Affiliation:
1. Department of Pharmacy, Institute of Advanced Pharmaceutical Technology, College of Medicine, Wuhan University of
Science and Technology, Wuhan 430081, China
2. Hubei Province Key Laboratory of Occupational Hazard Identification
and Control, Wuhan University of Science and Technology, Wuhan 430081, China
Abstract
Background:
Alzheimer's disease (AD) is the most common brain disorder and remains a major
health concern worldwide. Considering the highly complex mechanisms of AD, the search for agents
based on a multitarget-directed ligands (MTDLs) strategy to treat AD may be more promising than the
traditional “one drug-one target” strategy. Inhibition of Poly (ADP-ribose) polymerases-1 (PARP-1) has a
potentially therapeutical effect on AD. Therefore, it is worthy to investigate compounds that target both
PARP-1 and cholinesterase, which perhaps produces new agents against AD.
Objective:
To search for new agents with PARP-1 and cholinesterase inhibitory activities for the treatment
of AD.
Methods:
A series of 21 novel compounds incorporated the respective pharmacophores of two marketed
drugs, namely the 4-benzyl phthalazinone moiety of a PARP-1 inhibitor, Olaparib, and the Nbenzylpiperidine
moiety of an AChE inhibitor, Donepezil, into one molecule was synthesized. The inhibitory
activities of all the synthesized compounds against the enzymes PARP-1, acetylcholinesterase
(AChE) and butyrylcholinesterase (BChE) were evaluated. The binding modes of the most potent compound
inside the PARP-1 and the human BChE (hBChE) were investigated by molecular docking.
Results:
N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4-
yl)methyl)benzamide (30) exhibited the most potent inhibitory effect on PARP-1 enzyme
(IC50=8.18±2.81nM) and moderate BChE inhibitory activity (IC50=1.63±0.52μM), while its AChE inhibitory
activity (IC50=13.48±2.15μM) was weaker than Donepezil (IC50=0.04±0.01μM). Further molecular
docking studies revealed that four hydrogen bonds were formed between 30 and PARP-1, meanwhile, 30
interacted with the critical residues His438 and Trp82 of hBChE through hydrogen bonds and hydrophobic
interactions, which were necessary for hBChE inhibitory potency.
Conclusion:
A new compound with potent PARP-1 inhibitory activity and moderate BChE inhibitory
activity was obtained, which merited to be further investigated as an anti-AD drug. The studies gave a
clue to search for new agents based on PARP-1 and cholinesterase dual-inhibited activities to treat AD.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine