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

Abstract

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.

Design, synthesis, and evaluation of 1H‐benzo[d]imidazole‐4‐carboxamide PARP‐1 inhibitors using different saturated nitrogen‐contained heterocycle as linker group

“…Compound 1 was obtained by reference to the synthesis of our group's previous research (Chen et al, 2021). Subsequently, four N‐boc‐protected saturated diazine heterocycles ( 2a‐2d ) were respectively condensed with furan carboxylic acids with different substituents ( 3a‐3e ) by HBTU, and then the Boc‐protecting group was removed in the hydrochloric acid/methanol system to obtain intermediates ( 5a‐5t ).…”

“…Compounds 6a‐6t were screened in vitro for their PARP‐1 enzyme inhibitory activity at the fixed concentration of 500 nM, and then the ones with PARP‐1 inhibitory rates greater than 50% were selected to further determine the IC 50 values. The corresponding results of 6a‐6t were expressed as IC 50 values and presented in Table 2, and 6u‐6x in Table 2 were from the paper published by our group in 2021 (Chen et al, 2021). These compounds 6a‐6t showed a wide range of inhibitory activities against PARP‐1 with IC 50 values varying from 8.65 nM to more than 500 nM.…”

Recent progress of research on anti‐tumor agents using benzimidazole as the structure unit

“…The benzimidazole carboxamide core provided the conserved hydrogen-bonding interactions with residues Ser904, Gly863, and His862, and π-π stacking interactions with residue Tyr907. Chen et al (2021) designed and synthesized a series of 2-(4-[4-acetylpiperazine-1-carbonyl] phenyl)-1Hbenzo[d]imidazole-4-carboxamide derivatives as novel and effective poly-ADP-ribose polymerases (PARP)-1 inhibitors. PARP kit assay and MTT method were used to evaluate the PARP-1 inhibitory activity and cell inhibitory activity of these derivatives against BRCA-1 deficient cells (MDA-MB-436) and wild-type cells (MCF-7).…”

“…Poly‐ADP‐ribose polymerase inhibitors can inhibit the repair process of DNA single‐strand damage, but this single‐strand DNA damage can be converted into double‐stranded damage (DSB) during the process of DNA replication forming a replication fork, which can still be repaired by the homologous recombination (HR) pathway (Chen et al, 2021). If tumor cells have homologous recombination repair defects (including BRCA‐1 and BRCA‐2 mutations), to make DSB damage unrepairable, it will cause synthetic lethal effects (Zandarashvili et al, 2020).…”

“…Chen et al (2021) designed and synthesized a series of 2‐(4‐[4‐acetylpiperazine‐1‐carbonyl] phenyl)‐1H‐benzo[d]imidazole‐4‐carboxamide derivatives as novel and effective poly‐ADP‐ribose polymerases (PARP)‐1 inhibitors. PARP kit assay and MTT method were used to evaluate the PARP‐1 inhibitory activity and cell inhibitory activity of these derivatives against BRCA‐1 deficient cells (MDA‐MB‐436) and wild‐type cells (MCF‐7).…”