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 highly complex mechanisms of AD, search for agents based on multitarget-directed ligands (MTDLs) strategy to treat AD may be more promising than traditional “one drug-one target” strategy. Inhibition Poly (ADP-ribose) polymerases-1 (PARP-1) has potentially therapeutical effect AD. Therefore, it worthy investigate compounds that target both PARP-1 cholinesterase, which perhaps produces new against Objective: To with cholinesterase inhibitory activities treatment Methods: A series 21 novel incorporated respective pharmacophores two marketed drugs, namely 4-benzyl phthalazinone moiety inhibitor, Olaparib, Nbenzylpiperidine an AChE Donepezil, into one molecule was synthesized. The all synthesized enzymes PARP-1, acetylcholinesterase (AChE) butyrylcholinesterase (BChE) were evaluated. binding modes potent compound inside human BChE (hBChE) 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 enzyme (IC50=8.18±2.81nM) moderate activity (IC50=1.63±0.52μM), while its (IC50=13.48±2.15μM) weaker Donepezil (IC50=0.04±0.01μM). Further docking studies revealed four hydrogen bonds formed between 30 meanwhile, interacted critical residues His438 Trp82 hBChE through hydrophobic interactions, necessary potency. Conclusion: obtained, merited further as anti-AD drug. gave clue dual-inhibited