Synthesis and preliminary biological evaluation of new phthalazinone derivatives with PARP-1 and cholinesterase inhibitory activities

Abstract The inhibition of Poly (ADP-ribose) polymerases-1 (PARP-1) has a potentially therapeutical value for AD. In order to search for a new agent based on multitarget-directed ligands (MTDLs) strategy, a series of 21 novel compounds incorporated the respective pharmacophores of two marketed drugs, namely 4-benzyl phthalazinone moiety of PARP-1 inhibitor Olaparib and N-benzylpiperidine moiety of AChE inhibitor Donepezil, into one molecule was synthesized. The inhibitory activities of all the synthesized compounds against the enzymes PARP-1, AChE and BChE were evaluated. Among them, 30 exhibited the most potent inhibitory effect on PARP-1 enzyme (8.18±2.81 nM) and moderate BChE inhibitory activity (1.63±0.52µM), while its AChE inhibitory activity (13.48±2.15µM) was weaker than Donepezil (0.04±0.01µM). Further molecular docking studies revealed that four hydrogen bonds were formed between 30 and PARP-1 which were similar with the interactions between Olaparib and PARP-1. 30 interacted with the critical residues His438 and Trp82 of huBChE through hydrogen bond and hydrophobic interaction which were necessary for huBChE inhibitory potency. Our research gave a clue to search for new agents based on PARP-1 and cholinesterase dual-inhibited activities to treat Alzheimer's disease.