Methyl Analogues of the Experimental Alzheimer Drug Phenserine:  Synthesis and Structure/Activity Relationships for Acetyl- and Butyrylcholinesterase Inhibitory Action

• Published in: Journal of medicinal chemistry Vol. 44; no. 24; pp. 4062 - 4071
• Main Authors: Yu, Qian-sheng, Holloway, Harold W, Flippen-Anderson, Judith L, Hoffman, Brian, Brossi, Arnold, Greig, Nigel H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.11.2001; Amer Chemical Soc
• Subjects: Acetylcholinesterase - metabolism; Biological and medical sciences; Butyrylcholinesterase - metabolism; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Chemistry, Medicinal; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Crystallography, X-Ray; Erythrocytes - chemistry; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physostigmine - analogs & derivatives; Physostigmine - chemical synthesis; Physostigmine - chemistry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Science & Technology; Structure-Activity Relationship; SENILE DEMENTIA; ANTICHOLINESTERASE ACTIVITIES; ACETYLCHOLINESTERASE INHIBITION; SPECIFICITY; KINETICS; DISEASE; SELECTIVE INHIBITORS; ANTIPODAL ISOMERS; CHOLINESTERASE-INHIBITORS; PHYSOSTIGMINE; Human; Enzyme; Alzheimer disease; Nitrogen heterocycle; Benzene derivatives; Enzyme inhibitor; Esterases; Inhibitor enzyme complex; Physostigmine; Acetylcholinesterase; Tricyclic compound; Organic carbamate; In vitro; Modeling; Cholinesterase; Carboxylic ester hydrolases; Structure activity relation; Molecular model; Force field method; Hydrolases; Aromatic compound; Anticholinesterase agent; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010080x

With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the phenyl group of the phenylcarbamoyl moieties, and with N-methyl and 6-methyl substituents (12, 13, 31, 33). We also quantified the inhibitory action of these compounds against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). An analysis of the structure/anticholinesterase activity relationship of the described compounds, together with molecular modeling, confirmed the catalytic triad mechanism of the binding of this class of carabamate analogues within AChE and BChE and defined structural requirements for their differential inhibition.