title: Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.
abstract: Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.
authors: Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors: Masashi
authors: M
authors: Shinada
authors: Fuminori
authors: F
authors: Narumi
authors: Yuji
authors: Y
authors: Osada
authors: Koji
authors: K
authors: Matsumoto
authors: Takayasu
authors: T
authors: Yoshida
authors: Kazuhiro
authors: K
authors: Higuchi
authors: Tomomi
authors: T
authors: Kawasaki
authors: Hiroyuki
authors: H
authors: Tanaka
authors: Mitsutoshi
authors: M
authors: Satoh
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C092280:phenserine