Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine.

Abstract

Reductive cyclization of 5-hydroxy-3-methyl-3-methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3,3a,8a-tatrahydrofuro[2,3-b]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.

• Authors: Weiming Luo, Qian-sheng Yu, Ming Zhan, Damon Parrish, Jeffrey R Deschamps, Santosh S Kulkarni, Harold W Holloway, George M Alley, Debomoy K Lahiri, Arnold Brossi, Nigel H Greig
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 4 Pg. 986-94 (Feb 24 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15715468 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Protein Precursor
• Benzofurans
• Carbamates
• Cholinesterase Inhibitors
• Oxepins
• Acetylcholinesterase
• Butyrylcholinesterase

Topics

• Acetylcholinesterase (chemistry, metabolism)
• Amyloid beta-Protein Precursor (biosynthesis, metabolism)
• Benzofurans (chemical synthesis, chemistry, pharmacology)
• Butyrylcholinesterase (chemistry)
• Carbamates (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Cell Survival (drug effects)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Crystallography, X-Ray
• Humans
• Models, Molecular
• Molecular Structure
• Neurons (cytology)
• Oxepins (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship