Hexahydrochromeno[4,3-b]pyrrole Derivatives as Acetylcholinesterase Inhibitors

• Published in: Journal of medicinal chemistry 2001-01, Vol.44 (1), p.105-109
• Main Authors: Bolognesi, Maria L, Andrisano, Vincenza, Bartolini, Manuela, Minarini, Anna, Rosini, Michela, Tumiatti, Vincenzo, Melchiorre, Carlo
• Format: Article
• Language: English
• Subjects: Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Biological and medical sciences; Cholinergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Chromatography, High Pressure Liquid; Kinetics; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Physostigmine - analogs & derivatives; Physostigmine - chemical synthesis; Physostigmine - chemistry; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000991r

In a search for less flexible analogues of caproctamine (1), a diamine diamide endowed with an interesting AChE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good AChE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4−6, and their biological evaluation has been assessed in vitro against human AChE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (−)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of AChE was observed for 3 and 4.