Anti-acetylcholinesterase Activity Constituents From Three Medicinal Plants

Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized clinically by the loss of memory and dysfunctions of language and behavior, which is the most common form of senile dementia. Currently, acetylcholinesterase inhibitors (AChEI) have become the most effective drug for used in the treatment of AD. The medicinal constituents of natural plant have many obvious advantages, including effective therapy, low side-effect, broaden action and suitable takeing. In this thesis, acetylcholinesterase (AChE ) inhibitory activity from three medicinal plants were investigated. The main contents and results were as follows:1. The research on activity constituents of anti-AChE from Uncaria rhynchophyllaSeven compounds have been isolated from Uncaria rhynchophylla by bioassay -guided. These compounds were identified as geissoschizine methyl ether (1), vallesiachotamine (2), hisuteine (3), hirsutine (4), isorhynchophylline (5), isocorynoxeine (6) and corynoxeine (7), respectively. Their anti-AChE activity were tested by modified Ellman's method. The results showed that compound 1 is a potent natural AChEI with an IC50 value 10μM. The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of the compound with AChE. The result revealed that the carbonyl at C-22 position of geissoschizine methyl ether (1) formed an H-bond with the hydroxyl of Tyr-72 in AChE, which may explain why geissoschizine methyl ether (1) has inhibitory effect on AChE.2. The research on activity constituents of anti-AChE from Fritillaria ussuriensisSix compounds have been isolated from Fritillaria ussuriensis by bioassay -guided. These compounds were identified as ussuriedine (8), Benzo[7,8] fluoreno[2,1-b]quinolizine cevane-3,6,16,20-tetrol (9), ebeiedinone (10), pingbeimuone A (11), pingbeimine C (12) and verticine (13), respectively. Of these, 11 is a new compound. Their anti-AChE activity were tested by modified Ellman's method. The results showed that these compounds have weak or no AChE inhibitory activity.3. The research on activity constituents of anti-AChE from Holarrhena antidysentericaFive compounds have been isolated from Holarrhena antidysenterica by bioassay -guided. These compounds were identified as conessine (14), isoconessimine (15), conessimin (16), conarrhimin (17) and conimin (18), respectively. Their anti-AChE activity were tested by modified Ellman's method. The results showed that compounds 14, 16, 17 and 18 are potent natural AChEI with IC50 value 21μM, 4μM, 28μM and 23μM, respectively. The results of molecular modeling indicated that compounds 16 and 14 could bind in the active site gorge of AChE by the same form and compounds 17 and 18 could also bind in the active site gorge of AChE by the other form. In both cases, compounds 14, 16, 17 and 18 are located in the hydrophobic gorge of AChE , which can be efficiently inhibit AChE. However, Compound 15 could not bind in the active of AChE. This is consistent with the experimental results of Ellman's method, and may explain the observed differences in inhibitory activity. The mode of AChE inhibition by 16 was reversible and non-competitive.Five compounds (1, 14, 16, 17 and 18) were first reported as potent AChE inhibitor in this thesis. These compounds can be became leads and then by the further modification of structure developed into new drugs for the treatment of AD.