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

AbstractBenzene‐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