## 5 Trepenes
### Pentacyclic Triterpene Acids  
Pentacyclic triterpenes are a group of terpenids identified in extracts of _U. tomentosa_. The core structure of pentacyclic triterpenes consists of five fused six-member rings. Common substitutions to the ring structure include a hydroxy group at C-3, methyl groups at C-10, C-8, C-27, C-19, and C-20, dimethyl groups at C-4 and C-20, carboxylic acids groups at C-17 and C-14, and a double bond at C-12. In general, these compounds are not very soluble in water giving them a low bioavailability and imparting challenges for biomedical applications. The plant biosynthesis of these compounds is thought to proceed through the intermediate \(\beta\)-amyrin [114]. It is known that these compounds accumulate in surface regions of stems and leaves, with evidence pointing toward a possible role in protection from dehydration or herbivores [114].  
The plant _U. tomentosa_ contains four varieties of pentacyclic triterpenes. The types of pentacyclic triterpenes include oleanolic, cincholic, torsolic, and quinovic acid (Figure 9). The pentacyclic triterpene families identified in _U. tomentosa_ include a hydroxy group at C-3, a dimethyl substitution at C-4, methyl substitutions at C-10 and C-8, and a carboxylic acid at C-17. Variations to the core structure that distinguish each type of pentacyclic triterpene exist at C-14, C-19, and C-20. Compound **63** contains a methyl group at C-14, and a dimethyl group at C-20, whereas **64** contains a carboxylic acid at C-14 and dimethyl group at C-20. Compound **65** contains a methyl group at C-14, C-19, and C-20, whereas **66** contains a methyl group at C-19 and C-20 and a carboxylic acid at C-14.  
Figure 9: Triterpene acid structures (63–66).  
Several of the above pentacyclic triterpene acids above have been investigated for antibacterial activity. Compound **65** is the most extensively studied of the group as an antibacterial, with both reviews and individual studies available. Antibacterial evidence collected on **65** reveals a stronger inhibitory effect on Gram-positive bacteria than Gram-negative bacteria [125]. There has been specific interest in testing **65** and its derivatives to combat MRSA, as well as other drug resistant bacteria [126]. The mechanisms of antibacterial activity can be attributed to several factors including its ability to adhere to the cell membrane, reducing the bacteria's ability to adhere to epithelial cells, as well as its ability to disrupt and impair the bacterial cell membranes both inside and outside the cell [125]. In addition to targeting the bacterial membrane, **65** also exhibits antibiofilm activity [125], with some evidence supporting its ability to reduce expression of genes related to biofilm production [127, 128]. Additional evidence supporting the synergistic effect of these compounds when used in combination with existing antibiotics also exists [126]. The issue surrounding the utilization of **65** is its low in vivo bioavailability, due to its poor solubility; however, these attributes can likely be improved by structural modifications, which has become a topic of several investigative studies [129, 130, 131].  
The antibacterial activity of **63** has also been investigated. Like **65**, activity seems to increase in Gram-positive bacteria compared to Gram-negative bacteria. MIC values obtained from a microbroth dilution test were 64 \(\upmu\)g/mL for _S. aureus_ (ATCC 25923), 32 \(\upmu\)g/mL for _S. aureus_ (ATCC 29213), and 8 \(\upmu\)g/mL for _E. faecalis_ (ATCC 29212), while reported values of 256 \(\upmu\)g/mL and above were found for _E. coli_ (ATCC 25922) and _P. aeruginosa_ (ATCC 27853) [132]. A review on the antibacterial activity of **63** against several bacterial strains can be found in reference [133]. A synergistic effect has also been noted when compound **63** and **65** were utilized with \(\beta\)-lactam-type antibiotics [134]. Antibacterial activity of compounds **64** and **66** was not found during the literature search.