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 IC50 values ranging from 5 to 40 μM. 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 pIC50 and experimental 1-octanol/water partition coefficient (log P), which described the prevailing behavior of the examined compounds (r2 = 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.

Several mono- and diester derivatives of annulated tetrahydroazocines, synthesized through an efficient 6 → 8 membered ring expansion procedure, exhibited acetylcholinesterase (AChE) inhibitory activity. The most potent derivatives 11 and 15 (IC50 ca. 5 μM) proved selective, with selectivity ratios versus BuChE of ca. 15 and more than 20, respectively.Figure optionsDownload as PowerPoint slide