| 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 ofcompounds 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 inhibitorsof either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibitingremarkable selectivity. Because the two series of carbamates (7−12) differ in their phenolicmoieties, their respective potency and selectivity for AChE versus BChE was governed by theirN-substituted groups. This same characteristic was also present in a series of physovenineanalogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure−activityrelations proved valuable in elucidating the mechanisms underpinning the interaction betweencarbamate-based cholinesterase inhibitors and their enzyme target. In addition, becausephysostigmine analogues have demonstrated activity in lowering the Alzheimer's diseaseprotein, amyloid precursor protein (APP), examples of the two new series of carbamates werecharacterized in culture assays of quantifying cell viability and synthesis of APP.
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