Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors.
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.
Bolognesi
M L
ML
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Andrisano
V
V
Bartolini
M
M
Minarini
A
A
Rosini
M
M
Tumiatti
V
V
Melchiorre
C
C
D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C419406:1-methyl-1,2,3,3a,4,9b-hexahydrochromeno(4,3-b)pyrrol-6-yl N-methylcarbamate; D001578:Benzopyrans; D002800:Cholinesterase Inhibitors; D011758:Pyrroles; D011759:Pyrrolidines; D010830:Physostigmine