Ester derivatives of annulated tetrahydroazocines: a new class of selective acetylcholinesterase inhibitors.
A series of ester derivatives of annulated tetrahydroazocines, namely 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indoles (5-10), 2,3,6,7-tetrahydro-1H-azocino[5,4-b]indoles (11-14), and 4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocines (15-18), synthesized through an efficient 6-->8 membered ring expansion procedure, were investigated for their acetylcholinesterase (AChE) inhibitory activities. Most of the compounds acted as AChE inhibitors in vitro, with IC(50) values ranging from 5 to 40 microM. The most potent compounds 11 and 15, both as racemic mixtures, proved selective toward AChE, exhibiting selectivity ratios versus butyrylcholinesterase (BuChE) of ca. 15 and more than 20, respectively. Structure-activity studies highlighted, among other factors, lipophilicity as a property modulating the AChE inhibition potency, as shown by a reasonable parabolic correlation between pIC(50) and experimental 1-octanol/water partition coefficient (logP), which described the prevailing behavior of the examined compounds (r(2)=0.665). Molecular docking simulations using the X-ray crystal structure of AChE from Torpedo californica suggested possible binding modes of the tetrahydroazocine ester derivatives 11 and 15.
Carotti
Andrea
A
Department of Pharmaceutical Chemistry, University of Bari, Via E. Orabona 4, I-70125 Bari, Italy.
de Candia
Modesto
M
Catto
Marco
M
Borisova
Tatiana N
TN
Varlamov
Alexey V
AV
Méndez-Alvarez
Estefanía
E
Soto-Otero
Ramón
R
Voskressensky
Leonid G
LG
Altomare
Cosimo
C
D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D001392:Azocines / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D004952:Esters; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D001392:Azocines; D002800:Cholinesterase Inhibitors; D004952:Esters; D000110:Acetylcholinesterase