Synthesis and evaluation of 2-(4-[4-acetylpiperazine-1-carbonyl] phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives as potential PARP-1 inhibitors and preliminary study on structure-activity relationship.

Although 1H-benzo[d]imidazole-4-carboxamide derivatives have been explored for a long time, the structure-activity relationship of the substituents in the hydrophobic pocket (AD binding sites) has not thoroughly discovered. Here in, a series of 2-(4-[4-acetylpiperazine-1-carbonyl]phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives have been designed, synthesized, and successful characterization as novel and effective poly ADP-ribose polymerases (PARP)-1 inhibitors to improve the structure-activity relationships about the substituents in the hydrophobic pocket. These derivatives were evaluated for their PARP-1 inhibitory activity and cellular inhibitory against BRCA-1 deficient cells (MDA-MB-436) and wild cells (MCF-7) using PARP kit assay and MTT method. The results indicated that compared with other heterocyclic compounds, furan ring-substituted derivatives 14n-14q showed better PARP-1 inhibitory activity. Among this derivatives, compound 14p displayed the strongest inhibitory effects on PARP-1 enzyme (IC50  = 0.023 μM), which was close to that of Olaparib. 14p (IC50  = 43.56 ± 0.69 μM) and 14q (IC50  = 36.69 ± 0.83 μM) displayed good antiproliferation activity on MDA-MB-436 cells and inactivity on MCF-7 cells, indicating that 14p and 14q have high selectivity and targeting. The molecular docking method was used to explore the binding mode of compound 14p and PARP-1, and implied that the formation of hydrogen bond was essential for PARP-1 inhibition activities. This study also showed that in the hydrophobic pocket (AD binding sites), the introduction of strong electronegative groups (furan ring, e.g.) or halogen atoms in the side chain of benzimidazole might improve its inhibitory activity and this strategy could be applied in further research.