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

Article Details

Citation

Luo W, Yu QS, Zhan M, Parrish D, Deschamps JR, Kulkarni SS, Holloway HW, Alley GM, Lahiri DK, Brossi A, Greig NH

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

J Med Chem. 2005 Feb 24;48(4):986-94.

PubMed ID
15715468 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DonepezilAcetylcholinesteraseIC 50 (nM)22N/AN/ADetails
GalantamineAcetylcholinesteraseIC 50 (nM)800N/AN/ADetails
Huperzine AAcetylcholinesteraseIC 50 (nM)47N/AN/ADetails
PhenserineAcetylcholinesteraseIC 50 (nM)22N/AN/ADetails
PhysostigmineAcetylcholinesteraseIC 50 (nM)28N/AN/ADetails
RivastigmineAcetylcholinesteraseIC 50 (nM)4150N/AN/ADetails
TacrineAcetylcholinesteraseIC 50 (nM)190N/AN/ADetails