Benzene-1,2-, 1,3-, and 1,4-di-N-substituted carbamates as conformationally constrained inhibitors of acetylcholinesterase.
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 degrees 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.
Lin
Ming-Cheng
MC
Institute of Medicine, Department of Cardiology, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
Hwang
Mei-Ting
MT
Chang
Han-Ging
HG
Lin
Chung-Sheng
CS
Lin
Gialih
G
D000109:Acetylcholine / Q000737:chemistry; D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001554:Benzene / Q000737:chemistry* / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004593:Electrophorus / Q000378:metabolism*; D007700:Kinetics; D016018:Least-Squares Analysis; D008968:Molecular Conformation; D013379:Substrate Specificity / Q000187:drug effects
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D001554:Benzene; D000109:Acetylcholine