Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Abstract

A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.

Studying the Binding Modes of Novel 2-Aminopyridine Derivatives as Effective and Selective c-Met Kinase Type 1 Inhibitors Using Molecular Modeling Approaches

“…The protein structure was prepared using the protein preparation module, including adding missing loop structure regions, protein protonation and automatic protein preparation. The torsion force of the ligand and the receptor were set to be rotatable and rigid respectively, by using the semi-flexible docking method [ 27 ]. The binding site radius was set to 10, top hits were set to 100, and other parameters were set as default.…”

Design, Synthesis and Antitumoral Activity of New O‐Alkylamidoximes

“…[32] Moreover, HIS862 and TYR907 are involved in the development of some other potential PARP-1 inhibitors. [32,33] It was also possible to observe that the aromatic portion of compound 3 a is directed into the active site of PARP-1 in a similar way to the phthalazin-1(2H)-one portion of olaparib, resulting in the interaction of the ester group present in 3 a with TYR889 residue (Figure 3). Such similarities support the hypothesis that this compound acts on the PARP-1 enzyme.…”

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

“…Another interesting approach in the search for MTDLs comes from Gao et al, who presented dual ChE and Poly(ADP-ribose) Polymerase-1 (PARP-1) inhibitors [ 54 ]. PARP-1 inhibitors have been extensively studied for their anticancer activity [ 55 ], but they may also serve as potential therapeutics for neurodegenerative diseases, with particular attention to AD and PD [ 56 ].…”