Benzene‐1,2‐, 1,3‐, and 1,4‐di‐ N ‐substituted carbamates as conformationally constrained inhibitors of acetylcholinesterase

Abstract Benzene‐1,2‐, 1,3‐, and 1,4‐di‐ N ‐substituted carbamates (1–15) are synthesized as the conformationally constrained inhibitors of acetylcholinesterase and mimic gauche , eclipsed , and anti ‐conformations of acetylcholine, respectively. All carbamates 1–15 are characterized as the pseudo substrate inhibitors of acetylcholinesterase. For a series of geometric isomers, the inhibitory potencies are as follows: benzene‐1,4‐di‐ N ‐substituted carbamate ( para compound) > benzene‐1,3‐di‐ N ‐substituted carbamate ( meta compound) > benzene‐1,2‐di‐ N ‐substituted carbamate ( ortho compound). Therefore, benzene‐1,4‐di‐ N ‐substituted carbamates ( para compounds), with the angle of 180° between two C(benzene)–O bonds, mimic the preferable anti C–O/C–N conformers of acetylcholine for the choline ethylene backbone in the acetylcholinesterase catalysis. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:348–353, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20202