2-methyl-6-(4-tolyl)nicotinohydrazide | 925005-65-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 2-methyl-6-(4-tolyl)nicotinohydrazide
• 英文别名: 2-methyl-6-(p-tolyl)nicotinohydrazide；2-Methyl-6-p-tolylpyridine-3-carbohydrazide；2-methyl-6-(4-methylphenyl)pyridine-3-carbohydrazide
• CAS: 925005-65-8
• 化学式: C₁₄H₁₅N₃O
• 分子量: 241.293
• InChiKey: KNIFBVXXQJQCIB-UHFFFAOYSA-N

物化性质

• 密度：
  1.159±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  68
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-methyl-6-(4-tolyl)nicotinohydrazide 在 盐酸 、 sodium nitrite 作用下， 以 水 为溶剂， 反应 2.0h， 生成 2-methyl-6-(p tolyl)nicotinoyl azide
  参考文献：
  名称：

  [EN] 2-(3-(2-METHYL-6-(P-TOLYL) PYRIDINE-3-YL) UREIDO) BENZENESULFONAMIDE AND DERIVATIVES AS INHIBITOR OF CARBONIC ANHYDRASE IX FOR THE TREATMENT OF CANCER
  [FR] 2-(3-(2-MÉTHYL-6-(P-TOLYL)PYRIDINE-3-YL)URÉIDO)BENZÈNESULFONAMIDE ET SES DÉRIVÉS EN TANT QU'INHIBITEUR DE L'ANHYDRASE CARBONIQUE IX POUR LE TRAITEMENT DU CANCER

  摘要：

  本发明涉及2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺（式I）化合物及相关吡啶基磺酰胺衍生物。该发明的化合物是一种瞄准碳酸酐酶的小分子，并且是碳酸酐酶活性和过度表达的抑制剂，因此在治疗和/或预防与增生性疾病相关的疾病，如癌症方面，作为药物剂量特别有用。

  公开号：

  WO2021246974A1
• 作为产物：
  描述：

  2-甲基-6-(4-甲基苯基)烟酸乙酯 在 一水合肼 作用下， 反应 3.0h， 以78%的产率得到2-methyl-6-(4-tolyl)nicotinohydrazide
  参考文献：
  名称：

  Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides

  摘要：

  合成了三系列6-芳基-2-甲基烟碱酰肼4a–i、N'-芳亚甲基-6-(4-溴苯基)-2-甲基烟碱酰肼7a–f和N'-(未/取代的2-氧代吲哚啉-3-亚甲基)-6-(4-氟苯基)-2-甲基烟碱酰肼8a–c，并评估了它们对结核杆菌的体外抗菌活性。结果显示，靛红酰肼8a–c相较于母体酰肼4c活性显著更高。酰肼8b和8c在所有测试化合物中显示出最高的活性（MIC分别为12.5和6.25 µg/mL）。化合物8b和8c对HT-29、PC-3、A549、HepG2和MCF-7癌细胞系也无明显细胞毒性。此外，8b和8c显示出良好的类药性得分，分别为0.62和0.41。这两个靛红酰肼为未来开发更强效的抗结核药物提供了极佳的基础。SAR研究表明，合成衍生物的亲脂性是影响其抗结核活性的关键因素。最后，建立了理论动力学研究来预测活性衍生物的ADME。

  DOI：

  10.3390/molecules20058800

文献信息

• Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides
  作者：Wagdy Eldehna、Mohamed Fares、Marwa Abdel-Aziz、Hatem Abdel-Aziz

  DOI：10.3390/molecules20058800

  日期：——

  Three series of 6-aryl-2-methylnicotinohydrazides 4a–i, N′-arylidene-6-(4-bromophenyl)-2-methylnicotino hydrazides 7a–f, and N′-(un/substituted 2-oxoindolin-3-ylidene)-6-(4-fluorophenyl)-2-methylnicotinohydrazides 8a–c were synthesized and evaluated for their potential in vitro antimycobacterial activity against M. tuberculosis. The results showed that isatin hydrazides 8a–c are remarkably more active than the parent hydrazide 4c. Hydrazides 8b and 8c exhibited the highest activity among all the tested compounds (MIC = 12.5 and 6.25 µg/mL, respectively). Compounds 8b and 8c were also devoid of apparent cytotoxicity to HT-29, PC-3, A549, HepG2 and MCF-7 cancer cell lines. Besides, 8b and 8c showed good drug-likeness scores of 0.62 and 0.41, respectively. Those two isatin hydrazides could offer an excellent framework for future development to obtain more potent antitubercular agents. The SAR study suggested that lipophilicity of the synthesized derivatives is a crucial element that accounts for their antimycobacterial activity. Finally, a theoretical kinetic study was established to predict the ADME of the active derivatives.

  合成了三系列6-芳基-2-甲基烟碱酰肼4a–i、N'-芳亚甲基-6-(4-溴苯基)-2-甲基烟碱酰肼7a–f和N'-(未/取代的2-氧代吲哚啉-3-亚甲基)-6-(4-氟苯基)-2-甲基烟碱酰肼8a–c，并评估了它们对结核杆菌的体外抗菌活性。结果显示，靛红酰肼8a–c相较于母体酰肼4c活性显著更高。酰肼8b和8c在所有测试化合物中显示出最高的活性（MIC分别为12.5和6.25 µg/mL）。化合物8b和8c对HT-29、PC-3、A549、HepG2和MCF-7癌细胞系也无明显细胞毒性。此外，8b和8c显示出良好的类药性得分，分别为0.62和0.41。这两个靛红酰肼为未来开发更强效的抗结核药物提供了极佳的基础。SAR研究表明，合成衍生物的亲脂性是影响其抗结核活性的关键因素。最后，建立了理论动力学研究来预测活性衍生物的ADME。
• Design, synthesis and pharmacophoric model building of novel substituted nicotinic acid hydrazones with potential antiproliferative activity
  作者：Hatem A. Abdel-Aziz、Tarek Aboul-Fadl、Abdul-Rahman M. Al-Obaid、Mohamed Ghazzali、Abdullah Al-Dhfyan、Alessandro Contini

  DOI：10.1007/s12272-012-0904-2

  日期：2012.9

  Novel 6-aryl-2-methylnicotinic acid hydrazides 4a-c and their corresponding hydrazones 5a-c and 6a-i were synthesized. X-ray single crystal diffraction of 6h confirmed the chemical structure of hydrazones 6a-i. Antiproliferative activity of the synthetic compounds was investigated against K562 leukemia cell lines. Variable cell growth inhibitory activities were obtained with IC50 range from 24.99 to 66.78 μM where the compound 6c exhibited the maximum activity. Structure activity relationship analysis has been performed and a common pharmacophore model for the synthesized derivatives has been obtained by using the pharmacophore elucidation module of the software MOE. The best model obtained is characterized by two projected locations of potential H-bond donors (F 3 and F4) and two Aromatic annotations (F1 and F2).

  合成了新型6-芳基-2-甲基 nicotine 酸肼（4a-c）及其对应的肼酮（5a-c和6a-i）。对6h的X射线单晶衍射确认了肼酮6a-i的化学结构。合成化合物的抗增殖活性在K562白血病细胞系上进行了研究，获得了不同的细胞生长抑制活性，IC50范围为24.99至66.78μM，其中化合物6c表现出最大的活性。进行了结构活性关系分析，并利用软件MOE的药效团阐明模块获得了合成衍生物的共同药效团模型。获得的最佳模型具有两个潜在H键供体的投影位置（F3和F4）和两个芳香标记（F1和F2）。
• Design and synthesis of 6-arylpyridine-tethered sulfonamides as novel selective inhibitors of carbonic anhydrase IX with promising antitumor features toward the human colorectal cancer
  作者：Wagdy M. Eldehna、Eslam E. Mohammed、Ghada H. Al-Ansary、Emanuela Berrino、Mostafa M. Elbadawi、Tamer M. Ibrahim、Maiy Y. Jaballah、Sara T. Al-Rashood、Faizah A. Binjubair、Meltem Celik、Alessio Nocentini、Fawzy A. Elbarbry、Fikrettin Sahin、Hatem A. Abdel-Aziz、Claudiu T. Supuran、Mohamed Fares

  DOI：10.1016/j.ejmech.2023.115538

  日期：2023.10

  and rapid tumor growth exceeding the oxygen supply, and can result in angiogenesis activation, increased invasiveness, aggressiveness, and metastasis, leading to improved tumor survival and suppression of anticancer drug therapeutic impact. SLC-0111, a ureido benzenesulfonamide, is a selective human carbonic anhydrase (hCA) IX inhibitor in clinical trials for the treatment of hypoxic malignancies. Herein

  缺氧是实体瘤的一个特征，是由于细胞过度增殖和肿瘤快速生长超过氧气供应而产生的，可导致血管生成激活、侵袭性、侵袭性和转移性增加，从而提高肿瘤存活率并抑制抗癌作用。药物治疗的影响。SLC-0111 是一种脲基苯磺酰胺，是一种选择性人碳酸酐酶(hCA) IX 抑制剂，目前正在临床试验中用于治疗缺氧恶性肿瘤。在此，我们描述了新型 6-芳基吡啶8a-l和9a-d作为 SLC-0111 结构类似物的设计和合成，旨在探索癌症相关 hCA IX 亚型的新选择性抑制剂。SLC-0111 中的对氟苯基尾部被特殊的 6-芳基吡啶基序取代。此外，还开发了邻位磺酰胺区域异构体和间磺酰胺区域异构体以及乙烯延伸类似物。使用停流 CO 2水合酶测定，体外筛选所有基于 6-芳基吡啶的 SLC-0111 类似物对一组 hCA（hCA I、II、IV 和 IX 亚型）的抑制潜力。此外，美国 NCI 开发治疗计划首次针对一组 57
• 10.1007/s13318-024-00903-6
  作者：Elbarbry, Fawzy A.、Ibrahim, Tamer M.、Abdelrahman, Mohamed A.、Supuran, Claudiu T.、Eldehna, Wagdy M.

  DOI：10.1007/s13318-024-00903-6

  日期：——

  catalytic activity of CYP2A6. Conclusions These findings point to the feasibility of utilizing these agents as promising chemopreventive agents (owing to inhibition of CYP2E1), and AW-9A as a smoking cessation aid (owing to inhibition of CYP2A6). Additional in-vivo studies should be conducted to examine the impact of CYP2A6 and CYP2E1 inhibition on drug interactions with probe substrates of these enzymes

  背景和目标 AW-9A（香豆素衍生物）和WES-1（磺酰胺衍生物）均被设计和合成为潜在的选择性碳酸酐酶抑制剂，并测试了其抗癌活性。本研究旨在调查它们对主要人类细胞色素 P450 (CYP) 药物代谢酶的潜在抑制作用。  方法 使用特定的 CYP 探针底物和经过验证的分析方法来测量测试的 CYP 酶的活性。此外，还进行了计算机模拟，以了解 AW-9A 和 WES-1 如何在分子水平上与 CYP2A6 结合。使用CYP2A6的高分辨率X射线结构、蛋白质数据库（PDB）ID：2FDV进行分子对接实验。  结果 AW-9A 和 WES-1 强烈抑制 CYP2E1 催化的氯唑沙宗-6'-羟基化，IC 50值分别为 0.084 µM 和 0.101 µM。 AW-9A 中度抑制 CYP2A6 催化的香豆素-7′-羟基化 (IC 50 = 4.2 µM)。两种药物均对 CYP1A2、CYP2C9、CYP2C19、CYP2D6
• Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents
  作者：Wagdy M. Eldehna、Ayman Altoukhy、Hoda Mahrous、Hatem A. Abdel-Aziz

  DOI：10.1016/j.ejmech.2014.12.010

  日期：2015.1

  A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin-pyridine hybrids. All the newly prepared hybrids (5a-o, 8 and 11a-d) were in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 +/- 0.39 mu M), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 +/- 2.05 mu M). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 +/- 1.15 and 6.3 +/- 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids. (C) 2014 Elsevier Masson SAS. All rights reserved.