Plant-derived terpenes are the prolific source of modern drugs such as taxol, chloroquine and artemisinin, which are widely used to treat cancer and malaria infections. There are research interests in recent years on terpene-derived metabolites (diterpenes, triterpenes and sesquiterpenes), which are believed to serve as excellent cholinesterase inhibitors. As cholinesterase inhibitors are the current treatment for Alzheimer’s disease, terpene-derived metabolites will have the potential to be involved in the future drug development for Alzheimer’s disease. Hence, a bibliographic search was conducted by using the keywords “terpene”, “cholinesterase” and “Alzheimer’s disease”, along with cross-referencing from 2011 to 2020, to provide an overview of natural terpenes with potential anticholinesterase properties. This review focuses on the extraction, chemical structures and anti-cholinesterase mechanisms of terpenes, which support and encourage future research on drug discovery and development in treating Alzheimer’s disease.

A new indole alkaloid, naucline (1) together with four known alkaloids, angustine (2), angustidine (3), nauclefine (4) and naucletine (5), were isolated from the bark of Nauclea officinalis. The structures of all isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS-IT-TOF. In addition to that of alkaloid 1, the complete ¹³C-NMR data of naucletine (5) were also reported. Naucline (1) showed a moderate vasorelaxant activity (90% relaxation at 1 × 10⁻⁵ M) whereas, angustine (2), nauclefine (4), and naucletine (5) showed potent vasorelaxant activity (more than 90% relaxation at 1 × 10⁻⁵ M) on an isolated rat aorta.

The mammalian hyaluronidase degrades hyaluronic acid by the cleavage of the β-1,4-glycosidic bond furnishing a tetrasaccharide molecule as the main product which is a highly angiogenic and potent inducer of inflammatory cytokines. Ursolic acid 1, isolated from Prismatomeris tetrandra, was identified as having the potential to develop inhibitors of hyaluronidase. A series of ursolic acid analogues were either synthesized via structure modification of ursolic acid 1 or commercially obtained. The evaluation of the inhibitory activity of these compounds on the hyaluronidase enzyme was conducted. Several structural, topological and quantum chemical descriptors for these compounds were calculated using semi empirical quantum chemical methods. A quantitative structure activity relationship study (QSAR) was performed to correlate these descriptors with the hyaluronidase inhibitory activity. The statistical characteristics provided by the best multi linear model (BML) (R² = 0.9717, R²_cv = 0.9506) indicated satisfactory stability and predictive ability of the developed model. The in silico molecular docking study which was used to determine the binding interactions revealed that the ursolic acid analog 22 had a strong affinity towards human hyaluronidase.

Phytochemical investigation on the bark of Nauclea officinalis led to the isolation of a new monoterpenoid indole alkaloid, nauclediol. The structure of the compound was identified through extensive spectroscopic analysis. Nauclediol displayed cholinesterase-inhibitory activities towards AChE and BChE with IC₅₀ values of 15.429 and 8.756 µM, respectively. Statistical analysis revealed that the mode of inhibition of nauclediol was non-competitive inhibitor for both AChE and BChE. Molecular docking revealed that nauclediol interacts with the choline-binding site and the catalytic triad of TcAChE and hBChE. This study also demonstrated the neuroprotective potential of nauclediol against amyloid beta-induced cytotoxicity and LPS-induced neuroinflammation activity in a dose-dependent manner.