = 0.2 \(\upmu\)M). These results suggest that in aspertene A (**11**) and B (**12**), the 1,2,5-trimethyl-4,9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic acid moiety is significant for the inhibition of BACE1. Indeed, the bridge between carbons C1 and C4 of the cyclootene and the extended conjugated system comprising the double bond between C2 and C3, the carboxylic group linked to C3, and the carbonyl group of C4 makes the molecule planar. Concerning the triterpenes, the conjugated system comprising the double bond between C14 and C15 and the carbonyl group of C16 of 218-hydroxyserrat-14-en-3,16-dione (**36**) makes the ring more planar. Thus, planarity and an extensive \(\uppi\) system in the molecule is one of the requirements for terpen be active against BACE1. Tetrahydroaylsulphurin-1 (**5**), a gracilin, increases the levels of the inactive isoform of GSK3\(\beta\) (57.1 \(\pm\) 24.75%) at 0.1 \(\upmu\)M. All the other gracilins (compounds **3**, **4**, and **6**) are inactive, suggesting that the fusion of the three rings on the scaffold of tetrahydroaylsulphurin-1 (**5**) is significant for the inhibition of GSK3\(\beta\). Unfortunately, this is the only result for the inhibition of GSK3\(\beta\), thus not allowing any other structure-inhibition relationships of GSK3\(\beta\) for the terpene compounds. The triterpenes methyl kulonate (methyl 3-oxo-16\(\beta\)-hydroxyeupha-7,24-dien-21-oate) (**66**) and 3\(\beta\)-hydroxy-24-nor-urs-4(23),12-dien-28-oic acid (**67**) exhibit potent inhibitory activity against NO production, with IC\({}_{50}\) values of 4.6 and 10.1 uM, respectively. Compound **66** presents on its scaffold a carbonyl group at C3, rendering planarity to ring A, as well as possible \(\pi\)-\(\pi\) stacking interactions with the enzyme. The double bond between C7 and C8 renders planarity to rings B and C. Compound **67** presents on its scaffold an exocyclic double bond between C4 and C23, also rendering planarity to ring A, as well as possible \(\pi\)-\(\pi\) stacking interactions with the enzyme. The double bond between C12 and C13 renders planarity to rings C and D.  
When considering the terpenes that inhibit AChE, the serrate-type terpene 3\(\beta\),21\(\alpha\)-diacetoxyserratan-14\(\beta\)-ol (**37**) is the most active terpene as inhibitor of AChE (IC\({}_{50}\) = 0.9 uM). Comparing the scaffold of 3\(\beta\),21\(\alpha\)-diacetoxyserratan-14\(\beta\)-ol (**37**) with that presented by 3\(\beta\),21\(\beta\),29-trihydroxyserrat-14-en-3\(\beta\)-yl _p_-dihydrocumarate (**34**) (IC\({}_{50}\) = 1.7 uM), it can be concluded that the presence of an acetyl group on C21 (compound **37**) increases the activity when it replaces a hydroxy group (compound **34**). 26-Nor-8-oxo-21-one-\(\alpha\)-onocerin (**148**) (IC\({}_{50}\) = 1.0 uM) also presents two carbonyl groups but in different carbons (C8 and C21). In conclusion, the presence of the two carbonyl groups is significant for the inhibition of AChE when serrate-type terpen are considered. The cucurbitane-type triterpenes colocynthenin A (**149**) (IC\({}_{50}\) = 2.6 uM) and colocynthenin C (**151**) (IC\({}_{50}\) = 3.1 uM) are significant inhibitors of AChE, suggesting that the opening of ring A of the triterpene and the presence of a carboxylic group is significant for the inhibition of AChE for the scaffold of cucurbitane-type triterpenes. The sesquiterpene megatigma-7,9-diene-1,4-epoxy-2-hydroxy-10-carboxylic acid (**134**) also presents an important inhibition of AChE (IC\({}_{50}\) = 9.3 uM).