Title : Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors - Gabr_2018_Bioorg.Chem_80_245
Author(s) : Gabr MT , Abdel-Raziq MS
Ref : Bioorg Chem , 80 :245 , 2018
Abstract :

Multi-target-directed ligands (MTDLs) centered on beta-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC50 value of 4.11nM) and BACE-1 inhibition (IC50 value of 18.3nM) in comparison to donepezil (IC50 values of 6.21 and 194nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.

PubMedSearch : Gabr_2018_Bioorg.Chem_80_245
PubMedID: 29966870

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Citations formats

Gabr MT, Abdel-Raziq MS (2018)
Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors
Bioorg Chem 80 :245

Gabr MT, Abdel-Raziq MS (2018)
Bioorg Chem 80 :245