Synthesis and Preliminary Biological Evaluation of New Phthalazinone Derivatives with PARP-1 and Cholinesterase Inhibitory Activities

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.