Steroidal alkaloids from Holarrhena antidysenterica as acetylcholinesterase inhibitors and the investigation for structure-activity relationships

Aims: Inhibition of acetylcholinesterase (AChE) is still considered as a strategy for the treatment of neurological disorders such as Alzheimer's disease (AD). Many plant derived alkaloids (such as huperzine A, galanthamine and rivastigmine) are known for their AChE inhibitory activity. The aim of the present work was to isolate and identify new AChE inhibitors from Holarrhen antidysenterica. Main methods: These compounds were tested for AChE inhibiting activity by the Ellman's method in 96-well microplates. In addition, molecular modeling was performed to explore the binding mode of inhibitors 1-5 at the active site of AChE, and the preliminary structure-activity relationships (SARs) were discussed. Key findings: In the course of searching for AChE inhibitors from herb medicines, the total alkaloidal extract from the seeds of H. antidysenterica was found having potent AChE inhibitory activity with an IC50 value of 6.1 mu g/mL Further bioactivity-guided chromatographic fractionation afforded five steroidal alkaloids, conessine 1, isoconessimine 2, conessimin 3, conarrhimin 4 and conimin 5. All the isolated compounds, except for 2, showed strong AChE inhibiting activity with IC50 values ranging from 4 to 28 mu M. The most active inhibitor is compound 3 with an IC50 value of 4 mu M. The mode of AChE inhibition by 3 was reversible and non-competitive. Significance: The results suggest that these alkaloids could be potential candidates for further development of new drugs against AD. (c) 2012 Elsevier Inc. All rights reserved.