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. © 2006.

Авторы
Carotti A.1 , De Candia M. , Catto M.1 , Borisova T.N. 2 , Varlamov A.V. 2 , Méndez-Álvarez E.3 , Soto-Otero R.3 , Voskressensky L.G. 2 , Altomare C.1
Номер выпуска
21
Язык
Английский
Страницы
7205-7212
Статус
Опубликовано
Том
14
Год
2006
Организации
  • 1 Department of Pharmaceutical Chemistry, University of Bari, Via E. Orabona 4, I-70125 Bari, Italy
  • 2 Organic Chemistry Department, the Russian peoples friendship University, 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
  • 3 Group of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, S. Francisco 1, E-15782 Santiago de Compostela, Spain
Ключевые слова
Acetylcholinesterase inhibitors; Annulated azocines; Structure-activity relationships
Дата создания
19.10.2018
Дата изменения
19.10.2018
Постоянная ссылка
https://repository.rudn.ru/ru/records/article/record/3322/