Multipotent AChE and BACE-1 inhibitors for the treatment of Alzheimer's disease: Design, synthesis and bio-analysis of 7-amino-1,4-dihydro-2 H -isoquilin-3-one derivates

摘要

Abstract In this paper, the preparation of a new class of multi-target-directed ligands (MTDLs) based on a 7-amino-1,4-dihydro-2 H -isoquilin-3-one, whose lead (compound I ) showed promising properties in acetylcholinesterase (AChE) inhibitory activity [1], is described. The results of in?vitro activities and molecular docking demonstrated that the target molecule (compounds 10a-n ) with three parts of aromatic moieties and appropriate structural length can interact with aromatic residues in catalytic active site (CAS), peripheral anionic site (PAS) and the channel of AChE. And the introduce of connecting amide bonds, enables the target molecules provide sufficient hydrogen bond donors and acceptors to interact with the catalytic site of BACE-1. Notably, compound 10d exerted excellent AChE inhibition (IC 50 ?=?18.93?±?1.02 pM, 181-fold more inhibitory effect compared with donepezil), BACE-1 inhibition (97.68?±?8.01% at 20?μM), and good metal chelating property, which can be chosen as lead compound for further optimization of novel small ligand for the treatment of Alzheimer's disease. Graphical abstract Display Omitted Highlights ? A series of novel derivates with 7-amino-1,4-dihydro-2 H -isoquilin-3-one skeleton were synthesized. ? Preliminary bioassay showed newly synthesized compounds exerting excellent AChE and BACE-1 inhibition activity. ? Molecular modeling illustrated the strong interaction between designed ligands and target enzyme. ? Difference UV-visible spectra expounded the metal chelation property of such class of derivates.