Synthesis and Study of Thiocarbonate Derivatives of Choline as Potential Inhibitors of Acetylcholinesterase

• Published in: Journal of medicinal chemistry Vol. 40; no. 19; pp. 3009 - 3013
• Main Authors: Boyle, Nicholas A. J, Talesa, Vincenzo, Giovannini, Elvio, Rosi, Gabriella, Norton, Scott J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 12.09.1997
• Subjects: Acetylcholinesterase - metabolism; Animals; Biological and medical sciences; Carbonates - chemical synthesis; Carbonates - chemistry; Carbonates - pharmacology; Cattle; Choline - analogs & derivatives; Choline - chemical synthesis; Choline - chemistry; Choline - pharmacology; Cholinergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Erythrocytes - enzymology; Humans; Indicators and Reagents; Kinetics; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Octopodiformes; Pharmacology. Drug treatments; Prosencephalon - enzymology; Structure-Activity Relationship; Organic cation; Alzheimer disease; Central nervous system; Ox; Esterases; Acetylcholinesterase; Organic thiocarbonate; Structure activity relation; Anticholinesterase agent; Chemical synthesis; Ungulata; Human; Enzyme; Calf; Red blood cell; Enzyme inhibitor; In vitro; Octopus; Carboxylic ester hydrolases; Quaternary ammonium compound; Cephalopoda; Vertebrata; Mammalia; Animal; Hydrolases; Artiodactyla; Invertebrata; Mollusca; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970141k

Fourteen alkyl and aryl thiocarbonate derivatives of choline were synthesized and studied as potential inhibitors of acetylcholinesterase (AChE). Twelve of the compounds inhibited AChEs derived from calf forebrain, human red blood cells, and octopus brain ranging from low to moderately high inhibition potency. The concentration of each inhibitory compound giving 50% inhibition of enzyme activity (IC50 values, which ranged from 1 × 10-2 to 8 × 10-7 M) was determined and is reported; inhibitor constants (K i values) for the most inhibitory compounds, (1-pentylthiocarbonyl)choline chloride and (1-heptylthiocarbonyl)choline chloride, were calculated from kinetic data and are also reported. The inhibitors are competitive with substrate, and they are not hydrolyzed by the AChE activities. Certain of these new compounds may provide direction for the development of new drugs that have anticholinesterase activity and may be used for the treatment of Alzheimer's disease.