title: Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines.
abstract: A series of phenylcarbamate analogues of geneserine (8, 10, 12, 14) were synthesized from their counterparts, the phenylcarbamate analogues of physostigmine (2-5), by oxidation. The geneserine analogues can undergo tautomerism between N-oxide and 1,2-oxazine structures in a pH- and time-dependent manner. Assessment by (1)H NMR indicated that the N-oxide structure is adopted at neutral pH and that the compound exists in an equilibrium between several epimers. Evaluation of their biological action to inhibit human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), ex vivo, demonstrated that the N-oxide (7, 9, 11, 13, 15) and 1,2-oxazine (6, 8, 10, 12, 14) structures possessed similar potencies against AChE, but the latter structures were more potent against BChE. With the exception of the BChE selective inhibitor, 12, none of the geneserine analogues were as potent or enzyme subtype selective as their physostigmine analogue counterparts.
authors.affiliation: Drug Design & Development Section, Laboratory of Neurosciences, Gerontology Research Center (4E02), National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland 21224-6825, USA.
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Zhu
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Noel F
authors.initials: NF
authors.lastname: Whittaker
authors.forename: Arnold
authors.initials: A
authors.lastname: Brossi
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000470:Alkaloids / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007536:Isomerism; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D003497:Cyclic N-Oxides; D010078:Oxazines; C060406:geneserine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase