The Alkaloidal Acetylcholinesterase Inhibitors From Plants

Alzheimer’s disease (AD) is a degenerative disorder of the central nervoussystem characterized clinically by the loss of memory and dysfunctions of languageand behavior, which is the most common form of senile dementia.Acetylcholinesterase inhibitors (AChEI) have become the most effective drug for usedin the treatment of AD. The medicinal constituents of natural plant have manyobvious advantages, including effective therapy, low side-effect, broaden action andsuitable takeing. In this thesis, to search for natural AChEIs, acetylcholinesterase(AChE) inhibitory activities of twenty-two species of plants total alkaloidal extractswhich collected from Wenxian and Zhouqu, Gansu Province were tested. And theAChE inhibitory activities for the alkaloidals from Stemona sessilifolia were alsoinvestigated.In this thesis, the total alkaloidal extracts of22species of plants were tested fortheir AChE inhibitory activity, for the alkaloidal extracts that were shown significantinhibition, the IC50values were also determined. The results showed that alkaloidalextracts from Thalictrum uncinulatum Franch.(Ranunculaceae), Mahnia bealei (Fort.)Steam.(Berberidaceae), Zanthoxylum dissitum Hemsl.(Rutaceae), Arisaemaaspeiatum N.E.Brown (Araceae), Arisaema erunescens (Wall.) Schott (Araceae),Decaisnea insignis (Griff) Hook.f.et thoms (Lardizabalaceae), Saxifraga stoloniferacurt.(Saxifragaceae) and Impotiens notolopha Maxim.(Balsaminaceae) exhibitedremarkable AChE inhibitory activities with the IC50values of2.3μg·mL-1、2.9μg·mL-1、3.5μg·mL-1、11.0μg·mL-1、16.9μg·mL-1、22.7μg·mL-1、25.3μg·mL-1and40.7μg·mL-1, respectively. The eight total alkaloidal extracts were found havingstrong activity against AChE, Which can be further performed bio-guided isolation toobtain responsible compounds. The rest of the alkaloidal extracts showed no or veryweak AChE inhibitory activity.In this thesis, AChE inhibitory activities for the alkaloidals which from Stemonasessilifolia were also investigated. Seven compounds have been isolated fromStemona radix by bioassay-guided. Based on the modern spectroscopic methods(1HNMR,13CNMR,2D-NMR, EI-MS, etc.), these compounds were identified as:Stenine A (1), Stenine B (2), Neostenine (3), Neotuberostemonine (4), Stenine (1),respectively. Of these, compound1and2are new compounds. Their anti-AChEactivities were tested by modified Ellman’s method. The results showed thatcompounds2and5are potent natural AChEI with IC50value2.1±0.2μM and 19.8±2.5μM, respectively. The mode of AChE inhibition by2was reversible andcompetitive. Molecular modelling was performed to explore the binding mode of thecompound with AChE. The results indicated that compounds2acts internally aroundthe Trp84, Oxygen in the lactone ring of compound2formed an H-bond with thehydroxyl of Tyr-130in AChE, which have the same hydrogen bonding interactionswith AChE as the huperzine A. This showed that the oxygen in the lactone ring iscrucial for compound2with high AChE inhibitory activity. In addition, the calculatedbinding free energy of compounds in molecular docking study was found to correlatewell with its inhibition. This showed that the AChE inhibitory activity of compoundsin the experiments were reliable.Two compounds (2,5) were first reported as potent AChEI and two newcompounds (1,2) were reported in this thesis. These compounds can be became leadsand then by the further modification of structure developed into new drugs for thetreatment of AD.