Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors

Moustafa T Gabr; Mohammed S Abdel-Raziq

doi:10.1016/j.bmcl.2018.07.019

Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors

Bioorg Med Chem Lett. 2018 Sep 15;28(17):2910-2913. doi: 10.1016/j.bmcl.2018.07.019. Epub 2018 Jul 11.

Authors

Moustafa T Gabr¹, Mohammed S Abdel-Raziq²

Affiliations

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA. Electronic address: gabr2003@gmail.com.
² Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia 4072, Queensland, Australia.

PMID: 30017317
DOI: 10.1016/j.bmcl.2018.07.019

Abstract

A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC₅₀ value of 14.7 nM) and BACE-1 inhibition (IC₅₀ value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied.

Keywords: Acetylcholinesterase; Donepezil; Hybridization; Multi-target-directed ligands; β-Secretase.

MeSH terms

Acetylcholinesterase / metabolism
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Blood-Brain Barrier / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Crystallography, X-Ray
Donepezil / chemical synthesis
Donepezil / chemistry
Donepezil / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Donepezil
Acetylcholinesterase
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human