4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoic acid
• 英文别名: 4-(4-Carbamoyl-1H-benzoimidazol-2-yl)-benzoic acid；4-(4-carbamoyl-1H-benzimidazol-2-yl)benzoic acid
• 化学式: C₁₅H₁₁N₃O₃
• 分子量: 281.271
• InChiKey: UKWIDUMSXQQLKC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoic acid 在 三乙胺 、 fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate 、 肼 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 以48%的产率得到2-(4-(hydrazinecarbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide
  参考文献：
  名称：

  Synthesis and Evaluation of a New Generation of Orally Efficacious Benzimidazole-Based Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors as Anticancer Agents

  摘要：

  Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic alpine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC50 and cellular EC50 values were as low as 1 nM or below. Compounds 24 (EC50 = 3.7 nM) and 44 (EC50 = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.

  DOI：

  10.1021/jm900697r
• 作为产物：
  描述：

  2-amino-3-nitrobenzoyl chloride 在 ammonium hydroxide 、 sodium hydrogen sulfate 、 水 、 一水合肼 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 为溶剂， 反应 2.0h， 生成 4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoic acid
  参考文献：
  名称：

  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

  摘要：

  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

  DOI：

  10.1002/ddr.21843

文献信息

• Resistance-Modifying Agents. 9. Synthesis and Biological Properties of Benzimidazole Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase
  作者：Alex W. White、Robert Almassy、A. Hilary Calvert、Nicola J. Curtin、Roger J. Griffin、Zdenek Hostomsky、Karen Maegley、David R. Newell、Sheila Srinivasan、Bernard T. Golding

  DOI：10.1021/jm000950v

  日期：2000.11.1

  PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition < 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR)

  核酶聚（ADP-核糖）聚合酶（PARP）促进DNA链断裂的修复，并与癌细胞对某些DNA破坏剂的抗性有关。PARP抑制剂作为抗药性改良剂具有临床潜力，能够增强放疗和某些形式的癌症化学疗法的细胞毒性。描述了2-芳基-1H-苯并咪唑-4-羧酰胺在癌症化疗中作为耐药修饰剂的临床前开发。1 H-苯并咪唑-4-羧酰胺，特别是2-芳基衍生物被认为是一类有效的PARP抑制剂。已经合成了其中苯环含有取代基的2-苯基-1H-苯并咪唑-4-羧酰胺的衍生物（23，K（i）= 15 nM）。这些衍生物中的许多衍生物对于PARP抑制作用的K（i）值<10 nM，其中2-（4-羟甲基苯基）-1H-苯并咪唑-4-羧酰胺（78，K（i）= 1.6 nM）是最有效的药物之一。通过研究2-（3-甲氧基苯基）-1H-苯并咪唑-4-羧酰胺之间形成的配合物，增强了对2-芳基-1H-苯并咪唑-4-羧酰胺的结构活性关系（SAR）的认识（44，K（
• Design, synthesis, and evaluation of 1 <i>H</i> ‐benzo[d]imidazole‐4‐carboxamide <scp>PARP</scp> ‐1 inhibitors using different saturated nitrogen‐contained heterocycle as linker group
  作者：Kaiyue Wu、Xiaoyu Peng、Yang Li、Miaojia Chen、Yunfan Liu、Dan Liu、Lizhi Jiang、Yan He、Junmei Peng、Xuan Cao

  DOI：10.1111/cbdd.14216

  日期：——

  (PARP-1) inhibitors have been successfully applied in the clinical treatment of various cancer. Side effects and drug resistant cases were reported, and more effective PARP-1 inhibitors were required. However, studies on the AD site of PARP-1 inhibitors are currently incomplete. Therefore, to synthesize more potential candidate PARP-1 inhibitors and disclose some AD site SAR of the PARP-1 inhibitors, herein

  聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂已成功应用于多种癌症的临床治疗。报道了副作用和耐药病例，需要更有效的 PARP-1 抑制剂。然而，目前对 PARP-1 抑制剂的 AD 位点的研究还不完整。因此，为合成更多有潜力的候选PARP-1抑制剂，并揭示PARP-1抑制剂的部分AD位点SAR，本文以不同饱和含氮杂环为连接基团的一系列2-苯基-苯并咪唑-4-甲酰胺衍生物( 6a-6t ) 已经设计、合成并评估了体外对 BRCA-1 突变体 MDA-MB-436 细胞系的 PARP-1 抑制活性和增殖抑制作用。结果显示6b(IC50 = 8.65 nM) 表现出最大的 PARP-1 酶抑制活性，与 VeliPARib (IC50 = 15.54 nM) 和 OlaPARib (IC50 = 2.77 nM) 相当；6m表现出最强的 MDA-MB-436 细胞抗增殖活性 (IC50 = 25
• 一种以哌嗪为连接基团的苯并咪唑-4-羧酰胺衍生物
  申请人：南华大学

  公开号：CN114907269A

  公开（公告）日：2022-08-16

  本发明涉及一系列以哌嗪为连接基团的苯并咪唑‑4‑羧酰胺衍生物，可作为新型有效的PARP‑1抑制剂。本发明使用PARP‑1试剂盒测定法和MTT法测试了这些衍生物的PARP‑1抑制活性以及对BRCA‑1缺陷细胞(MDA‑MB‑436)和野生细胞(MCF‑7)的抑制作用。结果表明，本发明化合物对PARP‑1酶表现出较好的抑制作用和对MDA‑MB‑436癌细胞有较好的抑制增殖作用。
• Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks
  作者：Uday Kiran Velagapudi、Élise Rouleau-Turcotte、Ramya Billur、Xuwei Shao、Manisha Patil、Ben E. Black、John M. Pascal、Tanaji T. Talele

  DOI：10.1042/bcj20230406

  日期：2024.3.20

  Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.