Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain

Abstract

A high throughput screening was carried out in order to search for inhibitors of acetylcholinesterase (AChE) from microorganism metabolites. An actinomycete strain was found to produce active compounds named N98-1272 A, B and C with IC₅₀ of 15.0, 11.5, 12.5 μM, respectively. Structural studies revealed that the three compounds are identical to the known antibiotics, Manumycin C, B and A. Kinetic analyses showed that N98-1272 C (Manumycin A) acted as a reversible noncompetitive inhibitor of acetylcholinesterase, with a Ki value of 7.2 μM. The cyclohexenone epoxide part of the structure plays a crucial role in the inhibitory activity against AChE. Compared with Tacrine, N98-1272 A, B, and C exhibit much better selectivity toward AChE over BuChE.

Keywords::

• Alzheimer's disease
• acetylcholinesterase
• noncompetitive inhibitor
• manumycin

Acknowledgements

This work was supported by the Chinese Ministry of Science and Technology in Mega-projects of Science Research for the 10th Five-Year Plan (Grant No. 2002AA2Z343D). We wish to express our thanks to Professor Yanchang Wang and Professor Randy Rill (Department of Biomedical Sciences, College of Medicine, Florida State University, U.S.A), Dr. Shaun K. Olsen and Dr. Yong Xie (Riken, Yokohama Institute, Japan) for their help in English revision and valuable suggestions.