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.

中文翻译：

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2-(4-[4-乙酰基哌嗪-1-羰基]苯基)-1H-苯并[d]咪唑-4-甲酰胺衍生物作为PARP-1潜在抑制剂的合成与评价及构效关系初步研究

尽管对 1H-苯并[d]咪唑-4-甲酰胺衍生物的探索已经很长时间，但疏水袋（AD 结合位点）中取代基的构效关系尚未彻底发现。在这里，设计、合成了一系列 2-(4-[4-乙酰基哌嗪-1-羰基]苯基)-1H-苯并[d]咪唑-4-甲酰胺衍生物，并成功表征为新型有效的聚 ADP -核糖聚合酶（PARP）-1抑制剂，以改善疏水袋中取代基的结构-活性关系。使用 PARP 试剂盒测定法和 MTT 方法评估这些衍生物的 PARP-1 抑制活性和对 BRCA-1 缺陷细胞 (MDA-MB-436) 和野生细胞 (MCF-7) 的细胞抑制作用。结果表明，与其他杂环化合物相比，14n-14q表现出更好的 PARP-1 抑制活性。在这些衍生物中，化合物14p对 PARP-1 酶的抑制作用最强（IC ₅₀  = 0.023 μM），与奥拉帕尼接近。14p (IC ₅₀  = 43.56 ± 0.69 μM) 和14q (IC ₅₀  = 36.69 ± 0.83 μM) 对 MDA-MB-436 细胞具有良好的抗增殖活性，对 MCF-7 细胞无活性，表明14p和14q具有高选择性和靶向性. 采用分子对接法探索化合物14p的结合方式和 PARP-1，并暗示氢键的形成对于 PARP-1 抑制活性至关重要。该研究还表明，在疏水袋（AD 结合位点）中，在苯并咪唑侧链引入强电负性基团（例如呋喃环）或卤素原子可能会提高其抑制活性，该策略可用于进一步研究.