Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine

Weiming Luo, Qian Sheng Yu, Ming Zhan, Damon Parrish, Jeffrey R. Deschamps, Santosh S. Kulkarni, Harold W. Holloway, George M. Alley, Debomoy Lahiri, Arnold Brossi, Nigel H. Greig

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Reductive cyclization of 5-hydroxy-3-methyl-3- methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3, 3a,8a-tatrahydrofuro[2,3-6]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.

Original languageEnglish
Pages (from-to)986-994
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number4
DOIs
StatePublished - Feb 24 2005

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Carbamates
Cholinesterase Inhibitors
Skeleton
Amyloid beta-Protein Precursor
Butyrylcholinesterase
Physostigmine
Isocyanates
X ray crystallography
X Ray Crystallography
Cyclization
Enzymes
Cell culture
Assays
Cell Survival
Alzheimer Disease
Cells

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Luo, W., Yu, Q. S., Zhan, M., Parrish, D., Deschamps, J. R., Kulkarni, S. S., ... Greig, N. H. (2005). Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine. Journal of Medicinal Chemistry, 48(4), 986-994. https://doi.org/10.1021/jm049309+

Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine. / Luo, Weiming; Yu, Qian Sheng; Zhan, Ming; Parrish, Damon; Deschamps, Jeffrey R.; Kulkarni, Santosh S.; Holloway, Harold W.; Alley, George M.; Lahiri, Debomoy; Brossi, Arnold; Greig, Nigel H.

In: Journal of Medicinal Chemistry, Vol. 48, No. 4, 24.02.2005, p. 986-994.

Research output: Contribution to journalArticle

Luo, W, Yu, QS, Zhan, M, Parrish, D, Deschamps, JR, Kulkarni, SS, Holloway, HW, Alley, GM, Lahiri, D, Brossi, A & Greig, NH 2005, 'Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine', Journal of Medicinal Chemistry, vol. 48, no. 4, pp. 986-994. https://doi.org/10.1021/jm049309+
Luo, Weiming ; Yu, Qian Sheng ; Zhan, Ming ; Parrish, Damon ; Deschamps, Jeffrey R. ; Kulkarni, Santosh S. ; Holloway, Harold W. ; Alley, George M. ; Lahiri, Debomoy ; Brossi, Arnold ; Greig, Nigel H. / Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 4. pp. 986-994.
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AU - Parrish, Damon

AU - Deschamps, Jeffrey R.

AU - Kulkarni, Santosh S.

AU - Holloway, Harold W.

AU - Alley, George M.

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AU - Greig, Nigel H.

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N2 - Reductive cyclization of 5-hydroxy-3-methyl-3- methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3, 3a,8a-tatrahydrofuro[2,3-6]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.

AB - Reductive cyclization of 5-hydroxy-3-methyl-3- methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3, 3a,8a-tatrahydrofuro[2,3-6]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.

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