Highly potent and selective aryl-1,2,3-triazolyl benzylpiperidine inhibitors toward butyrylcholinesterase in Alzheimer's disease

de Andrade, Peterson; Mantoani, Susimaire P.; Goncalves Nunes, Paulo Sergio; Magadan, Carlos Roca; Perez, Concepcion; Xavier, Danilo Jordao; Sakamoto Hojo, Elza Tiemi; Campillo, Nuria E.; Martinez, Ana; Carvalho, Ivone

Abstract

Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective ( > 58,000-fold) hBuChE inhibitor ever reported.

Más información

Título según WOS: ID WOS:000462478700002 Not found in local WOS DB
Título de la Revista: BIOORGANIC & MEDICINAL CHEMISTRY
Volumen: 27
Número: 6
Editorial: PERGAMON-ELSEVIER SCIENCE LTD
Fecha de publicación: 2019
Página de inicio: 931
Página final: 943
DOI:

10.1016/j.bmc.2018.12.030

Notas: ISI